Marine Natural Products from Indonesian Waters

marine drugs

Review Marine Natural Products from Indonesian Waters

Novriyandi Hanif 1,* , Anggia Murni 2, Chiaki Tanaka 3 and Junichi Tanaka 4

1 Department of Chemistry, Faculty of Mathematics and Natural Sciences, IPB University (Bogor Agricultural University), Bogor 16680, Indonesia 2 Tropical Biopharmaca Research Center, IPB University (Bogor Agricultural University), Bogor 16128, Indonesia; [email protected] 3 Department of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812–8582, Japan; [email protected] 4 Department of Chemistry, Biology, and Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan; [email protected] * Correspondence: [email protected]; Tel.: +62-251-862-4567

Received: 30 May 2019; Accepted: 11 June 2019; Published: 19 June 2019

Abstract: Natural products are primal and have been a driver in the evolution of organic chemistry and ultimately in science. The chemical structures obtained from marine organisms are diverse, reflecting biodiversity of genes, species and ecosystems. Biodiversity is an extraordinary feature of life and provides benefits to humanity while promoting the importance of environment conservation. This review covers the literature on marine natural products (MNPs) discovered in Indonesian waters published from January 1970 to December 2017, and includes 732 original MNPs, 4 structures isolated for the first time but known to be synthetic entities, 34 structural revisions, 9 artifacts, and 4 proposed MNPs. Indonesian MNPs were found in 270 papers from 94 species, 106 genera, 64 families, 32 orders, 14 classes, 10 phyla, and 5 kingdoms. The emphasis is placed on the structures of organic molecules (original and revised), relevant biological activities, structure elucidation, chemical ecology aspects, biosynthesis, and bioorganic studies. Through the synthesis of past and future data, huge and partly undescribed biodiversity of marine tropical invertebrates and their importance for crucial societal benefits should greatly be appreciated.

Keywords: biodiversity; structure elucidation; chemical synthesis; biosynthesis; structural revision; cytotoxicity; enzyme inhibitor; bioorganic chemistry; biogeography

1. Introduction Natural products have been the core of the evolution of organic chemistry. About 40 molecules have been detected that have had revolutionary eﬀects and become indispensable for human society [1]. In particular, three MNPs, (+)-palytoxin, (+)-brevetoxin B, and (–)-ecteinascidin 743, are engines for its development. The beautiful and challenging structures of MNPs have been disclosed by several methods, including classic and modern structure elucidation, even though they are often available only in invisibly small amounts and have unprecedented properties in nature. This is becoming the predominant task of organic chemistry [2]. MNPs are deﬁned as secondary metabolites produced by marine organisms, both macro- and microorganisms, as responses that are part of their defense strategies, responses to the food chain, or as communication signals with their environment. Moreover, these functions are related to biodiversity, which is considered an important key for obtaining diverse metabolites, the structures of which are responsible for the characteristics of a vast range of chemical reactions, both in living and non-living systems.

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Biodiversity generally refers to the number of species living in a particular ecosystem. The accepted number of species on land is 0.45–1.9 million [3,4], while the species richness in the oceans is estimated to be 0.30–10 million [5]. Some of the highest concentrations of species are located in the tropical region [6]. Due to high diversity of species, and hence the high competition for survival, MNPs exhibit chemical structures and biological activities that are different from those of traditionally investigated terrestrial natural products. The uniqueness of skeletons, functional groups (FGs) and remote chiral centers are some features of MNPs that are presented in this review. To date, eight marine-derived natural products [7–10] have been recorded as approved drugs, of which seven molecules have been used to date. (–)-Ecteinascidin 743 (Yondelis®) was derived directly from the Caribbean ascidian Ecteinascidia turbinata (the true producer was recently established as γ-proteobacterial endosymbiont Candidatus endoecteinascidia frumentensis [11]). The molecule is used for treatment of advanced soft tissue sarcoma and for treatment of recurrent platinum-sensitive ovarian cancer when combined with liposomal doxorubicin. The peptide ω-conotoxin MVIIa (Prialt®) from the venom of the cone snail Conus magus is used for analgesic treatment. The anticancer agent (–)-eribulin mesylate (Halaven®) is a synthetic truncated derivative of the polyketide halichondrin B, a super-carbon chain compound isolated from the Japanese sponge Halichondria okadai. The last approved anticancer drug related to MNPs is the antibody drug conjugate (ADC) brentuximab vedotin − (Adcetris®). It consists of a tumor-specific antibody and the pentapeptide auristatin E, a derivative of dolastatin 10 derived from the Indian sea hare Dolabella auricularia. The molecule is used for the treatment of primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) in those who have received prior systemic therapy. In addition, the ADC is used to treat untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy. A mixture of two ethyl esters of fish-derived ω-3 polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentanaenoic acid (EPA) was approved under the trade name Lovaza® and is used for reducing serum triglycerides. Iota-carrageenan (Carragelose®), isolated from red algae Eucheuma/ Cnondrus, works as an anti-viral barrier in the nasal cavity. Two nucleosides, the anticancer agent (+)-cytarabine (Cytosar®) and the antiviral drug against herpes simplex virus (–)-vidarabine (Vira-A®) are derivatives of spongothymidine and spongouridine from the Caribbean sponge Tethya crypta, respectively. (–)-Vidarabine (Vira-A®) has been discontinued in the US and in Europe. The structural diversities of natural products affording unique pharmacological or physiological activities and intricate structures have contributed to breakthroughs in basic (i.e., organic) chemistry and applied sciences (e.g., marine biotechnology), and have even led to a few Nobel Prizes [12]. Ultimately, the diversity of chemicals and biological activities can provide excellent tools for other scientific fields, including biology, agriculture, medicine, materials, energy, and the environment. These facts have made marine organisms attractive targets for research endeavors. Indonesia is located at one of the centers of biodiversity hotspots [13], endowed with a coral reef triangle, and is an epicenter of marine biodiversity covering 10.36 million km2 of ocean and coastal waters surrounding Indonesia, Malaysia, Papua New Guinea, the Philippines, Timor Leste, and Australia [14]. The country consists of 34 provinces (Figure1)[ 15] and surrounding water areas encompassing 5.79 million km2, of which 1.08% or 62,600 km2 is protected as national parks [16]. The features of this area include not only species richness, endemism and habitat diversity, but its relatively pristine condition. An understanding of the fundamental biodiversity [17,18] gained through investigation of bioactive molecules is required by having skills to do individual chemical investigations with small specimens to reduce costs and to minimize environmental impact. Another way is to use fermentation and culture of marine microbes. Although permission to collect and export specimens has been given, researchers must be aware and respectful of indigenous knowledge and cultural sensitivities [19]. Chemists are not yet adept at easily creating molecules with high potency for use as medicines, whereas nature has an enormous, almost incomprehensible, capacity for diversity and adaptation [20,21]. Perhaps the most important way of solving biodiversity problems is through the synthesis of past and future data not only on the basis of taxonomic and spatial distribution, but also Mar. Drugs 2019, 17, 364 3 of 69 Mar. Drugs 2019,, 17,, xx FORFOR PEERPEER REVIEWREVIEW 3 of 71 medicinal—perspectives.through chemical and biological—including This would be in ecological tandem andwith genetic, national as and well international as medicinal—perspectives. collaborative researchThis would programs be in tandem [22,23]. with The national wise use and of internationalcutting-edge collaborativetechnology and research access programs to biodiversity [22,23]. throughThe wise benefit-sharing use of cutting-edge agreements technology are andbelieved access to to conserve biodiversity our global through ecosystems benefit-sharing while agreements advancing science.are believed to conserve our global ecosystems while advancing science.

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Figure 1. Map of Indonesia and its 34 provinces [15]: SRA (Special Region of Aceh), NST (North Figure 1.1. MapMap of of Indonesia Indonesia and and its 34its provinces 34 provinces [15]: SRA[15]: (SpecialSRA (Special Region Region of Aceh), of NST Aceh), (North NST Sumatra), (North Sumatra), RAU (Riau), RUI (Riau Islands), WST (West Sumatra), JMI (Jambi), BKU (Bengkulu), SST RAUSumatra), (Riau), RAU RUI (Riau), (Riau Islands), RUI (Riau WST Islands), (WestSumatra), WST (W JMIest (Jambi),Sumatra), BKU JMI (Bengkulu), (Jambi), BKU SST (Bengkulu), (South Sumatra), SST (South Sumatra), BBI (Bangka–Belitung Islands), LPG (Lampung), BTN (Banten), JSCR (Jakarta BBI(South (Bangka–Belitung Sumatra), BBI Islands),(Bangka–Be LPGlitung (Lampung), Islands), BTN LPG (Banten), (Lampung), JSCR (Jakarta BTN (Banten), Special Capital JSCR Region),(Jakarta Special Capital Region), WJV (West Java), CJV (Central Java), SRY (Special Region of Yogyakarta), WJVSpecial (West Capital Java), Region), CJV (Central WJV (West Java), Java), SRY CJV (Special (Central Region Java), of SRY Yogyakarta), (Special Region EJV (Eastof Yogyakarta), Java), BLI EJV (East Java), BLI (Bali), WNT (West Nusa Tenggara), ENT (East Nusa Tenggara), WKM (West (Bali),EJV (East WNT Java), (West BLI Nusa (Bali), Tenggara), WNT (West ENT Nusa (East Te Nusanggara), Tenggara), ENT (East WKM Nusa (West Tenggara), Kalimantan), WKM (West CKM Kalimantan), CKM (Central Kalimantan), EKM (East Kalimantan), SKM (South Kalimantan), NKM (CentralKalimantan), Kalimantan), CKM (Central EKM (EastKalimantan), Kalimantan), EKM SKM (East (South Kalimantan), Kalimantan), SKM (South NKM (NorthKalimantan), Kalimantan), NKM (North Kalimantan), NSW (North Sulawesi), GTO (Gorontalo), WSW (West Sulawesi), CSW (Central NSW(North (North Kalimantan), Sulawesi), NSW GTO (North (Gorontalo), Sulawesi), WSWGTO (Gorontalo), (West Sulawesi), WSW CSW(West (CentralSulawesi), Sulawesi), CSW (Central SSW Sulawesi), SSW (South Sulawesi), SES (Southeast Sulawesi), NMU (North Maluku), MLU (Maluku), (SouthSulawesi), Sulawesi), SSW (South SES (SoutheastSulawesi), Sulawesi),SES (Southeast NMU Sulawesi), (North Maluku), NMU (North MLU Maluku), (Maluku), MLU SRWP (Maluku), (Special SRWP (Special Region of West Papua), and PUA (Papua). RegionSRWP (Special of West Region Papua), of and We PUAst Papua), (Papua). and PUA (Papua).

Although Indonesian MNPs have been reviewed [24–26], [24–26], there there is is no no comprehensive comprehensive review review from from the earliest research of IndonesianIndonesian MNPsMNPs toto thethe present.present. The earliest observation of marine products was realizedrealized by by poisoning poisoning with with clupeoid clupeoid ﬁsh fish [27 ],[27], while while the ﬁrstthe MNPfirst MNP discovered discovered in Indonesian in Indonesian waters () waterswas ( )-25-hydroxy-24was ()25-hydroxy-24ξ-methylcholesterolξ-methylcholesterol1 [28], isolated 1 [28],[28], isolatedisolated in 1972 (Figureinin 197219722 (Figure(Figure). 2).2). −

Figure 2. Structure of (–)-25-hydroxy-24ξ-methylcholesterol 1. Figure 2. Structure of (–)-25-hydroxy-24 ξ-methylcholesterol 1.

To provideprovide a a current current status status of Indonesianof Indonesian MNPs, MNPs, we performed we performed a literature a literature review ofreview new chemical of new chemicalstructures structures found in Indonesian found in waters,Indonesian including waters, their including chemistry, their biological chemistry, activities, biological spatio-temporal activities, spatio-temporaldimensions, taxonomy, dimensions, and dissemination taxonomy, and of dissemination information from of inform marineation macro- from and marine microorganisms macro- and microorganismspublished during published the period during January the period 1970–December January 1970–December 2017. An estimated 2017. An 15,500 estimated new MNPs 15,500 were new MNPsdiscovered were worldwide discovered between worldwide 1970 between and 2010 197 [290], amongand 2010 which [29], about among 486 which new molecules about 486 (3.1%) new moleculeswere found (3.1%) in Indonesia. were found In the in period Indonesia. 1990–2009, In the the period number 1990–2009, of new MNPs the worldwide number of was new 9812 MNPs [30], worldwidewhile that from was Indonesian9812 [30], while waters that was from 406 (4.1%).Indone Thesian presentwaters workwas 406 covered (4.1%). atotal The ofpresent 732 original work coveredMNPs, with a total 4 known of 732 tooriginal be synthetic MNPs, compounds, with 4 known 34 revised,to be synthetic and 9 unnatural compounds, MNPs, 34 revised, from January and 9 1970unnatural to December MNPs, 2017from (Figure January3A). 1970 In addition, to December 43 MNPs 2017 were (Figure isolated 3A). asIn mixtures, addition, while 43 MNPs 130 MNPs were isolatedisolated asas mixtures,mixtures, whilewhile 130130 MNPsMNPs werewere reportedreported withwith incompleteincomplete stereochemistry.stereochemistry. OfOf 732732 MNPs,MNPs, none of them has been approved or is under clinical trial.

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Mar.were Drugs reported 2019, 17 with, x FOR incomplete PEER REVIEW stereochemistry. Of 732 MNPs, none of them has been approved4 of or 71 is under clinical trial. BeforeBefore 1990, thethe explorationexploration trendtrend of of Indonesian Indonesian MNPs MNPs was was relatively relatively steady; steady; however, however, after after 1990 1990the discovery the discovery of new of moleculesnew molecules has increased has increased significantly significantly (Figure (Figure3B). More 3B). specifically,More specifically, in the periodin the periodof 1970–1979, of 1970–1979, 31 terpenoids 31 terpenoids were the were only the MNPs only reported. MNPs reported. In the next In the decade, next 1980–1989,decade, 1980–1989, the structural the structuraltypes of Indonesian types of Indonesian MNPs were MNPs alkaloids were (4 alkaloids molecules) (4 andmolecules) polyketides and (2polyketides molecules). (2 Frommolecules). 1990 to From1999, the1990 numbers to 1999, of Indonesianthe numbers MNPs of Indonesian were: 27 terpenoids, MNPs were: 19 alkaloids, 27 terpenoids, 11 polyketides, 19 alkaloids, 5 peptides, 11 polyketides,1 fatty acid, and 5 peptides, 1 carbohydrate. 1 fatty Theacid, discovery and 1 carb ofohydrate. new Indonesian The discovery MNPs was of atnew its highestIndonesian in the MNPs period was2000–2009, at its highest with 139 in terpenoids,the period 2000–2009, 121 alkaloids, with 44 139 polyketides, terpenoids, 30 121 peptides, alkaloids, and 844 fatty polyketides, acids. In 30 the peptides,current decade, and 8 fatty 2010–2017, acids. In the the structural current decade, types of 2010–2017, Indonesian the MNPs structural were 116types alkaloids, of Indonesian 79 terpenoids, MNPs were64 polyketides, 116 alkaloids, 25 peptides, 79 terpenoids, 4 fatty acids,64 polyketides, and 1 carbohydrate. 25 peptides, Alongside 4 fatty acids, improvement and 1 carbohydrate. of techniques Alongsidefor structure improvement elucidation, of separation, techniques and for synthesis, structure the elucidation, increased numberseparation, of bioactiveand synthesis, Indonesian the increasedMNPs in thenumber last two of bioactive decades mayIndonesian be due MNPs to logistical in the ease,last two as manydecades Indonesian may be due biodiversity to logistical hotspots ease, asare many in remote Indonesian areas. biodiversity hotspots are in remote areas. TheThe original IndonesianIndonesian MNPsMNPs were were reported reported in in 266 266 papers papers in 39in di39ff erentdifferent journals. journals. Among Among them, them,J. Nat. J. Prod.Nat. Prod.is placed is placed for for top top tier tier dissemination dissemination (296 (296 molecules, molecules, 40.4%) followed followed by by TetrahedronTetrahedron (103 molecules, 14.1%), 14.1%), TetrahedronTetrahedron Lett. (42(42 molecules, molecules, 5.7%), 5.7%), and and J.J. Org. Org. Chem. Chem. (41(41 molecules, molecules, 5.6%) 5.6%) (Figure3 3C).C). Of Of 266 266 papers, papers, 117 117 papers papers (44.0%) (44.0%) were were written written by by local local researchers researchers who who are aareffi liatedaffiliated with withIndonesian Indonesian research research centers centers/universities./universities.

A B 60

Number of MNPs of Number 10

1971 1981 1991 2001 2011 Year

Figure 3. Statistics of new Indonesian MNPs from January 1970 to December 2017 (A). Distribution of new MNPs on the basis of their publication per year (B) and journal titles (C). Figure 3. Statistics of new Indonesian MNPs from January 1970 to December 2017 (A). Distribution of new MNPs on the basis of their publication per year (B) and journal titles (C).

The chemical diversity of Indonesian MNPs has been analyzed with respect to carbon skeleton, functional group, rare motif, and atomic diversity. New carbon skeletons were observed in 28

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The chemical diversity of Indonesian MNPs has been analyzed with respect to carbon skeleton, functional group, rare motif, and atomic diversity. New carbon skeletons were observed in 28 molecules, while rare FGs and motifs were found in 18 and 44 molecules, respectively (Figure4). A few examples of new carbon skeletons can be seen in vannusal A (198), halioxepine (281), manadomanzamine A (318), and phormidolide (702), while rare FGs and motifs can be seen in sinulasulfone (44), polycarpaurine C (487), siladenoserinol A (505), lanesoic acid (541), and petroquinone A (734), to name a few. In this review, the MNPs are organized into their structural types, consisting of 276 terpenoids (37.7%), 260 alkaloids (35.5%), 60 peptides (8.2%), 13 fatty acids and linear molecules (1.8%), 121 polyketides (16.5%), and 2 carbohydrates (0.3%) (Figure4B). Among 97 chemical types of Indonesian MNPs, piperidine alkaloids (48 molecules), tyrosine alkaloids (38 molecules), indole alkaloids (37 molecules), aromatic polyketides (34 molecules), and quinones (33 molecules) are listed as the top five chemical types (Figure4C). The evaluation of atomic diversity within Indonesian MNPs (Figure4D) shows that 27 molecules (written in red numbers) contain 6 different atoms in 1 molecule, while the majority (326 molecules) containMar. Drugs 3 di2019fferent, 17, x atomsFOR PEER in 1REVIEW molecule. Most of them contain C, H, O, N, with the addition of Br and5 of 71 I (4 molecules), as in enisorine E (438), agelanesins B (464) and D (466), 1-O-methylhemibastadinol 4 (molecules,440); Br and while Cl (1 rare molecule), FGs and as motifs in diazonamide were found E ( 611in 18); Brand and 44 S,molecules, as in mauritamides respectively D ((Figure462), B (4).467 A) andfew Cexamples (468); Cl andof new S (4 molecules),carbon skelet as inons dysithiazolamide can be seen in ( 552vannusal), biakamides A (198 A–D), halioxepine (742–745); P(281 and), Smanadomanzamine (12 molecules), as inA siladenoserinols(318), and phormidolide A–L (505 –(516702);), Nawhile and rare S (1 FGs molecule), and motifs as in can cupolamide be seen Ain (sinulasulfone564). Of 732 molecules,(44), polycarpaurine 373 (51.0%) C are (487 nitrogenous), siladenoserinol molecules. A Further(505), lanesoic inspection acid of the(541 atomic), and diversitypetroquinone indicated A (734 that), to 122 name molecules a few. (16.7%)In this review, possess athe ratio MN ofPs H are/C

B A

Figure 4. Cont.

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FigureFigure 4. 4.Distribution Distribution ofof newnew IndonesianIndonesian MNPs on the basis of chemical skeletons skeletons ( (AA),), classes classes (B (B),), chemicalchemical types types ( C(C),), and and atomic atomic diversities diversities ((DD).).

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The chemical diversity of Indonesian MNPs can also be reflected by the use of several orthogonal-tactic-classic and modern structure elucidations describing the nature of Indonesian MNPs, such as molecular size, complexity, and type and distribution of functional groups. Having a single crystal molecule, the structure elucidation task is more straightforward and secured to perform by employing X-ray crystallography to reveal the 2D and 3D molecular structure, including absolute configuration and conformation. Of 732 original MNPs, 30 MNPs were determined by X-ray crystallography in combination with other spectroscopic data. In addition, three revised MNPs, vannusal B (199b), trans, trans-[D-allo-ile] ceratospongamide (566b) and 659b, were securely determined with the aid of X-ray diffraction. The presence and position of nitrogen atoms and their correlations to hydrogen or carbon atoms within the molecules can be detected by 15N NMR and NH-HMBC as in manadomanzamine A (318), neo-kauluamine (321), lanesoic acid (541), polycarpathiamine A (544), sintokamide A (553), and cis, cis-ceratospongamide (565), while P-containing molecules can be evaluated by the use of 31P NMR as in siladenoserinol A (505). The planar structure of the 10-membered polysulfur ring, as in lissoclibadin 1 (498), could be elucidated by applying NOEs with a combination of other tactics such as quantum chemical calculation (QCC). The presence of a sulfate group can be detected by infrared (IR) and confirmed by mass spectrometry (MS)/MS fragmentation, as in polycarpaurines B and C (497–498). For cyclic molecules with rigid three- to six-membered rings, their relative stereochemistry 1 1 3 can be elucidated by analyzing H– H spin coupling constants ( JHH), chemical shifts and NOEs. For geometrically flexible molecules such as multiple stereocenters of acyclic chains or macrocycles, it cannot be concluded with NOEs. To handle such molecules, NMR-based approaches including J-based configuration analysis (JBCA), universal NMR database (UDB), theoretical calculation of NMR parameters and residual dipolar couplings (RDCs) [32] were applied as tools to determine the relative configuration of natural products. Of 732 molecules, relative stereochemistry of at least four molecules 541, 552, 702, and 708 were elucidated with the aid of JBCA method, while the relative configuration of one molecule as in 595 was elucidated by JBCA-QCC tactics. The absolute configurations (ACs) of MNPs can be elucidated by NMR in two approaches: (a) substrate analysis without derivatization (i.e., by the addition of a chiral solvating agent (CSA)) and (b) analysis of the diastereomeric derivatives prepared with a chiral derivatizing agent (CDA) [33]. The ACs of 31 Indonesian MNPs were determined by applying CDA. If chiral molecules possess appropriate chromophore(s), electronic circular dichroism (ECD) can be applied, as in 56 MNPs. Comparison of the ECD calculated by the time-dependent density functional theory (TDDFT) with the experimental ECD spectra was performed for the ACs of as-exemplified lamellodysidine A (41), niphatheolide A (128), sulawesin A (133), and nakamuric acid (448a). However, nakamuric acid (448a) was first revised to 448b1 by synthesis [34], and later to 448b2 based on the comparison of experimental and calculated ECD spectra [35]. Molecular modelling, total synthesis, and QCC were used to determine the structure of vannusals A (198) and B (199)[36–43]. Combination of NMR and chemical degradation helped to determine the long carbon chain molecules, karatungiols A (655) and B(626)[44]. For small heterocyclic molecules with the ratio of H/C < 1, total synthesis is helpful for confirming unusual rings, as in latonduine A (450)[45] and polycarpathiamine A (544)[46]. With respect to phylogeny, new MNPs have been discovered from 5 kingdoms, 10 phyla, 14 classes, 32 orders, 64 families, 106 genera, and 94 species (Figure5A,B) in Indonesian waters over the past 47 years. Three phyla (Porifera, Cnidaria, and Chordata) are found to be the major sources (498 molecules, 68.0%; 116 molecules, 15.8%; and 60 molecules, 8.2%, respectively) of novel metabolites. The remaining 8.0% were discovered from the following phyla: Mollusca (3 molecules, 0.4%), Rhodophyta (3 molecules, 0.4%), Ciliophora (2 molecules, 0.3%), Dinoflagellate (2 molecules, 0.3%), Ascomycota (45 molecules, 6.1%), Cyanobacteria (1 molecule, 0.1%), and Actinobacteria (2 molecules, 0.3%). The phylum Porifera, the largest source of Indonesian MNPs, consists of three classes: Demospongiae (91.8%), Homoscleromorpha (6.6%) and Calcarea (1.6%). Among these, Demospongiae is comprised of 11 orders and 32 families. The Cnidaria is comprised of 1 class Mar. Drugs 2019, 17, x FOR PEER REVIEW 8 of 71 chemical degradation helped to determine the long carbon chain molecules, karatungiols A (655) and B (626) [44]. For small heterocyclic molecules with the ratio of H/C < 1, total synthesis is helpful for confirming unusual rings, as in latonduine A (450) [45] and polycarpathiamine A (544) [46]. With respect to phylogeny, new MNPs have been discovered from 5 kingdoms, 10 phyla, 14 classes, 32 orders, 64 families, 106 genera, and 94 species (Figure 5A,B) in Indonesian waters over the past 47 years. Three phyla (Porifera, Cnidaria, and Chordata) are found to be the major sources (498 molecules, 68.0%; 116 molecules, 15.8%; and 60 molecules, 8.2%, respectively) of novel metabolites. The remaining 8.0% were discovered from the following phyla: Mollusca (3 molecules, 0.4%), Rhodophyta (3 molecules, 0.4%), Ciliophora (2 molecules, 0.3%), Dinoflagellate (2 molecules, 0.3%), Ascomycota (45 molecules, 6.1%), Cyanobacteria (1 molecule, 0.1%), and Actinobacteria (2 molecules, 0.3%). The phylum Porifera, the largest source of Indonesian MNPs, consists of three classes: Demospongiae (91.8%), Homoscleromorpha (6.6%) and Calcarea (1.6%). Among these, DemospongiaeMar. Drugs 2019, 17 ,is 364 comprised of 11 orders and 32 families. The Cnidaria is comprised of 1 8class of 69 (Anthozoa), 3 orders (Alcyonacea, Pennatulacea, Actinaria), and 9 families (Alcyoniidae, Nephtheidae,(Anthozoa), 3 ordersXeniidae, (Alcyonacea, Briareidae, Pennatulacea, Ellisellidae, Actinaria), Isididae, and 9 familiesVeretillidae, (Alcyoniidae, Pennatulidae, Nephtheidae, and Stichodactylidae).Xeniidae, Briareidae, Ellisellidae, Isididae, Veretillidae, Pennatulidae, and Stichodactylidae). The top top 10 10 genera genera reported reported for for new new MNPs MNPs are are Achantostrongylophora Achantostrongylophora (4.4%), (4.4%), Xestospongia Xestospongia (3.6%), Sinularia (3.4%), Apysinella, Theonella and Strepsichordaia (each 2.9%), Plakortis, Petrosia, Spongia, (3.6%), Sinularia (3.4%), Apysinella, Theonella and Strepsichordaia (each 2.9%), Plakortis, Petrosia, Melophlus (each 2.6%), Agelas, Rhabdastrella, and Lissoclinum (each 2.5%). Unknown genera were the Spongia, Melophlus (each 2.6%), Agelas, Rhabdastrella, and Lissoclinum (each 2.5%). Unknown genera sources of 6.2% of new MNPs. Symbiotic relationships are generally found between sponges and were the sources of 6.2% of new MNPs. Symbiotic relationships are generally found between sponges fungi, algae and fungi, and dinoflagellates and acoel flatworms. The list of Indonesian marine and fungi, algae and fungi, and dinoflagellates and acoel flatworms. The list of Indonesian marine organisms producing new MNPs is described in Figure 6. organisms producing new MNPs is described in Figure6.

A B

Figure 5. Distribution of new Indonesian MNPs on the basis of biological sources (A,B). Figure 5. Distribution of new Indonesian MNPs on the basis of biological sources (A,B).

The most frequently evaluated biological activities of Indonesian MNPs is cytotoxicity (122 molecules, 16.7%) (Figure7). Results are generally expressed in the terms of the dose or concentration that inhibits cell growth to 50% of the control (ED50, EC50, ID50, IC50, LD50, LC50 in µg/mL or µM), and the criterion for a cytotoxic compound is ED50 < 4 µg/mL [47]. Cytotoxic evalution has been performed on cell-based (120 human, 26 murine, and 1 monkey Cercopithecus aethiops cell lines), enzyme-based (mainly protease and kinase), and brine shrimp (Artemia salina) assays. Of 122 molecules, four molecules—60, 619, 652, and 702—showed signiﬁcant toxicity against A. salina. Antibacterial activity has been the second most frequently used bioassay for Indonesian MNPs, with 43 molecules (5.9%) showing signiﬁcant results followed by anticancer (4.0%), cytostatic (3.0%), antifungal (2.7%), and antiparasitic activity (2.6%). Of 4.0% anticancer molecules, only 2.3% showed anticancer activity without cytotoxicity. It is noteworthy that at least 86 out of 260 alkaloids have been isolated and tested as salt forms against various targets of assays. In addition, about 609 molecules have been used for in vitro assay, while 10 molecules had been used for in vivo evaluation.

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22 21 19 18 18 18

16 16 15 14 14 14 14 14 13 12 12 12 12 11 10 10 9 9 9 8 8 7 7 7 7 7 7 7 7 7 6 6 6 6 6 6 5 5 5 5 5 5 5 5 44 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 22 2 2 22 2 2 2 2 2 2 2 2 2 2 2 2 2 22 2 2 2 2 2 2 2 2 2 2 2 1 1 111 1 1 1 1 1 1 1 1 1 111 1 1111 11 1 1 111 11 1 1 1 1 1 1 1 1 1 Aaptos suberitoides Aaptos sp. Achanthostyotella sp. Achantostrongylophora ingens Achantostrongylophora sp. Achantodendrilla sp. Agelas sp. Agelas nakamurai Agelas linnaei Amphidinium sp. Anthelia sp. Aplidium sp. Aplysinella strongylata Aspergillus versicolor Aspergillus sp. Axinella carteri Biemna fortis Briareum excavatum Briareum sp. Botryllus sp. Callyspongia aerizussa Callyspongia pseudoreticulata Callyspongia sp. Capnella imbricata Candidaspongia sp. Carteriospongia foliascens Cinachyrella sp. Ceratodictyon spongiosum Cladiella sp. Cladosporium herbarum Clathria basilana Coelocarteria cfr. singaporensis Corticium simplex Corticium sp. Cosmopora vilior Curvularia lunata Dactylospongia elegans Dactylospongia metachromia Daedalopelta sp. Daldinia eschsholzii Dasychalina sp. Dendronephthya rubeola Diacarnus megaspinorhabdosa Diazona sp. Didemnum sp. Didemnum molle Drechslera hawaiiensis Dysidea herbacea Dysidea sp. Echinochalina sp. Eudistoma sp. Euplotes vannus Eusynstyela latericius Fascaplysinopsis reticulata Fusarium sp. Halichondria sp. Haliclona fascigera Haliclona sp. Heteractis aurora Hippospongia sp. Histodermella sp. Hyattella sp. Hyrtios erectus Hyrtios reticulatus Hyrtios sp. Ianthella basta Iotrochota purpurea Iotrochota cf. iota Ircinia dendroides Isis hippuris Jaspis splendens Junceella fragilis Kaliapsis sp. Lamellodysidea herbacea Lissodendroryx fibrosa Lissoclinum patella Lissoclinum cf. badium Lissoclinum bistratum Litophyton viridis Lemnalia carnosa Lemnalia africana Lendenfeldia sp. Leptoclinides dubius Leucetta chagosensis Leucetta microraphis Lobophytum cristagalli Lobophytum crassum Lobophytum sp. Lobophytum ehrenbergi Lobophytum sp. Luffariella variabilis Melophlus sarassinorum Minabea sp. Mycale euplectellioides Mycelium sterillium Myrothecium sp. Niphates olemda Neopeterosia cf. exigua Nephthea chabrolii Nephthea sp. Oceanapia sp. Pachyclavularia violacea Penicillium verruculosum Penicillium citreonigrum Penicillium cf. montanense Penicillium albobiverticillium Petrosaspongia sp. Petrosia strongylata Petrosia alfiani Petrosia sp. Phomopsis sp. Phormidium sp. Phyllidia varicosa Phyllospongia sp. Phyllospongia papyrecea Plakinastrella sp. Plakortis nigra Plakortis cf. lita Plakortis cfr. simplex Plakortis sp. Pleurobranchus forskalii Polycarpa aurata Psammocinia sp. Prianos sp. Pteroeides sp. Rhabdastrella globostellata Siliquariaspongia mirabilis Sidonops microspinosa Sinularia mayi Sinularia flexibilis Sinularia asterolobata Sinularia dissecta Sinularia sp. Spongia ceylonensis Spongia sp. Strepsichordaia aliena Strepsichordaia lendenfeldi Streptomyces sp. KS3 Stylissa carteri Stylissa sp. Theonella swinhoei Theonella cf. swinhoei Theonella cupola Theonella sp. Topsentia sp. Tricoderma longibrachiatums Unknown unknown Uknown unknown (Ascomycota) Unknown unknown (Didemnidae) Uknown unknown (Xylariales) Unknown unknown (Petrossidae) Unknown unknown (Polycitoridae) Veretillum malayense Vidalia sp. Xenia sp. Xestospongia cf. carbonaria Xestospongia sp. Figure 6. Distribution of new Indonesian MNPs on the basis of biological sources and a list of species of Indonesian marine organisms reported to contain new Figure 6. Distribution of new Indonesian MNPs on the basis of biological sources and a list of species of Indonesian marine organisms reported to contain new MNPs. MNPs. Unknown unknown is an unidentified species from certain phyla. Unknown unknown is an unidentiﬁed species from certain phyla.

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TheThe mostmost frequentlyfrequently evaluatedevaluated biological activitiesties ofof IndonesianIndonesian MNPsMNPs isis cytotoxicitycytotoxicity (122 (122 molecules, 16.7%) (Figure 7). Results are generally expressed in the terms of the dose or concentration molecules, 16.7%) (Figure 7). Results are generally expressed in the terms of the dose or concentration that inhibits cell growth to 50% of the control (ED50, EC50, ID50, IC50, LD50, LC50 in μg/mL or μM), and that inhibits cell growth to 50% of the control (ED50, EC50, ID50, IC50, LD50, LC50 in μg/mL or μM), and the criterion for a cytotoxic compound is ED50 < 4 μg/mL [47]. Cytotoxic evalution has been performed the criterion for a cytotoxic compound is ED50 < 4 μg/mL [47]. Cytotoxic evalution has been performed on cell-based (120 human, 26 murine, and 1 monkey Cercopithecus aethiops cell lines), enzyme-based on cell-based (120 human, 26 murine, and 1 monkey Cercopithecus aethiops cell lines), enzyme-based (mainly protease and kinase), and brine shrimp (Artemia salina) assays. Of 122 molecules, four (mainly protease and kinase), and brine shrimp (Artemia salina) assays. Of 122 molecules, four molecules—60, 619, 652, and 702—showed significant toxicity against A. salina. Antibacterial activity molecules—60, 619, 652, and 702—showed significant toxicity against A. salina. Antibacterial activity has been the second most frequently used bioassay for Indonesian MNPs, with 43 molecules (5.9%) has been the second most frequently used bioassay for Indonesian MNPs, with 43 molecules (5.9%) showing significant results followed by anticancer (4.0%), cytostatic (3.0%), antifungal (2.7%), and showing significant results followed by anticancer (4.0%), cytostatic (3.0%), antifungal (2.7%), and antiparasitic activity (2.6%). Of 4.0% anticancer molecules, only 2.3% showed anticancer activity antiparasitic activity (2.6%). Of 4.0% anticancer molecules, only 2.3% showed anticancer activity without cytotoxicity. It is noteworthy that at least 86 out of 260 alkaloids have been isolated and tested without cytotoxicity. It is noteworthy that at least 86 out of 260 alkaloids have been isolated and tested as salt forms against various targets of assays. In addition, about 609 molecules have been used for Mar.as Drugs salt 2019forms, 17 against, 364 various targets of assays. In addition, about 609 molecules have been used10 for of 69 in vitro assay, while 10 molecules had been used for in vivo evaluation. in vitro assay, while 10 molecules had been used for in vivo evaluation.

Figure 7. Distribution of new Indonesian MNPs on the basis of their significant biological activity. Figure 7. Distribution of new Indonesian MNPs on the basis of their signiﬁcant biological activity. Figure 7. Distribution of new Indonesian MNPs on the basis of their significant biological activity. BiogeographyBiogeography of of Indonesian Indonesian MNPsMNPs shows that that 18 18 (NST, (NST, WST, WST, BTN, BTN, JSCR, JSCR, WJV, WJV, CJV, CJV, BLI, BLI, ENT, ENT, EKM,EKM, NSW,Biogeography NSW, GTO, GTO, CSW, CSW,of Indonesian SSW, SSW, SES, SES, MNPs NMU, NMU, shows MLU, MLU, that SRWP,SRWP, 18 (NST, and PUA) PUA) WST, of ofBTN, 34 34 provinces provinces JSCR, WJV, are are sources CJV, sources BLI, of newENT, of new EKM,MNPs. NSW, Among GTO, the CSW, 18 provinces,SSW, SES, NMU,more thanMLU, 70 SRWP,% of theand totalPUA) new of 34 MNPs provinces are aresupplied sources by of five new MNPs. Among the 18 provinces, more than 70% of the total new MNPs are supplied by ﬁve provinces: MNPs.provinces: Among NSW the (33.0%), 18 provinces, SSW (12.7%), more MLU than (10.4%), 70% ofBLI the (7.8%), total and new EKM MNPs (6.6%) are (Figure supplied 8A,B). by The five NSW (33.0%), SSW (12.7%), MLU (10.4%), BLI (7.8%), and EKM (6.6%) (Figure8A,B). The frequent provinces:frequent discovery NSW (33.0%), of Indonesian SSW (12.7%), MNPs MLU in the (10.4%), Eastern BLI part (7.8%), of Indonesia and EKM may (6.6%) be due (Figure to it being 8A,B). closer The discovery of Indonesian MNPs in the Eastern part of Indonesia may be due to it being closer to the frequentto the center discovery of Coral of IndonesianTriangle. MNPs in the Eastern part of Indonesia may be due to it being closer center of Coral Triangle. toA the center of Coral Triangle.

Figure 8. Distribution of new Indonesian MNPs on the basis of their biogeography hotspots (A,B) (OPV other provinces).

From the above results, it can be seen that Indonesian marine macro- and micro-organisms are still largely underexplored and may provide viable sources and inspiration for a large number of new chemical entities. Modern structure elucidation and other strategies are keys to providing new therapeutic agents and/or new tools for life science studies. Data presented in Figures1–37, Figures S1–S22 and Tables S1–S22 were assembled from the SciFinder®, Scopus®, and MarinLit databases and through manual curation of all published articles from an extensive panel of journals in chemistry and chemical biology fields. We emphasized new structures and structural revisions as elucidated through a variety of modern methods. Biological activities, origins of organisms, bioorganic studies on the MNPs, and syntheses that led to revision of structures or stereochemical assignments were also highlighted. We hope this comprehensive review will provide a useful overview and will help direct future efforts in Indonesian scientific development, governance, resource management, and conservation regarding the value of marine biodiversity. Mar. Drugs 2019, 17, 364 11 of 69

2. New MNPs Discovered from Indonesian Waters in the Period 1970–2017

2.1. General There are five important components in MNP research programs: (1) collection and identification of marine organisms or culture of microorganisms, (2) screening of crude extracts for bioactivity or chemical structures, (3) isolation and structure elucidation of MNPs, (4) pharmacological evaluation of isolated compounds, and (5) further development of MNPs for science and technolgy. Self-contained underwater breathing apparatus (SCUBA) diving is generally used to collect shallow-water marine biota. SCUBA is also used to take photographs for characterization of specimens and to record ecological information on marine biota. The specimens are sorted and stored either frozen in aqueous ethanol or as dried material. Voucher specimens are prepared for taxonomic studies. At greater depths, specimens are collected by rebreather diving, dredging, trawling, and submersibles. Many challenges must be overcome for this work. The presence of inorganic salt may become a problem if the sample amount is minuscule and the compounds are water-soluble, making them more difficult to handle than lipophilic compounds. When the bioassay is based on the behavior of marine organisms, it is difficult to mimic the marine environment. A routine procedure for isolation work is to group molecules by the level of their polarity, followed by separation and purification of target fractions using a variety of chromatographic methods. Bioassay or a signature of functional groups (substructures) or even molecular weight can be used as a guide for isolation or identification of MNPs. As a rule, in vitro bioassays require very little material, and take a shorter time to perform. It is normal to screen crude extracts with in vitro assays and reserve in vivo assays for pure compounds. Thin layer chromatography (TLC), NMR, and MS spectra can be used to identify characteristic extracts or fractions as guides for isolation work. Modern structure elucidation requires a variety of spectroscopic methods (NMR, MS, IR, ultraviolet (UV), ECD, X-ray diffraction, vibrational circular dichroism (VCD), and others), chemical transformations (derivatives or selective degradation or total synthesis), molecular modeling or computational calculations, information technology with molecular networking, and biosynthetic consideration in order to reveal the planar and stereostructure of target molecules. In general, the chemical structure of molecules with low H/C ratios (<1) is challenging to elucidate [31]. To find a new molecule, one should consider a strategy of dereplication using NMR, LC-MS, MS/MS, or DNA sequence [48], in addition to exploring new groups of marine organisms and geographical selection of collection sites [30]. On the other hand, known molecules can be screened with a set of new assays in order to find new function of molecules.

2.2. Terpenoids A total of 276 marine terpenoids were discovered within the period, consisting of 38 sesquiterpenoids, 84 diterpenoids, 50 sesterterpenoids, 21 triterpenoids, 52 steroids, 5 saponins, and 26 meroterpenoids. Among them, six molecules 10a, 33a, 70a, 71a, 198a, and 199a have been revised. One molecule, 53, was isolated as a natural product, while it had been synthesized previously. Five molecules, 16c, 17c, 18c, 45c, 200c, and 252c, were isolated as derivatives. Of 276 terpenoids, ACs of 18 molecules were determined by X-ray crystallography. In addition, ACs can also be revealed by the use of ECD as in 21 terpenoids. Modified Mosher’s method was applied for 14 chiral terpenoids, while total syntheses proved the ACs of 3 terpenoids. Since the biological activity of true natural products is preferable, one should consider replacing the FG with the original one. Alternatively, the chromatography system can be modified so that the original molecule can be obtained. Indonesian marine terpenoids were found to show cytotoxic (37 molecules), cytostatic (18 molecules), anticancer without cytotoxicity (4 molecules), antifungal (5 molecules), antibacterial (3 molecules), antidiabetic (2 molecules), ichthyotoxic, algicidal, antiinsecticidal, anti-inflammatory, anti-Alzheimer, physicoactive (CB receptor ligand), antiangiogenic, antiatherosclerotic, and antioxidant activity (each 1 molecule). Mar. Drugs 2019, 17, 364 12 of 69

2.2.1. Sesquiterpenoids Sesquiterpenoids isolated from Indonesian waters from January 1970 to December 2017 are summarized in Figure9A, Figure S1 and Table S1 of the Supplementary Materials. As shown in Figure9B, some sesquiterpenoids had been discovered in an earlier period (1970–1980). The marine sesquiterpenoids are comprised of 38 new natural products, 3 revised molecules (2 new and 1 known), 3 derivatives 16c, 17c and 18c, and 6 mixtures (Figure9C). Two molecules, 2/3 and 41, have been reported to have new skeletons, and 1 molecule, 39/40, contains a rare functional group (Figure9D). Fourteen diﬀerent types of carbon skeletons (Figure9E) are observed. Among them, capnellane (12 molecules), nardosinane (6 molecules), and hirsutane (4 molecules) are top three. Two molecules remain to be determined with respect to their stereochemistry (2/3 and 39/40). The ACs of six sesquiterpenoids, 4, 7, 22, 31, 35, and 38, and one derivative, 16c, have been determined by X-ray crystallography. In addition, ECD was applied to 6 molecules, 2/3, 12, 38, 41, and 42. The modiﬁed Mosher’s method was applied to 31. Of 38 molecules, one molecule, 10a, was revised to 10b by total synthesis [49–52]. The structure of 15a was corrected to 15b after total synthesis [53–57]. Hirsutanol C (33a) was revised to 33b by the work of a fungal metabolite [58]. Four phyla, Ascomycota (4 molecules), Porifera (5 molecules), Cnidaria (27 molecules),Mar. Drugs and 2019 Mollusca, 17, x FOR PEER (2 REVIEW molecules), were recorded to be sources of new sesquiterpenoids12 of 71

(Figure9F). The new molecules are mainly found in NSW and MLU (Figure9G).

C 8 B D 7 6 5 4

3 2

1 0 1971 1976 1981 1986 1991 1996 2001 2006 2011 2016 E F

Figure 9. Cont.

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Mar. Drugs 2019, 17, 364 13 of 69 Mar. Drugs 2019, 17, x FOR PEER REVIEW 13 of 71 G

Figure 9. Structures of marine sesquiterpenoids from Indonesian waters found in 1970–2017 (A): representative.FigureFigure 9. 9.Structures Structures Distribution of of marine marine of new sesquiterpenoidssesquiterpenoids marine sesquiterpenoids from from Indonesian Indonesian by yearwaters waters (B found). foundStatistics in in1970–2017 1970–2017 of new ( Amarine): (A ): representative. Distribution of new marine sesquiterpenoids by year (B). Statistics of new marine sesquiterpenoidsrepresentative. ( DistributionC). Distribution of new of marinenew marine sesquiterpenoids sesquiterpenoids by year on (B ).the Statistics basis of of their new skeletons marine sesquiterpenoidssesquiterpenoids (C ).(C Distribution). Distribution of newof new marine marine sesquiterpenoids sesquiterpenoids on on the the basis basis of their of their skeletons skeletons (D,E ), (D,E), biological sources (F), and biogeography (G). biological(D,E), biological sources (sourcesF), and ( biogeographyF), and biogeography (G). (G).

TheThe Thefirst first firstsesquitepenoid sesquitepenoid sesquitepenoid found found found in inin Indonesian IndonesianIndonesian waters was waswas africanol africanolafricanol (35 ( 35()35 )from) from from LemnaliaLemnalia Lemnalia africana africana africana andand LemnaliaandLemnalia Lemnalia nitida nitida nitida, collected, collected, collected off o offff Tanimbar,Tanimbar, Tanimbar, MLU.MLU. ItsIts structure,structurstructure,e, including includingincluding AC, AC, AC, was was was established established established by by by X-rayX-rayX-ray analysis analysis analysis [59] [59 [59] and] and and confirmed confirmedconfirmed by by bytotal total total synthesis synthesis synthesis [60,61]. [60,61 It It]. was was It wasproposed proposed proposed that that 35 that was35 was35 derivedwas derived derived from from a humulenefroma humulene a humulene through through through its CTits CT its(cross (cross CT (crossand and parallel parallel and parallel rearrangements rearrangements rearrangements of of two two of double twodouble double bonds) bonds) bonds)conformer conformer conformer 35-I, 35-I, which35-Iwhich, undergoes which undergoes undergoes acid-catalyzed acid-catalyzed acid-catalyzed closure closure closure to to thethe to the 9-africyl9-africyl 9-africyl cationcation cation 35-II 35-II35-II, followed, ,followed followed by bybyproton protonproton loss loss lossand and and hydration to provide 35 (Figure 10). Africanol (35) showed toxicity against guppy Lebistes reticulatus hydrationhydration to to provide provide 3535 (Figure 10 10).). Africanol Africanol (35 (35) showed) showed toxicity toxicity against against guppy guppyLebistes Lebistes reticulatus reticulatusand and unicellular algae Chaetoceros septentrionalis, Astrionella japonica, Thallasioscira excentricus, andunicellular unicellular algae algaeChaetoceros Chaetoceros septentrionalis septentrionalis, Astrionella, Astrionella japonica, Thallasioscira japonica, excentricusThallasioscira, Protocentrum excentricus, Protocentrum micans, and Amphidinium carterae [62]. Protocentrummicans, and micansAmphidinium, and Amphidinium carterae [62]. carterae [62].

Figure 10. Plausible biosynthetic pathway of (+)-africanol 35. FigureFigure 10. 10. PlausiblePlausible biosynthetic biosynthetic pathway ofof (+(+)-africanol)-africanol 35. 35. 2.2.2. Diterpenoids 2.2.2. Diterpenoids 2.2.2. DiterpenoidsDiterpenoids are molecules more frequently found from Cnidarian (56 molecules, 66.7%), particularlyDiterpenoids Alcyonacea are molecules (57.1%), than more from frequently Porifera (28 found molecules, from 33.3%). Cnidarian The (56diterpenoids molecules, found 66.7%), in Diterpenoids are molecules more frequently found from Cnidarian (56 molecules, 66.7%), particularlyIndonesian Alcyonacea waters from (57.1%), January than 1970 from Poriferato December (28 molecules, 2017 are 33.3%).compiled The in diterpenoids Table S2 in found the in particularly Alcyonacea (57.1%), than from Porifera (28 molecules, 33.3%). The diterpenoids found in IndonesianSupplementary waters fromMaterials, January Figures 1970 to11A December and S2. 2017 As are for compiled sesquiterpenoids, in Table S2 ininitial the Supplementary studies on Indonesian waters from January 1970 to December 2017 are compiled in Table S2 in the Materials,diterpenoids Figure were 11 Aperformed and Figure in 1970s, S2. As and for publicat sesquiterpenoids,ion increased initial after 1996 studies (Figure on diterpenoids11B). All of these were Supplementaryperformedefforts resulted in 1970s,Materials, in 84 and new, publication Figures 2 revised, 11A increased1 derivative, and afterS2. and 1996As 1 knownfor (Figure sesquiterpenoids, but 11 firstB). Allfrom of marine these initial e(Figurefforts studies resulted 11C). on Among the new molecules, 4 have new skeletons, 80, 100, 117, and 128 (Figure 11D), 2 molecules diterpenoidsin 84 new, 2were revised, performed 1 derivative, in 1970s, and and 1 known publicat bution first increased from marine after (Figure 1996 (Figure 11C). Among 11B). All the of new these contain rare FGs, sulfoxide or sulfone, and 5 molecules are listed to possess a rare structural motif, effortsmolecules, resulted 4 havein 84 new new, skeletons, 2 revised,80 ,1 100derivative,, 117, and and128 1(Figure known 11 butD), first 2 molecules from marine contain (Figure rare FGs, 11C). 77, 79, 113, 119, and 124 (Figure 11D). The chemical diversity of Indonesian marine diterpenoids (84 Amongsulfoxide the ornew sulfone, molecules, and 5 4 molecules have new are skeletons, listed to 80 possess, 100, a117 rare, and structural 128 (Figure motif, 11D),77, 79 2, 113molecules, 119, molecules) was proved, as there were 15 different skeletons: 19 spongianes, 18 each of briaranes and containand 124 rare(Figure FGs, 11sulfoxideD). The chemicalor sulfone, diversity and 5 molecules of Indonesian are marinelisted to diterpenoids possess a rare (84 molecules)structural wasmotif, cembranes, 7 cladiellanes, 6 xenicanes, 3 each of nor-cembranes and acyclic peroxide diterpenes, 2 77, 79, 113, 119, and 124 (Figure 11D). The chemical diversity of Indonesian marine diterpenoids (84 proved,each of as copalanes there were and 15 acyclic different diterpenes, skeletons: and 19 1 spongianes, each of niphatane, 18 each offlexibilane, briaranes seco and-cladiellane, cembranes, molecules)7 cladiellanes, was proved, 6 xenicanes, as there 3 eachwere of15 nor-cembranes different skeletons: and acyclic19 spongianes, peroxide 18 diterpenes, each of briaranes 2 each ofand cembranes, 7 cladiellanes, 6 xenicanes, 3 each of nor-cembranes and acyclic peroxide diterpenes, 2 each of copalanes and acyclic diterpenes, and 1 each of niphatane, flexibilane, seco-cladiellane,

Mar. Drugs 2019, 17, 364 14 of 69 copalanes and acyclic diterpenes, and 1 each of niphatane, flexibilane, seco-cladiellane, dollabelane, isocopalane, and seco-isocopalane (Figure 11F). Four molecules, 101, 108, 110, and 112, were determined by X-ray analysis. ECD was used to reveal the ACs of 8 molecules, 43, 44, 79, 82, 88, 89, 90, and 128. InMar. particular, Drugs 2019, 17 5, molecules, x FOR PEER REVIEW82, 88– 90 and 128, were elucidated by comparing actual spectra14 andof 71 calculated ECD. The modified Mosher’s method was applied for 8 molecules, 54–57, 63, 70a, 113, anddollabelane,124. Two isocopalane, molecules, 70a andand seco71a-isocopalane, were revised (Figure to 70b 11F).and Four71b molecules,. NSW is the 101 most, 108, favored110, and place 112, forwere finding determined new marine by X-ra diterpenesy analysis. (41ECD molecules, was used 48.8%),to reveal followed the ACs of by 8 MLU molecules, (10 molecules, 43, 44, 79, 11.9%)82, 88, (Figure89, 90, and11H). 128 One. In molecule,particular,45c 5 molecules,, was isolated 82, 88 as–90 a derivative,and 128, were while elucidated molecule by53 comparingwas isolated actual as aspectra natural and product calculated for the ECD. first The time, modified but was Mosher’s previously method known was as a applied semisynthetic. for 8 molecules, 54–57, 63, 70a,The 113, ACand of124 niphateolide. Two molecules, A (128 70a), and an inhibitor71a, were ofrevised p53-Hdm2 to 70b and interaction 71b. NSW [63 is] fromthe most the favored sponge Niphatesplace for olemda, findingwas new established marine diterpenes as 10R,11R (41by ECDmolecules, measurements 48.8%), followed in the vacuum-ultraviolet by MLU (10 molecules, region based11.9%) on (Figure theoretical 11H). calculation. One molecule, The remaining 45c, was stereocenter isolated asat a C17 derivative, remains unsolved.while molecule 53 was isolated as a natural product for the first time, but was previously known as a semisynthetic. A

Figure 11. Cont. Mar.Mar. Drugs Drugs2019 2019, 17, 17, 364, x FOR PEER REVIEW 1515 of of71 69

10 B C D 9 E 8 7

6 5 4 3 2 1 0

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

F G

Figure 11. Structures of marine diterpenoids from Indonesian waters found in 1970–2017 (A): Figure 11. Structures of marine diterpenoids from Indonesian waters found in 1970–2017 (A): representative. Distribution of new marine diterpenoids by year (B). Statistics of new marine representative. Distribution of new marine diterpenoids by year (B). Statistics of new marine diterpenoids (C). Distribution of new marine diterpenoids on the basis of their skeletons (D,F), diterpenoids (C). Distribution of new marine diterpenoids on the basis of their skeletons (D,F), significant biological activity (E), biological sources (G), and biogeography (H). signiﬁcant biological activity (E), biological sources (G), and biogeography (H).

Mar. Drugs 2019, 17, x FOR PEER REVIEW 16 of 71

The AC of niphateolide A (128), an inhibitor of p53-Hdm2 interaction [63] from the sponge Niphates olemda, was established as 10R,11R by ECD measurements in the vacuum-ultraviolet region Mar. Drugs 2019, 17, 364 16 of 69 based on theoretical calculation. The remaining stereocenter at C17 remains unsolved.

2.2.3.2.2.3. SesterterpenoidsSesterterpenoids TheThe sestertepenoids sestertepenoids found found in in Indonesian Indonesian waters waters from from January January 1970 1970 to Decemberto December 2017 2017 are are shown shown in Tablein Table S3 and S3 and Figure Figures 12A, Figure12A, S3. S3. The The first first sesterterpenoids sesterterpenoids were were 147–152 and 173–178,, isolatedisolated fromfrom StrepsichordaiaStrepsichordaia aliena alienain in 2000. 2000. Of Of the the 56 56sesterterpenoids sesterterpenoids reported, reported, 50 50 werewere new new and and 66 werewere isolated isolated as as mixturesmixtures (Figure (Figure 12 12C).C). The The molecules molecules are comprisedare comprised of 24 of tetracylic 24 tetracylic followed followed by 7 pentacyclic, by 7 pentacyclic, 6 bicyclic, 6 5bicyclic, each of 5 monocyclic each of monocyclic and acyclic and sesterterpenoids, acyclic sesterterpenoids, and 5 acyclic and 5 acyclic norsesterterpenoids norsesterterpenoids (Figure (Figure 12D). Three12D). Three molecules, molecules,148, 165 148,and 165 174and, 174 including, including their their ACs, ACs, were were revealed revealed by by X-ray X-ray crystallography,crystallography, whilewhile the the ACs ACs of of 2 2 molecules,molecules,160 160and and161 161,, werewere disclosed disclosed by by comparingcomparing calculated calculated and and experimental experimental ECD.ECD. TheThe ACAC ofof165 165was was determined determined by by the the modified modified Mosher’s Mosher’s method. method. TheThe biologicalbiological sourcessources ofof IndonesianIndonesian sesterterpenoidssesterterpenoids areare exclusivelyexclusively fromfrom thethe phylumphylum Porifera,Porifera, classclass DemospongiaeDemospongiae withwith 6,6, 9,9, andand 1010 didifferrentfferrent families, families, genera,genera, andand species,species, respectivelyrespectively (Figure(Figure 12 12E).E). InIn regardregard toto biologicalbiological activities,activities, significant significant cytotoxicity cytotoxicity was was observed observed for 9 molecules,for 9 molecules, while others while were others recorded were asrecorded exhibiting as anticancerexhibiting activityanticancer without activity cytotoxic without (2 cytotoxic molecules), (2 molecules), cytostatic, antidiabetic,cytostatic, antidiabetic, and antifungal and antifungal activities (1activities molecule (1 each)molecule (Figure each) 12 (FigureD). Marine 12D). sesterterpenoids Marine sesterterpenoids were mainly were found mainly in found specimens in specimens in SSW (25in SSW molecules) (25 molecules) and EKM and (18 EKM molecules) (18 molecules) (Figure 12 (FigureG). 12G).

B E 18 17 18 16 15 14 13 7 12 6 5 4 11 3 3 2 10 1 1 9 8 7 6 5 4 Hyattella sp.

3 Psammocinia sp. Hippospongia sp.Hippospongia 2 Phyllospongia sp. Achantodendrilla sp. 1 Strepsichordaia aliena Mycale euplectellioides

0 Phyllospongia papyrecea

foliascens Carteriospongia Diacarnus megaspinorhabdosa 1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

Figure 12. Cont.

Mar. Drugs 2019, 17, x FOR PEER REVIEW 17 of 71

Mar. Drugs 2019, 17, x FOR PEER REVIEW 17 of 71 Mar. Drugs 2019, 17, 364 17 of 69 C D C D

F F

FigureFigure 12. 12.Structures Structures of of marinemarine sesterterpenoids sesterterpenoids from from Indonesian Indonesian waters waters found found in 1970–2017: in 1970–2017: (FigureA) representative.(A) representative. 12. Structures Distribution Distribution of marine of newof sesterterpenoids new marine marine sesterterpenoids sesterterpenoids from Indonesian by by year year waters (B ().B Statistics). Statistics found of in of new 1970–2017: new marine sesterterpenoids(A) marinerepresentative. sesterterpenoids (C ). Distribution Distribution (C). Distribution of new new marinemarine of new sesterterpenoids sesterterpenoids marine sesterterpen on by theoids year basis on the( ofB). their basis Statistics skeletons of their of new(D), biologicalmarineskeletons sesterterpenoids sources (D), biological (E), and (sourcesbiogeographyC). Distribution (E), and (biogeographyF). of new marine (F). sesterterpenoids on the basis of their 2.2.4. Triterpenoids skeletons (D), biological sources (E), and biogeography (F). 2.2.4. Triterpenoids 2.2.4. TriterpenoidsIndonesian marine triterpenoids (Table S4 and Figures 13A, S4) are comprised of 21 new, 7 mixtures,Indonesian 1 derivative, marine triterpenoids and 2 revised molecules (Table S4 (Figure and Figure 13C). 13 TheA, triterpenes Figure S4) are are grouped comprised into three of 21 new, Indonesian marine triterpenoids (Table S4 and Figures 13A, S4) are comprised of 21 new, 7 7 mixtures,structural 1 classes: derivative, squalane and (1), 2 revised isomalabaricanes molecules (18) (Figure and vannusanes 13C). The (2 triterpenes molecules). are Of grouped21, only into mixtures, 1 derivative, and 2 revised molecules (Figure 13C). The triterpenes are grouped into three threevannusals structural A ( classes:198) and squalaneB (199) were (1), found isomalabaricanes to have a new (18)skeleton. and vannusanesThe 3 skeletons (2 were molecules). obtained Of 21, structuralfrom 3 species,classes: Euplotessqualane vannus (1), forisomalabaricanes 198a and 199a, Rhabdastrella (18) and vannusanes globostellata for (2 180molecules).–197, and HyrtiosOf 21, only only vannusals A (198) and B (199) were found to have a new skeleton. The 3 skeletons were obtained vannusalserectus forA (179198 )(Figure and B 13C,D). (199) were The ACfound of 1 to molecule, have a new199b , skeleton.was solved The by 3X-ray skeletons analysis. were Of theobtained from 3 species, Euplotes vannus for 198a and 199a, Rhabdastrella globostellata for 180–197, and Hyrtios fromtriterpenoids, 3 species, Euplotes six were vannus found tofor show 198a significantand 199a ,cytostatic Rhabdastrella activity. globostellata The metabolites for 180 were–197 ,mainly and Hyrtios erectus for 179 (Figure 13C,D). The AC of 1 molecule, 199b, was solved by X-ray analysis. Of the erectusisolated for 179 from (Figure specimens 13C,D). collected The in AC SSW of (1 21 molecules)molecule, (Figure 199b, 13F).was Twosolved molecules, by X-ray 198a analysis. and 199a ,Of the triterpenoids, six were found to show signiﬁcant cytostatic activity. The metabolites were mainly triterpenoids,were revised six to were198b andfound 199b to [36–41]. show Thesignificant stereochemistry cytostatic of vannusal activity. B The (199b metabolites) was also examined were mainly isolated from specimens collected in SSW (12 molecules) (Figure 13F). Two molecules, 198a and 199a, isolatedby density from specimensfunctional theory collected (DFT) in calculationSSW (12 molecules) [42]. A plausible (Figure biosynthetic 13F). Two pathway molecules, of vannusals 198a and 199a, wereA revised (198b) and to 198b B (199band) was199b proposed[36–41 ].(Figure The stereochemistry 14) [43]. of vannusal B (199b) was also examined were revised to 198b and 199b [36–41]. The stereochemistry of vannusal B (199b) was also examined by density functional theory (DFT) calculation [42]. A plausible biosynthetic pathway of vannusals A by density functionalA theory (DFT) calculation [42]. A plausible biosynthetic pathway of vannusals (198b) and B (199b) was proposed (Figure 14)[43]. A (198b) and B (199b) was proposed (Figure 14) [43]. A

Figure 13. Cont. Mar.Mar. Drugs Drugs2019 2019, 17, 17,, 364 x FOR PEER REVIEW 18 of18 71 of 69 Mar. Drugs 2019, 17, x FOR PEER REVIEW 18 of 71

12 B 12 B C 10 C D 10 D

8 8

6 6 E E 4 4 2 2

0 0

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016 1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

F F

Figure 13. Structures of marine triterpenoids from Indonesian waters found in 1970–2017: (A) FigureFigure 13. 13. StructuresStructures of of marine marine triterpenoids triterpenoids from from Indonesian Indonesian waters waters found foundin 1970–2017: in 1970–2017: (A) representative. Distribution of new marine triterpenoids by year (B). Statistics of new marine (Arepresentative.) representative. Distribution Distribution of ne ofw new marine marine triterpenoids triterpenoids by byyear year (B). ( BStatistics). Statistics of new of new marine marine triterpenoids (C). Distribution of new marine triterpenoids on the basis of their skeletons (D), triterpenoids (C). Distribution of new marine triterpenoids on the basis of their skeletons (D), triterpenoidsbiological sources (C). Distribution (E), and biogeography of new marine (F). triterpenoids on the basis of their skeletons (D), biological sourcesbiological (E), sources and biogeography (E), and biogeography (F). (F). OPP OH OPP OH OHC CHO CHO OHC CHO CHO OH OH CHO CHO CHO OH CHO CHO OH 198/99X1 CHO198/99X2 198/99X3 198/99X4 198/99X1 198/99X2 198/99X3 198/99X4 OAc OH OH OAc OH OH OH OH

CHO CHO CHO CHO CHO CHO CHO O OH O CHO CHO O 198/99X8 OH 198/99X7 O198/99X6 CHO 198/99X5 198/99X8 198/99X7 198/99X6 198/99X5

O O OH O O CHO CHO O O OH O O (-)-198b CHO CHO O O O O O O (-)-198b OH O O CHO (-)-199b O OH OH OH O O CHO (-)-199b O OH OH 198/99X9 198/99X10 198/99X11 198/99X9 198/99X10 198/99X11 Figure 14. Plausible biosynthetic pathway of (–)-vannusals A 198b and B 199b. FigureFigure 14. 14.Plausible Plausible biosynthetic pathway pathway of of (–)-vannusals (–)-vannusals A A198b198b andand B 199b B 199b. . 2.2.5. Steroids 2.2.5.2.2.5. Steroids Steroids Indonesian marine steroids found in the period of 1970–2017 are comprised of 52 pure molecules andIndonesian 4Indonesian mixtures marine(Figure marine 15C) steroids steroids and foundfoundare shown in the in period periodTable S5of of in1970–2017 1970–2017 Supplementary are are comprised comprised Materials ofof 52and 52pure Figures pure molecules molecules 15A, andandS5. 4 The 4 mixtures mixtures discovery (Figure (Figure trend 15 15C) increasedC) and are in theshown shown first in 5 in yearTable Tables andS5 S5 in also in Supplementary Supplementary in the years after Materials Materials 1990 (Figure and and Figures 15B). Figure The15A, 15 A, FigureS5.ratio The S5.among discovery The discoverynew trendskeletons, trendincreased increasedrare infunctional the infirst the 5 groups,year ﬁrsts 5 and years and also andrare in also themotifs years in the is after years1:1:5 1990 (Figure after (Figure 1990 15D). (Figure15B). Four The 15 B). Theratiodifferent ratio among amongskeletons new new skeletons,are observed skeletons, rare in functionalrare52 steroids functional groups, (Figure groups, and15E). rare Among and motifs rare them, is motifs 1:1:5Δ5-sterols is(Figure 1:1:5 constitute 15D). (Figure Four the 15 D). Fourdifferentmajority diﬀerent (18skeletons molecules). skeletons are areobserved Sulfat observeded steroidsin 52 in 52steroids were steroids reported (Figure (Figure 15E).as 20315 E).Among, 206 Among and them, 224 them,–226 Δ5-sterols,∆ while5-sterols aconstitute phosphated constitute the the majoritymajoritysteroid (18was (18 molecules). observedmolecules). in SulfatedSulfat217. Fromed steroids 1970–2017, were Indonesian reported reported as asmarine 203203, 206, 206 sulfated andand 224224 steroids–226–226, while, have while a contributed phosphated a phosphated steroidsteroid was was observed observed in in217 217.. FromFrom 1970–2017,1970–2017, Indonesian Indonesian marine marine sulfated sulfated steroids steroids have have contributed contributed 3.3% of the total marine sulfated steroids worldwide, while Indonesian marine phosphated steroids

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3.3% of the total marine sulfated steroids worldwide, while Indonesian marine phosphated steroids areare expected expected to contribute to contribute 20% 20% of total of total marine marine phosphated phosphated steroids. steroids. The The ACs ACs of three of three steroids, steroids, 201201, , 204204 andand 241241, were, were disclosed disclosed by byX-ray X-ray analysis, analysis, while while that that of 241 of 241 waswas determined determined by byECD ECD spectrum. spectrum. ForFor two two molecules, molecules, 224224 andand 239239, their, their absolute absolute configurations configurations were were determined determined by byMTPA MTPA esters esters and and PGMEPGME methods, methods, respectively. respectively. With With regardregard toto the the biological biological sources, sources, the steroidsthe steroids were mainlywere mainly obtained obtainedfrom the from phyla the Cnidariaphyla Cnidaria (29 molecules) (29 molecules) and Porifera and Porifera (23 molecules), (23 molecules), as listed as in Figurelisted in 15 FigureF. In regard 15F. to In biologicalregard to activities,biological 10activities, molecules 10 showedmolecules significant showedcytotoxicity, significant cytotoxicity, while 11 molecules while 11 were molecules cytostastic were(Figure cytostastic 15G). The(Figure molecules 15G). wereThe molecules isolated mainly were fromisolated specimens mainly fromfrom NSWspecimens (14 molecules) from NSW and (14 ENT molecules)(11 molecules) and ENT (Figure (11 molecules) 15H). (Figure 15H). TheThe unique unique molecules molecules in the in steroids the steroids are cortistatins are cortistatins isolated isolatedfrom the fromsponge the Corticium sponge simplexCorticium collectedsimplex offcollected Flores, oENT,ff Flores, with ENT, a new with skeleton a new skeletoncomprised comprised of a 9(10-19)-abeo-androstane of a 9(10-19)-abeo-androstane and isoquinolineand isoquinoline [64]. The [ 64structure]. The structure of cortistatin of cortistatin A (241) was A (determined241) was determined by X-ray analysis by X-ray and analysis the ECD and excitionthe ECD chirality excition method. chirality Molecules method. 241 Molecules–244 showed241–244 selectiveshowed antiproliferative selective antiproliferative properties propertiesagainst humanagainst umbilical human umbilicalvein endothelial vein endothelial cells (HUVECs). cells (HUVECs). The most The potent most potent member, member, cortistatin cortistatin A (241 A (241), ), showedshowed a selectivity a selectivity index index of more of more than than 3000 3000 against against HUVECs HUVECs in comparison in comparison with with human human fibroblast fibroblast (NHDF)(NHDF) and and several several other other tumor tumor cells cells KB31, KB31, K562 K562 and and Neuro Neuro 2A. 2A. Additional Additional members, members, cortistatins cortistatins E (250E(250), F ),(251 F (),251 G ),(248 G), (248 and), H and (249) H (with249) Nwith-methylN-methyl piperidine piperidine or 3-methyl or 3-methylpyridinepyridine unit isolated unit isolatedfrom thefrom same the source, same source,also showed also showed antiproliferative antiproliferative activity activity against against HUVECs HUVECs [65]. [ 65Three]. Three additional additional cortistatinscortistatins J (245 J (245), K), ( K246 (246) and) and L (247 L (247) were) were isolated isolated from from the the same same source source [66]. [66 The]. The first first synthesis synthesis of of 241241 verifiedverified its its3D3D structure, structure, featuring featuring an aninexpens inexpensiveive terrestrial terrestrial steroid steroid prednisone prednisone as asthe the starting starting materialmaterial [67]. [67 The]. The seco secondnd total total synthesis synthesis of 241 of 241 waswas achieved achieved by byusing using intra-molecular intra-molecular oxa-Michael oxa-Michael addition/aldol/dehydrationaddition/aldol/dehydration cascade cascade reaction, reaction, Sonogashira, Sonogashira, and and Suzuki-Miyaura Suzuki-Miyaura couplings couplings [68]. [68 ]. MoleculesMolecules 241241 andand 245245 werewere confirmed confirmed to show to show an anantiprolif antiproliferativeerative effect effect on onadditional additional cancer cancer cellcell lines: lines: MCF7, MCF7, NCI-H460, NCI-H460, SF268, IA9, SF268, PTX22, IA9, and PTX22, A8, including and A8, drug-resistant including drug-resistant ones [69]. Structure– ones [69]. activityStructure–activity relationships with relationships natural cortistatins with natural and cortistatinssynthetic analogues and synthetic suggeste analoguesd that substitution suggested at that positionsubstitution 7’ of isoquinoline at position is 7’a key of isoquinolinedeterminant of is the a keyphenotypic determinant effects ofof thecortistatins phenotypic [69–71]. eff ectsIt is of hypothesizedcortistatins that [69– the71]. biological It is hypothesized activity of that241 is the due biological to inhibition activity of on ofe 241or moreis due protein to inhibition kinases. of Moleculeone or more241 inhibits protein the kinases. function Molecule of several241 differentinhibits thekinases function in vitro. of several It is proposed different that kinases 241 inmay vitro . occupyIt is proposedthe ATP-binding that 241 sitemay of occupyat least one the of ATP-binding the following site enzymes: of at least Rho one associated, of the following protein enzymes:kinase (ROCK),Rho associated, or cyclin-dependent protein kinase kinase (ROCK), (CDK) or8 and cyclin-dependent 11 [72]. The X-ray kinase crystallographic (CDK) 8 and 11analysis [72]. The of the X-ray ligand-proteincrystallographic complex analysis disclosed of the that ligand-protein the isoquinoli complexne binds disclosed to the thatkinase the hinge, isoquinoline that the binds steroid to the regionkinase of the hinge, molecule that the is steroidcomplementary region of to the the molecule shape of is the complementary ATP-binding to cleft, the that shape the of terminal the ATP-binding polar A ringcleft, is that exposed the terminal to solvent, polar and A that ring a salt is exposed bridge exists to solvent, between and an that aspartate a salt bridgeside chain exists (ROCK between I only)an and aspartate dimethylamino side chain (ROCKgroup of I only)241 [72]. and dimethylamino group of 241 [72].

Figure 15. Cont.

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14 B C D 12 10

2 0

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

18 E F G 15 12

5-Sterol

C(3) ketone Degraded or contracted sterol

5-Oxidized sterol Δ

Figure 15.15.Structures Structures of marineof marine steroids steroids from Indonesianfrom Indonesi watersan foundwaters in 1970–2017:found in (1970–2017:A) representative. (A) Distributionrepresentative. of Distribution new marine of steroids new marine by year steroids (B). Statistics by year of(B new). Statistics marine of steroids new marine (C). Distribution steroids (C). of newDistribution marine steroidsof new onmarine the basissteroids of their on skeletonsthe basis (ofD ,theirE), biological skeletons sources (D,E), (biologicalF), significant sources biological (F), activitysignificant (G ),biological and biogeography activity (G (),H and). biogeography (H). 2.2.6. Saponins 2.2.6. Saponins Only five saponins 253–257 with 1 derivative 252c were discovered in Indonesian waters in the Only five saponins 253–257 with 1 derivative 252c were discovered in Indonesian waters in the period 1970–2017 (Table S6 and Figure 16A, Figure S6). All the saponins retain a lanostane skeleton with period 1970–2017 (Table S6 and Figures 16A,S6). All the saponins retain a lanostane skeleton with five sugar moieties. ECD spectrum has been used to reveal the stereochemistry of 252c. Four molecules, five sugar moieties. ECD spectrum has been used to reveal the stereochemistry of 252c. Four 253molecules,–256, were 253– found256, were in a found specimen in a specimen of the sponge of theMelophlus sponge Melophlus sarassinorum sarassinorumfrom SSW, from while SSW,257 whilewas from257 was a Petrosia from asp. Petrosia of NSW. sp. Significantof NSW. Significant antifungal antifungal activity was activity observed was observed for sarasinoside for sarasinoside J (253). J (253).

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Mar. Drugs 2019, 17, 364 21 of 69

A A

Figure 16. Structures of marine saponins from Indonesian waters found in 1970–2017: (A) FigureFigurerepresentative. 16. 16.Structures Structures of marine of marine saponins saponins from Indonesian from Indonesian waters found waters in 1970–2017: found (inA ) representative.1970–2017: (A) representative. 2.2.7.2.2.7. Meroterpenoids Meroterpenoids 2.2.7.Marine MarineMeroterpenoids meroterpenoids, meroterpenoids, comprised comprised of of 26 26 pure pure compounds compounds and and 2 mixtures,2 mixtures, have have been been discovered discovered since 2000 (Table S7 and Figure 17A–C, Figure S7). Marine meroterpenoids are composed of various sinceMarine 2000 (Tablemeroterpenoids, S7 and Figures comprised 17A–C, of 26 S7). pure Ma compoundsrine meroterpenoids and 2 mixtures, are havecomposed been discovered of various skeletons, as shown in 264–265, 281 and 282, while a rare motif is exhibited by 276. The majority of sinceskeletons, 2000 as(Table shown S7 inand 264 Figures–265, 281 17A–C, and 282 S7)., while Ma rinea rare meroterpenoids motif is exhibited are bycomposed 276. The ofmajority various of marine meroterpenoids found in Indonesian waters are the 21 merosesquiterpenoids, followed by the skeletons,marine meroterpenoids as shown in 264 found–265, in281 Indonesian and 282, while wate rsa rareare themotif 21 ismerosesquiterpenoids, exhibited by 276. The followedmajority ofby 3 meroditerpenoids and the 2 merotriterpenoids (Figure 17E). X-ray crystallography was used for two marinethe 3 meroditerpenoids meroterpenoids andfound the in 2 merotriterpenoidsIndonesian waters (Figure are the 17E). 21 merosesquiterpenoids, X-ray crystallography followedwas used byfor molecules, 264–265, to determine their ACs, while ECD spectra were used to elucidate the ACs of thetwo 3 molecules,meroditerpenoids 264–265 and, to thedetermine 2 merotriterpenoids their ACs, while (Figure ECD 17E). spectra X-ray were crystallography used to elucidate was used the ACs for 261–262. The marine meroterpenoids were isolated from the phyla Ascomycta (4 molecules), Porifera twoof 261 molecules,–262. The 264 marine–265, to meroterpenoids determine their were ACs, isolatedwhile ECD from spectra the phyla were usedAscomycta to elucidate (4 molecules), the ACs (19 molecules), and Chordata (3 molecules). More speciﬁcally, 19 molecules from Porifera were found ofPorifera 261–262 (19. The molecules), marine meroterpenoidsand Chordata (3 weremolecules). isolated More from specifically, the phyla 19Ascomycta molecules (4 from molecules), Porifera in 3 families: Dysideidae (2 molecules), Chalinidae (3 molecules), and Dictyodendrillidae (2 molecules). Poriferawere found (19 molecules),in 3 families: and Dysideidae Chordata (2 (3 molecules), molecules). Chalinidae More specifically, (3 molecules), 19 molecules and Dictyodendrillidae from Porifera With regard to their biological activities, 8 molecules showed signiﬁcant cytotoxicity, followed by were(2 molecules). found in 3 With families: regard Dysideidae to their biological (2 molecules), activities, Chalinidae 8 molecules (3 molecules), showed andsignificant Dictyodendrillidae cytotoxicity, 1 molecule as antiatherosclerotic and 1 molecule as antioxidant and antidiabetic (Figure 17G). The marine (2followed molecules). by 1 Withmolecule regard as antiatheroscleroticto their biological acti andvities, 1 molecule 8 molecules as antioxidant showed significantand antidiabetic cytotoxicity, (Figure merosesquiterpeoids were isolated from specimens from MLU (9 molecules), while meroditerpenoids followed17G). The by marine 1 molecule merosesquiterpeoids as antiatherosclerotic were isolatedand 1 molecule from specimens as antioxidant from MLU and antidiabetic(9 molecules), (Figure while (2 molecules) and merotriterpenoids (2 molecules) were found from SSW and NMU, respectively 17G).meroditerpenoids The marine merosesquiterpeoids (2 molecules) and merotriterpenoidswere isolated from (2specimens molecules) from were MLU found (9 molecules), from SSW while and (Figure 17H). meroditerpenoidsNMU, respectively (2 (Figure molecules) 17H). and merotriterpenoids (2 molecules) were found from SSW and NMU, respectively (Figure 17H). A H O A O H O O O OMe OH OH O HO O O H OMe OH OH OH OH OH OO H O HO HO OO H N H O OH H O OH OH O H O O O O HO O O N H O O H O O O O O OO O O O O O ( )-276 (+)-281 (+)-263O O O( )-264 (+)-265O HO ( )-276 (+)-281 (+)-263 ( )-264 (+)-265 HO

CO2H HO HO H H CO2H HO O HO HH H

O ( )-282 H ( )-282

Figure 17. Cont.

Mar. Drugs 2019, 17, 364 22 of 69 Mar. Drugs 2019, 17, x FOR PEER REVIEW 22 of 71

B F G 6 5

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016 C D

Figure 17. Structures of marine meroterpenoids from Indonesian waters found in 1970–2017: (AFigure) representative. 17. Structures Distribution of marine of meroterpenoids new marine meroterpenoids from Indonesian by yearwaters (B). found Statistics in 1970–2017: of new marine (A) meroterpenoidsrepresentative. (DistributionC). Distribution of new of new marine marine meroterpenoids meroterpenoids by onyear the (B basis). Statistics of their of skeletons new marine (D,E), biologicalmeroterpenoids sources (C (F).), Distribution significant biological of new marine activity meroterpenoi (G), and biogeographyds on the basis (H of). their skeletons (D,E), biological sources (F), significant biological activity (G), and biogeography (H). 2.3. Alkaloids 2.3. Alkaloids The alkaloids from Indonesian marine sources are comprised of 260 new molecules, 5 revised moleculesThe alkaloids (332a, 333a from, 348a Indonesian, 403a, and marine404a ),sources 3 derivatives are comprised (328c, 452cof 260and new453c molecules,), and 3 molecules5 revised thatmolecules were known, (332a, 333a but, 348a had, been 403a, isolatedand 404a for), 3 thederivatives first time (328c as, natural452c and products 453c), and (397 3 moleculesand 546– that547). Ofwere these, known, 102 andbut had 91 moleculesbeen isolated were for isolatedthe first time as freebases as natural and products salt forms, (397 and respectively, 546–547). Of and these, 7 as mixtures.102 and 91 The molecules total of 260 were Indonesian isolated as marine freebases alkaloids and salt can forms, be grouped respectively, into 48 piperidines,and 7 as mixtures. 7 pyridines, The 37total indoles, of 260 13Indonesian acridines, marine 11 quinolines alkaloids orcan isoquinolines, be grouped into 38 48 tyrosines, piperidines, 31 pyrroles, 7 pyridines, 13 imidazoles,37 indoles, 1413 polysulfur acridines, aromatics, 11 quinolines 15 serines, or isoquinolines, and 33 others. 38 The tyrosines, last group 31 ispyrroles, comprised 13 imidazoles, of a pyrroloimino-quinone, 14 polysulfur 5aromatics, ceramides, 15 15 serines, tetramic and acids, 33 2others. nucleosides, The last 2 formamides,group is comprised a polycyclic of a diamine,pyrroloimino-quinone, a pterin alkaloid, 5 2ceramides, thiadiazoles, 15 tetramic a pyrazole, acids, an 2 azirine,nucleosides, and 2 2 formamides, simple amines a polycyclic/amides. diamine, Purification a pterin ofalkaloids alkaloid, 2 is oftenthiadiazoles, challenging a pyrazole, due to thean presenceazirine, and of nitrogen2 simple atomsamines/amides. and their behaviorPurification as aof base. alkaloids To tackle is often this problem,challenging researchers due to the often presence adjust of the nitrogen pH of atoms mobile and phases theirof behavior chromatography as a base. To by tackle adding this formic problem, acid orresearchers trifluoroacetic often acid, adjust or modify the pH the of stationary mobile phases phase intoof chromatography a suitable one. Because by adding of their formic basic acid nature, or manytrifluoroacetic alkaloids acid, are tested or modify as salt the forms. stationary Significant phase activity into a suitable was observed one. Because for 118 of molecules their basic consisting nature, many alkaloids are tested as salt forms. Significant activity was observed for 118 molecules consisting of cytotoxic (49), antibacterial (29), anticancer without cytotoxicity (1), antiparasitic (9), antifungal (8), of cytotoxic (49), antibacterial (29), anticancer without cytotoxicity (1), antiparasitic (9), antifungal (8),

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Mar. Drugs 2019, 17, x FOR PEER REVIEW 23 of 71 immunosuppresive (2 molecules), antiviral, anti-cystic fibrosis, immunomodulatory, anti-neurodisease, andimmunosuppresive electrophysiological (2 activitymolecules), (each 1antiviral, molecule). anti-cystic fibrosis, immunomodulatory, anti- neurodisease, and electrophysiological activity (each 1 molecule). 2.3.1. Piperidine Alkaloids 2.3.1. Piperidine Alkaloids The majority of piperidine alkaloids are manzamine-related molecules characterized by the presenceThe of majority a unique of polycyclic piperidine ring alkaloids system. Theare manzamine-related molecules are compiled molecules in Table characterized S8 in Supplementary by the presence of a unique polycyclic ring system. The molecules are compiled in Table S8 in Materials and are drawn as in Figure 18A, Figure S8. The first piperidine alkaloid found in Indonesian Supplementary Materials and are drawn as in Figures 18A, S8. The first piperidine alkaloid found in waters was halicyclamine A (322), from a Haliclona sponge, in 1994, followed by more alkaloids Indonesian waters was halicyclamine A (322), from a Haliclona sponge, in 1994, followed by more after 2001 (Figure 18B). As mentioned earlier in Figure4C, piperidine alkaloids constitute one of the alkaloids after 2001 (Figure 18B). As mentioned earlier in Figure 4C, piperidine alkaloids constitute dominant groups of Indonesian MNPs, with 48 molecules, which were classified into 33 manzamines, one of the dominant groups of Indonesian MNPs, with 48 molecules, which were classified into 33 284–286, 297–302, 309–312, and 318–321, 2 degraded β-carbolines, 313 and 314, 3 ircinal-related manzamines, 284–286, 297–302, 309–312, and 318–321, 2 degraded β-carbolines, 313 and 314, 3 ircinal- molecules, 315–317, 6 molecules with two piperidines, 322–327, one fused piperidine-pyran, 329a, related molecules, 315–317, 6 molecules with two piperidines, 322–327, one fused piperidine-pyran, one329a zoanthamine,, one zoanthamine,330, and 2330 molecules, and 2 withmolecules a piperidine with a in piperidine a tricyclic system,in a tricyclic331–332 system,. Inspection 331–332 of the. chemicalInspection structures of the allowedchemical us structures to identify allowed new skeletons us to identify in 313 andnew318 skeletons, rare functional in 313 and groups 318, inrare309 andfunctional329a, and groups 6 molecules in 309 withand 329a rare, structuraland 6 molecules motifs with in 306 rare–308 structural, 311 and motifs320–321 in(Figure 306–308 18, 311D). and X-ray analysis320–321 was (Figure used 18D). to reveal X-ray ACs analysis of molecules was used289 to, reveal324 and ACs327 of. ACsmolecules of three 289306, 324, 313 andand 327328c. ACswere of determinedthree 306, by313 comparing and 328c were experimental determined and by calculated comparing ECD experi spectra,mental while and threecalculated others, ECD290 spectra,, 293 and 330while, were three elucidated others, with290, 293 modified and 330 Mosher’s, were elucidated method. In with terms modified of their Mosher’s biological method. activities, In significantterms of antibacterialtheir biological (14), activities, cytotoxic significant (11), anticancer antibacterial without (14), cytotoxicity cytotoxic (11), (1), anticancer antiparasitic without (5), antifungal cytotoxicity (5), antiviral(1), antiparasitic and immunosuppresive (5), antifungal (5), activity antiviral (each and 1 molecule) immunosuppresive were observed activity (Figure (each 18 1E). molecule) The sources wereof piperidineobserved alkaloids(Figure 18E). are Porifera The sources (45), Cnidaria of piperidine (1), and alkaloids Chordata are (2 Porifera molecules). (45), In Cnidaria total, 48 molecules(1), and wereChordata isolated (2 frommolecules). specimens In total, of NSW 48 molecules (31), JSCR were (7), isolated ENT, BLI from (3), specimens and SES, NMU,of NSW PUA (31), (1 JSCR molecule (7), each)ENT, (Figure BLI (3), 18 andG). SES, NMU, PUA (1 molecule each) (Figure 18G).

Figure 18. Cont.

Mar.Mar. Drugs Drugs2019 2019, 17, 17, 364, x FOR PEER REVIEW 2424 of of71 69

B C D 8

7 6 5 4

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016 E

Figure 18. Structures of marine piperidine alkaloids from Indonesian waters found in 1970–2017: (A) Figure 18. Structures of marine piperidine alkaloids from Indonesian waters found in 1970–2017: representative. Distribution of new marine piperidines by year (B). Statistics of new marine (A) representative. Distribution of new marine piperidines by year (B). Statistics of new marine piperidines (C). Distribution of new marine piperidine molecules on the basis of their skeletons (D), piperidines (C). Distribution of new marine piperidine molecules on the basis of their skeletons (D), significant biological activity (E), biological sources (F), and biogeography (G). significant biological activity (E), biological sources (F), and biogeography (G). Manadomanzamines A (318) and B (319) (Figures 18A, S8), obtained from a sponge Manadomanzamines A (318) and B (319) (Figure 18A, Figure S8), obtained from a sponge Acanthostrongylophora sp. collected off Manado, have a novel skeleton [73]. Their ACs and Acanthostrongylophora sp. collected off Manado, have a novel skeleton [73]. Their ACs and conformation conformation were determined by ECD, NOESY and molecular modelling analysis. Molecules 318 were determined by ECD, NOESY and molecular modelling analysis. Molecules 318 and 319 showed and 319 showed growth inhibition against HIV-1 and against fungi causing opportunistic infection growth inhibition against HIV-1 and against fungi causing opportunistic infection with acquired immune with acquired immune deficiency syndrome (AIDS). Biosynthesis of 318 and 319 is proposed, as deficiency syndrome (AIDS) 318 319 shown (Figure 19). . Biosynthesis of and is proposed, as shown (Figure 19).

Mar. Drugs 2019, 17, 364 25 of 69 Mar. Drugs 2019, 17, x FOR PEER REVIEW 25 of 71

H N HN N HN HN N N H N O H H H H H H H H H H H H H H Mar. Drugs 2019, 17, x FOR PEER REVIEW 25 of 71 O O O H O N N N N

HN HN HN H HN N HN N HN HN N N H N O H H H H H H H H H H H H H H 318/9-IV 318/9-I 318/9-II 318/9-III O O O H O N N N N OH HN HN HN R HN N N N N N N H 318/9-II H 318/9-III 318/9-IVH 22 318/9-IH H H H H O OH H H N OH N OH N OH R N N N N N HN H N H H 22 H H H H H O OH HNH H HN N N OH N OH

HN ( )-318 R = HN 318/9-IV HN 318/9-V ( )-319 R = 318/9-IV 318/9-V Figure 19. Plausible( )-318 biosynthetic R = pathwa pathwayy of (–)-manadomanzamines A 318,B, B 319. ( )-319 R = 2.3.2. Pyridine Alkaloids Figure 19. Plausible biosynthetic pathway of (–)-manadomanzamines A 318, B 319. Only2.3.2. 7 moleculesPyridine Alkaloids were classiﬁedclassified asas pyridinepyridine alkaloids,alkaloids, asas shownshown inin TableTable S9 S9 and and in in Figure Figures 20 20A–A–C, FigureC, S9. The S9. moleculesOnly The 7 molecules molecules were were werereported classified reported recent as pyridine recently,ly, in alkaloids, 2016–2017 in 2016–2017 as shown (Figure in (Figure Table 20B). S9 20andOneB). in Onemolecule,Figures molecule, 20A– 333a,333a was, wasrevised revised C,to S9. the toThe theknown molecules known 333b 333bwere after reportedafter comparing comparing recently, NMR in NMR 2016–2017 data data of (Figure of total total 20B).synthesis synthesis One molecule, work work [74]. [333a74]. , The Thewas incorrect structurerevised of 333a to the was known due toto333b thethe after misinterpretationmisinterpr comparingetation NMR ofofdata HMBCHMBC of total signals.signals. synthesis work [74]. The incorrect structure of 333a was due to the misinterpretation of HMBC signals.

A A

B C D 4 3 B C D 4 3

1 11 2 1 11 2 1

Haliclona sp. Xestospongia sp. Xestospongia 1 0 Clathria basilana

Aspergillus versicolor 1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

Haliclona sp.

Xestospongia sp. Xestospongia 0 Clathria basilana E Aspergillus versicolor

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

Figure 20. Structures of marine pyridine alkaloids from Indonesian waters found in 1970–2017:

(A) representative. Distribution of new alkaloids by year (B). Statistics of new marine pyridine molecules (C). Distribution of new marine pyridine molecules on the basis of biological sources (D), and biogeography (E).

Mar. Drugs 2019, 17, x FOR PEER REVIEW 26 of 71

Figure 20. Structures of marine pyridine alkaloids from Indonesian waters found in 1970–2017: (A) representative. Distribution of new alkaloids by year (B). Statistics of new marine pyridine molecules (C). Distribution of new marine pyridine molecules on the basis of biological sources (D), and Mar. Drugsbiogeography2019, 17, 364 (E). 26 of 69

2.3.3. Indole Alkaloids 2.3.3. Indole Alkaloids There have been 37 new and 1 proposed 356d indole alkaloids in the Indonesian MNPs (Table S10, ThereFigure have 21A–C, been S10). 37 new ECD and wa 1 proposeds used to 356ddetermineindole ACs alkaloids of (–)- in360 the. IndonesianIn addition, MNPs the ACs (Table of S10,two Figureindoles, 21 340A–C, and Figure 341, S10).were ECDdetermined was used by tototal determine synthesis. ACs Cyto oftoxicity (–)-360. was In addition, the dominant the ACs biological of two indoles,activitiy340 reportedand 341 for, were indole determined alkaloids by (7), total followed synthesis. by Cytotoxicity antiparasitic was and the anticancer dominant biologicalactivity (1 activitiymolecule reported each). The for indolealkaloids alkaloids were (7),found followed to be from by antiparasitic Porifera (31), and Cnidarian anticancer (2) activity and Chordata (1 molecule (4 each).molecules). The alkaloids were found to be from Porifera (31), Cnidarian (2) and Chordata (4 molecules).

10 B 9 C D 8 7 6 5 4 3 2 1 0 1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

FigureFigure 21.21. StructuresStructures of of marine marine indole indole alkaloids alkaloids from from Indon Indonesianesian waters waters found found in 1970–2017: in 1970–2017: (A) (Arepresentative.) representative. Distribution Distribution of ofnew new marine marine indole indole alkaloids alkaloids by by year year ( (BB).). Statistics ofof newnew marinemarine indole alkaloids (C). Distribution of new marine indole alkaloids, biological activity (D), biological sources (E), and biogeography (F). Mar. Drugs 2019, 17, x FOR PEER REVIEW 27 of 71 Mar. Drugs 2019, 17, 364 27 of 69 indole alkaloids (C). Distribution of new marine indole alkaloids, biological activity (D), biological sources (E), and biogeography (F). 2.3.4. Acridine Alkaloids 2.3.4.In Acridine total, 13 Alkaloids new and 1 revised acridine alkaloids were reported from Indonesian waters (FigureIn 22 total,A–C, 13 Figure new and S11 1 andrevised Table acridine S11). alkaloid Of 13 molecules,s were reported six were from isolated Indonesian as free waters bases, (Figures while the remaining22A–C, S11 seven and Table were obtainedS11). Of 13 as molecules, salts. One six molecule, were isolated385a, as has free been bases, revised while to the385b remaining. A new seven skeleton waswere proposed obtained for as 390salts.. ResearchOne molecule, on marine 385a, has acridines been revised began to with 385b the. A discovery new skeleton of styelsamines was proposed A–D (378for– 390381.) Research in 1988 (Figure on marine 22B). acridines The structure began with of the the alkaloid discovery390 ofwas styelsamines determined A–D by ( X-ray378–381 analysis.) in Six1988 molecules (Figure 22B). showed The signiﬁcantstructure of cytotoxicity. the alkaloid 390 The was acridine determined alkaloids by X-ray were analysis. isolated fromSix molecules Porifera (8) andshowed Chordata significant (5 molecules). cytotoxicity. The acridine alkaloids were isolated from Porifera (8) and Chordata (5 molecules). A

O N N N MeN OH OH NH OH O O O N N N H N N HN NMe 385a 385b 390 NHAc

379

B C 44 D 4 3

3 11 2

latericius 0 Eusynstyela carbonaria Biemna fortis Oceanapia sp.

Didemnum sp. Xestospongia cf. Xestospongia 1971 1976 1981 1986 1991 1996 2001 2006 2011 2016 E

Figure 22. Structures of marine acridine alkaloids from Indonesian waters foundn in 1970–2017: (A) Figure 22. Structures of marine acridine alkaloids from Indonesian waters found in 1970–2017: representative. Distribution of new marine acridine alkaloids by year (B). Statistics of new marine (A) representative. Distribution of new marine acridine alkaloids by year (B). Statistics of new marine acridine molecules (C). Distribution of new marine acridine-containing molecules on the basis of their acridinebiological molecules sources (DC),). and Distribution biogeography of new (E). marine acridine-containing molecules on the basis of their biological sources (D), and biogeography (E). The ascidian Eusynstyla latericius, collected off Makassar, SSW, was found to contain Eusynstyla latericius styelsaminesThe ascidian A–D (378–381, Figures 23A,, collected S11) which off Makassar, showed SSW,cytotoxic was effect found against to contain HCT116 styelsamines cells A–D[75]. (A378 biomimetic–381, Figure synthesis 23A, Figureof styelsamine S11) which B (379 showed) was conducted cytotoxic from effect kynuramine against HCT116 (379-I) and cells N- [75]. Aacetyl biomimetic dopamine synthesis (379-II of) (Figure styelsamine 23) featuring B (379 )a wasCeCl conducted3-catalyzed fromoxidative kynuramine coupling ( of379-I 379-I) and andN 379--acetyl dopamineII in the presence (379-II) of (Figure silver 23oxide) featuring [76]. The a structure CeCl3-catalyzed of styelsamine oxidative C (380 coupling) was also of 379-Iconfirmedand 379-II by a in thetotal presence synthesis of silverutilizing oxide biaryl [76 Suzuki]. The structurecross-coupling of styelsamine [77]. The preparation C (380) was of also 379 confirmedand 381 was by also a total synthesisachieved utilizing by using biaryl a simple Suzuki biomimetic cross-coupling synthetic [77]. method The preparation [78]. Styelsamine of 379 and D381 (381was) could also achievedbe a bybiosynthetic using a simple intermediate biomimetic for a large synthetic subset method of pyridoacridine [78]. Styelsamine alkaloids D[79]. (381 Styelsamines) could be aB biosynthetic(379) and intermediateD (381) showed for high a large affinity subset to calf of pyridoacridinethymus DNA [78]. alkaloids [79]. Styelsamines B (379) and D (381) showed high affinity to calf thymus DNA [78]. Mar. Drugs 20192019,, 1717,, x 364 FOR PEER REVIEW 28 of 6971 Mar. Drugs 2019, 17, x FOR PEER REVIEW 28 of 71

Figure 23. Biomimetic synthesis of styelsamine B (379) from kynuramine (379-I) and N-acetyl FigureFigure 23. 23.Biomimetic Biomimetic synthesis synthesis of styelsamineof styelsamine B (379 B) from(379) kynuraminefrom kynuramine (379-I) and(379-IN-acetyl) and dopamineN-acetyl dopamine (379-II). (379-IIdopamine). (379-II). 2.3.5. Quinoline and Isoquinoline Alkaloids 2.3.5.2.3.5. Quinoline Quinoline andand IsoquinolineIsoquinoline Alkaloids In total, 11 natural quinoline or isoquinoline alkaloids were discovered in Indonesian waters InIn total,total, 1111 naturalnatural quinolinequinoline or isoquinoline alkaloidsalkaloids werewere discovereddiscovered inin Indonesian Indonesian waters waters (Figure 24A–C, Figure S12, Table S12). The very first member of this group is an aaptamine derivative (Figures(Figures 24A–C,24A–C, S12,S12, TableTable S12).S12). The very first membermember ofof thisthis groupgroup isis anan aaptamineaaptamine derivative derivative obtained off Jakarta, JSCR (Figure 24B). Of 11 molecules, nine were isolated as free bases, while two obtainedobtained offoff Jakarta,Jakarta, JSCRJSCR (Figure(Figure 24B). Of 11 molecules, ninenine werewere isolatedisolated as as free free bases, bases, while while two two were obtained as salts. Two molecules, 391 and 395, of the class contained a rare motif. With respect to werewere obtained obtained asas salts.salts. TwoTwo molecules, 391 and 395,, ofof thethe classclass containedcontained a a rare rare motif. motif. With With respect respect biological activity, 3 molecules showed significant cytotoxicity, while 2 molecules were antibacterial toto biologicalbiological activity,activity, 33 moleculesmolecules showed signsignificantificant cytotoxicity,cytotoxicity, whilewhile 22 moleculesmolecules werewere Aaptos suberitoides Aaptos (Figureantibacterialantibacterial 24D). All(Figure(Figure the compounds 24D).24D). All werethe foundcompounds from the werewere marine foundfound sponges fromfrom thethe marinemarine spongessponges(5), AaptosAaptossp. (2)suberitoidessuberitoides and Xestospongia (5),(5), AaptosAaptossp. sp.sp. (4 (2)(2) molecules) andand Xestospongia (Figure 24sp.sp.E). (4(4 JSCR molecules)molecules) (4 molecules) (Figure(Figure 24E). and24E).MLU JSCR JSCR (4(4 (4 molecules)molecules) molecules) wereand and theMLUMLU major (4 (4 molecules) molecules) source areas werewere of the the major group source (Figure areas 24F). of thethe groupgroup (Figure(Figure 24F). 24F).

BB CC DD 55 EE 44 44

33 2 2

Aaptos sp. Aaptos sp. Aaptos 00

Xestospongia sp. Xestospongia sp. 1971 1976 1981 1986 1991 1996 2001 2006 2011 2016 Aaptos suberitoides 1971 1976 1981 1986 1991 1996 2001 2006 2011 2016 Aaptos suberitoides

F F

Figure 24. Structures of marine quinoline or isoquinoline alkaloids from Indonesian waters found in Figure 24. StructuresStructures of of marine marine quinoline quinoline or or isoquinoline isoquinoline alkaloids alkaloids from from Indonesian Indonesian waters waters found found in 1970–2017: (A) representative. Distribution of the alkaloids by year (B). Statistics of new marine in1970–2017: 1970–2017: (A) ( Arepresentative.) representative. Distribution Distribution of ofthe the alkaloids alkaloids by by year year (B (B).). Statistics Statistics of of new marinemarine quinoline or isoquinoline alkaloids (C). Distribution of new marine quinoline and isoquinoline quinoline oror isoquinoline isoquinoline alkaloids alkaloids (C). ( DistributionC). Distribution of new of marinenew marine quinoline quinoline and isoquinoline and isoquinoline alkaloids alkaloids on the basis of their biological activity (D), biological sources (E), and biogeography (F). onalkaloids the basis on ofthe their basis biological of their biological activity (D activity), biological (D), biological sources (E sources), and biogeography (E), and biogeography (F). (F).

Mar. Drugs 2019, 17, 364 29 of 69

2.3.6.Mar. Tyrosine Drugs 2019 Alkaloids, 17, x FOR PEER REVIEW 29 of 71 2.3.6.A total Tyrosine of 38 tyrosine Alkaloids alkaloids were found in Indonesian waters. Of 38 molecules, 7 molecules were isolated asA mixturestotal of 38 (Figuretyrosine 25 alkaloidsA–C, Figure were S13,found Table in Indonesian S13). The waters. ﬁrst member Of 38 molecules, of this class 7 molecules was bastadin reportedwere inisolated 1994. as The mixtures chemical (Figures structures 25A–C, of S13, this Table class S13). contained The first 1member new skeleton of this class405 .was With bastadin respect to biologicalreported activity, in 1994. antiparasitic The chemical activity structures was of seen this forclass 3 contained molecules 1 followednew skeleton by one405. cytotoxicWith respect molecule to (Figurebiological 25E). The activity, sources antiparasitic of tyrosine activity alkaloids was seen are for Porifera 3 molecules consisting followed of 3by species one cytotoxic and 1 molecule undescribed species(Figure (Figure 25E). 25 TheF). sources Most moleculesof tyrosine alkaloids were found are Porifera from specimens consisting of of 3 BLIspecies (21), and EKM 1 undescribed (7), CSW (7), and NSWspecies (2 (Figure molecules) 25F). Most (Figure molecules 25G). were found from specimens of BLI (21), EKM (7), CSW (7), and NSW (2 molecules) (Figure 25G).

A Br HO O Br N H N OH OH OH OH N H N Br Br O

O HO HO N NH Br O OH 405 Br

21 B C D 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

FigureFigure 25. 25.Structures Structures of marine marine tyrosine tyrosine alkaloids alkaloids from from Indonesian Indonesian waters watersin 1970–2017: in 1970–2017: (A) (A) representative.representative. Distribution Distribution of the of thealkaloids alkaloids by year by year(B). Statistics (B). Statistics of new of tyrosine new tyrosine alkaloids alkaloids (C). (C). Distribution of new marine tyrosine-containing alkaloids on the basis of their, biological activity (D), biological sources (E), and biogeography (F). Mar. Drugs 2019, 17, x FOR PEER REVIEW 30 of 71

Mar. DrugsDistribution2019, 17, 364 of new marine tyrosine-containing alkaloids on the basis of their, biological activity (D30), of 69 biological sources (E), and biogeography (F). 2.3.7. Pyrrole Alkaloids 2.3.7. Pyrrole Alkaloids A total of 31 pyrrole alkaloids have been discovered from the Indonesian waters in addition to A total of 31 pyrrole alkaloids have been discovered from the Indonesian waters in addition to 2 revised and 2 derivatives (Figure 26A–C, Figure S14 and Table S14). Nineteen molecules out of 2 revised and 2 derivatives (Figures 26A–C, S14 and Table S14). Nineteen molecules out of 31 were 31 were isolated as free bases, while 9 were isolated as salts. The first member, 441, was discovered isolated as free bases, while 9 were isolated as salts. The first member, 441, was discovered in 1995, in 1995, and 12 molecules were reported in 2010 (Figure 26B). This class of alkaloids contains 1 new and 12 molecules were reported in 2010 (Figure 26B). This class of alkaloids contains 1 new skeleton skeleton in 450 and 1 rare motif in 448. The ACs of two molecules, 443 and 448b2, of this class were in 450 and 1 rare motif in 448. The ACs of two molecules, 443 and 448b2, of this class were determined determined by ECD spectra, while 1 molecule, 450, was confirmed by total synthesis. Cytotoxicity by ECD spectra, while 1 molecule, 450, was confirmed by total synthesis. Cytotoxicity (2 molecules) (2 molecules) and anti-cystic fibrosis (1 molecule) are the signature of significant biological activity of and anti-cystic fibrosis (1 molecule) are the signature of significant biological activity of the pyrrole the pyrrole alkaloids (Figure 26E). The sources of pyrrole alkaloids are exclusively Porifera, consisting alkaloids (Figure 26E). The sources of pyrrole alkaloids are exclusively Porifera, consisting of 3 of 3 families (Agelasidae 22 molecules, Axinellidae 1 molecule, and Scopalinidae 8 molecules). families (Agelasidae 22 molecules, Axinellidae 1 molecule, and Scopalinidae 8 molecules).

B C D 12 11 10 9 8 7 6

5 4 3 2 1

0 1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

Figure 26. Cont.

Mar. Drugs 2019, 17, 364 31 of 69 Mar. Drugs 2019, 17, x FOR PEER REVIEW 31 of 71 Mar. Drugs 2019, 17, x FOR PEER REVIEW 31 of 71 E E

F F

Figure 26. StructuresStructures of of marine marine pyrrole pyrrole alkaloids alkaloids from from Indonesi Indonesianan waters waters found found in 1970–2017: in 1970–2017: (A) (representative.FigureA) representative. 26. Structures Distribution Distribution of marine of thepyrrole of thealkaloids alkaloids alkaloids by byyear from year ( BIndonesi ().B ).Statistics Statisticsan waters of of new new found pyrrole pyrrole in 1970–2017:alkaloids alkaloids ( (CCA).).) Distributionrepresentative. of new Distribution marine pyrrole-containing of the alkaloids by alkalo alkaloids yearids (B on on). Statisticsthe the basis basis of of their, their,new biological pyrrole alkaloids activity ( (DC),).), biologicalDistribution sources of new (E ),marine and biogeographybiogeography pyrrole-containing ((F).). alkaloids on the basis of their, biological activity (D), biological sources (E), and biogeography (F). Two dimeric bromopyrrole alkaloids, nakamuric acid (448a) and its methyl ester, 449, showing Two dimeric bromopyrrole alkaloids, nakamuric acid (448a) and its methyl ester, 449, showing antibiotic activity against B. subtilis, were isolated from the sponge Agelas nakamurai, collected in antibioticTwo activitydimeric againstbromopyrrole B. subtilis al,kaloids, were isolated nakamuric from theacid sponge (448a) Agelasand its nakamurai methyl ester,, collected 449, showing in MLU MLU [80]. A total synthesis of (9R,10S,9 R,10 S)-nakamuric acid (449a) was accomplished by the [80].antibiotic A total activity synthesis against of (9B.R subtilis,10S,9′,R were,10′S isolated)-nakamuric0 0 from acid the sponge (449a) wasAgelas accomplished nakamurai, collected by the minimal in MLU minimal use of protective groups with exploration of 2-aminoimidazole [34]. The AC of 448a was use[80]. of A protective total synthesis groups of with(9R,10 exploratioS,9′R,10′Sn)-nakamuric of 2-aminoimidazole acid (449a [34].) was The accomplished AC of 448a wasby the established minimal established to be (9S,10R,9 S,10 R) by comparison of the experimental and calculated ECD spectra [35]. touse be of (9 protectiveS,10R,9′S,10 groups′R) by withcomparison0 exploratio0 of then of experimental 2-aminoimidazole and calculated [34]. The ECD AC ofspectra 448a was[35]. established Thus, 448a Thus, 448a was proved to be an enantiomer of the synthetic one. The sponge Stylissa carteri from wasto be proved (9S,10R to,9 ′beS,10 an′R enantiomer) by comparison of the of synthetic the experimental one. The andsponge calculated Stylissa ECD carteri spectra from SSW [35]. wasThus, found 448a SSW was found to contain two unprecedented molecules, latonduines A (450) and B (451d)[45]. towas contain proved two to unprecedentedbe an enantiomer molecules, of the synthetic latonduines one. The A (450 sponge) and Stylissa B (451d carteri) [45]. Theirfrom SSWstructures was found were Their structures were elucidated by analysis of spectroscopic data and conﬁrmed by total synthesis elucidatedto contain two by analysisunprecedented of spectroscopic molecules, da latonduinesta and confirmed A (450 )by and total B (451d synthesis) [45]. ofTheir 450 structures. It is proposed were of 450. It is proposed that ornithine is the biogenetic precursor to the aminopyrimidine fragment, thatelucidated ornithine by isanalysis the biogenetic of spectroscopic precursor da tota the and aminopyrimidine confirmed by total fragment, synthesis as shownof 450. inIt isFigure proposed 27. asthat shown ornithine in Figure is the 27 biogenetic. precursor to the aminopyrimidine fragment, as shown in Figure 27. NH H2N NH H NH2 NH2 N NH H2N NH HO2C HO C H 2 HO2C NH2 NH 2 N NH NH HO2C HO C HO2C Br NH 2 NH Br H2NNH2 Br Br Br H2NNH2 Br NH NH Br NH Br N Br N NH N NH Br H NH Br HN O Br H N O 450-I N O 450-II H H O H O 450-I O 450-II NH2 NH2 NH2 NH2 N NH2 N NH N NH2 N NH2 2 N NH N N N HO C N N O N HO2C 2 NH N HO C N Br N HOBr 2C Br 2 BrO Br Br Br Br 441 NH NH NH Br NH 441 Br N Br N NH N NH Br N NH H Br H NH Br HN O Br N O N O Br HN O H H H O O O H O 451d 450 450-III 450-IV 451d 450 450-III 450-IV Figure 27. The plausible biosynthetic pathway of latonduines A 450, B 451d, and (Z)-3- Figure 27. The plausible biosynthetic pathway of latonduines A 450,B 451d, and (Z)-3-bromohymenialdisine bromohymenialdisineFigure 27. The plausible 441. biosynthetic pathway of latonduines A 450, B 451d, and (Z)-3- 441bromohymenialdisine. 441. 2.3.8. Imidazole Alkaloids 2.3.8. Imidazole Alkaloids The marine sponges Lissodendroryx fibrosa ﬁbrosa, Leucetta chagosensis, and Leucetta microraphis, as well The marine sponges Lissodendroryx fibrosa, Leucetta chagosensis, and Leucetta microraphis, as well as the ascidian Polycarpa aurata (Figure 28E),28E), are the sources of 13 imidazole alkaloids, which were as the ascidian Polycarpa aurata (Figure 28E), are the sources of 13 imidazole alkaloids, which were isolated asas freefree bases bases (8) (8) and and salts salts (5 molecules)(5 molecules) (Figure (Figures 28A–C, 28A–C, S 15, TableS15, S15).Table CompoundS15). Compound483 retains 483 isolated as free bases (8) and salts (5 molecules) (Figures 28A–C, S15, Table S15). Compound 483 1retains new skeleton, 1 new skeleton, while four while compounds, four compounds,475, 484, 485 475, and, 484487, 485, have, and rare 487 structural, have rare motifs structural (Figure motifs 28D). (Figureretains 128D). new Withskeleton, regard while to biologicalfour compounds, activity, 475significant, 484, 485 antifungal, and 487 ,(1) have and rare cytotoxic structural activity motifs (3 (Figure 28D). With regard to biological activity, significant antifungal (1) and cytotoxic activity (3

Mar. Drugs 2019, 17, 364 32 of 69

WithMar. regard Drugs to2019 biological, 17, x FOR PEER activity, REVIEW signiﬁcant antifungal (1) and cytotoxic activity (3 molecules)32 of 71 was found (Figure 28E). The sources of imidazole alkaloids were collected at 3 regions (NSW, 6; SSW, 5; molecules) was found (Figure 28E). The sources of imidazole alkaloids were collected at 3 regions MLU, 2 molecules). (NSW, 6; SSW, 5; MLU, 2 molecules).

A OH OMe OH O O OMe H N N O N O H N O O H2N 2 N N N H H OH NHMe OMe 483 484 OH (+)-475 O HN O CF3 OMe NH2 MeN H N Me S N OMe H2N HN N S N Me O H2 O SO O O CF3 OMe 485 487

B C D

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

Figure 28. Structures of marine imidazole alkaloids from Indonesian waters found in 1970–2017: (A) Figurerepresentative. 28. Structures Distribution of marine of imidazolethe alkaloids alkaloids by year from (B). IndonesianStatistics of watersimidazole found alkaloids in 1970–2017: (C). (A) representative.Distribution of new Distribution marine imidazole of the alkaloids alkaloids on bythe yearbasis of (B their). Statistics chemical of skeletons imidazole (D), biological alkaloids (C). Distributionsources ( ofE), new and marinebiogeography imidazole (F). alkaloids on the basis of their chemical skeletons (D), biological sources (E), and biogeography (F). Lissodendrins A (483) and B (484) (Figures 28A, S15), 2-amino imidazole alkaloids, were isolated Lissodendrinsfrom the sponge A Lissodendoryx (483) and B(Acanthodoryx (484) (Figure) fibrosa 28A, collected Figure off S15), Ambon, 2-amino MLU imidazole [81]. The latter alkaloids, were isolated from the sponge Lissodendoryx (Acanthodoryx) ﬁbrosa collected oﬀ Ambon, MLU [81]. The latter compound contains a (p-hydroxyphenyl)glyoxal moiety as an unprecedented skeleton.

A plausible biosynthetic scheme for these compounds was proposed, as in Figure 29[81]. Mar. Drugs 2019, 17, x FOR PEER REVIEW 33 of 71 Mar. Drugs 2019, 17, x FOR PEER REVIEW 33 of 71 compound contains a (p-hydroxyphenyl)glyoxal moiety as an unprecedented skeleton. A plausible Mar.compound Drugs 2019, 17 contains, 364 a (p-hydroxyphenyl)glyoxal moiety as an unprecedented skeleton. A plausible33 of 69 biosynthetic scheme for these compounds was proposed, as in Figure 29 [81]. biosynthetic scheme for these compounds was proposed, as in Figure 29 [81].

FigureFigure 29. 29.The The plausible plausible biosynthetic biosynthetic pathway of of lissodendrins lissodendrins A A483483 andand B 484 B 484. . Figure 29. The plausible biosynthetic pathway of lissodendrins A 483 and B 484. 2.3.9.2.3.9. Polysulfur Polysulfur Aromatic Aromatic Alkaloids Alkaloids 2.3.9. Polysulfur Aromatic Alkaloids PolysulfurPolysulfur aromatic aromatic alkaloids alkaloids are are anan unusualunusual class of of MNPs. MNPs. To To date, date, there there have have been been 14 MNPs 14 MNPs Polysulfur aromatic alkaloids are an unusual class of MNPs. To date, there have been 14 MNPs isolatedisolated as as salts salts (Figure (Figures 30 30A–C,A–C, Figure S16, and S16, Table and S16). Table The S16). polysulfur The polysulfur aromatic alkaloids aromatic were alkaloids reported were isolated as salts (Figures 30A–C, S16, and Table S16). The polysulfur aromatic alkaloids were reported reportedin 2005 in (3), 2005 2007 (3), (6), 2007 and (6), 2009 and (5 2009 molecules) (5 molecules) (Figure (Figure30B). The 30 B).first The discovery ﬁrst discovery of this group of this was group in 2005 (3), 2007 (6), and 2009 (5 molecules) (Figure 30B). The first discovery of this group was lissoclibadin 1 (498) [82]. Three molecules, 498, 499 and 501, of polysulfur aromatic alkaloids retain waslissoclibadin lissoclibadin 1 ( 1498 (498) [82].)[82 Three]. Three molecules, molecules, 498, 499498 and, 499 501and, of501 polysulfur, of polysulfur aromatic aromatic alkaloids alkaloids retain new skeletons. With respect to biological activity, significant cytotoxic (12), antibacterial (7), and retainnew new skeletons. skeletons. With With respect respect to biological to biological activity activity,, significant signiﬁcant cytotoxic cytotoxic (12), antibacterial (12), antibacterial (7), and (7), antifungal activity (1 molecule) was reported (Figure 30D). All the molecules were found from andantifungal antifungal activity activity (1 (1 molecule) molecule) was was reported reported (F (Figureigure 30D). 30D). All All the the molecules molecules were were found found from from Lissoclinum cf. badium collected in NSW. LissoclinumLissoclinumcf. badiumcf. badiumcollected collected in in NSW. NSW.

A A

B C D B C D 6 6

5 5

4 4

3 3

2 2

1 1

0 0 1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

Figure 30. Structures of marine polysulfur aromatic alkaloids from Indonesian waters found in

1970–2017: (A) representative. Distribution of the alkaloids by year (B). Statistics of polysulfur aromatic alkaloids (C). Distribution of new marine polysulfur aromatic-containing alkaloids on the basis of their biological activity (D). Mar. Drugs 2019, 17, x FOR PEER REVIEW 34 of 71

Figure 30. Structures of marine polysulfur aromatic alkaloids from Indonesian waters found in 1970– 2017: (A) representative. Distribution of the alkaloids by year (B). Statistics of polysulfur aromatic Mar. Drugsalkaloids2019, 17(C,). 364 Distribution of new marine polysulfur aromatic-containing alkaloids on the basis of34 of 69 their biological activity (D). 2.3.10. Serine-Derived Alkaloids 2.3.10. Serine-Derived Alkaloids A total of 15 serine-derived alkaloids have been discovered (Figure 31A–C, Figure S17, Table S17). A total of 15 serine-derived alkaloids have been discovered (Figures 31A–C, S17, Table S17). Among them, 2 molecules, 503a and 504a, were revised to 503b and 504b. All the alkaloids share Among them, 2 molecules, 503a and 504a, were revised to 503b and 504b. All the alkaloids share a a common structural feature: 6,8-dioxabicyclo[3.2.1]octane (6,8-DOBCOs). One of them, 502, possesses common structural feature: 6,8-dioxabicyclo[3.2.1]octane (6,8-DOBCOs). One of them, 502, possesses a new skeleton. The ﬁrst discovery in this group was reported in 1999 (3 molecules), which was a new skeleton. The first discovery in this group was reported in 1999 (3 molecules), which was followed by another 12 molecules before 2013 (Figure 31B). The ACs were determined for 505 by ECD followed by another 12 molecules before 2013 (Figure 31B). The ACs were determined for 505 by ECD and for 503b, 504b and 505 by total synthesis. With regard to biological activities, signiﬁcant anticancer and for 503b, 504b and 505 by total synthesis. With regard to biological activities, significant activity without cytotoxicity was reported for 4 molecules. Tunicates were proved as the sole source of anticancer activity without cytotoxicity was reported for 4 molecules. Tunicates were proved as the this class of MNPs. The majority of the molecules were isolated from specimens collected in NSW (12) sole source of this class of MNPs. The majority of the molecules were isolated from specimens and NMU (3 molecules). collected in NSW (12) and NMU (3 molecules).

31 A (+)-502 R1 = O OH NH OH 2 R2 = Ac, R3 =

O 31 (+)-503a R1 = O OH OEt NH2 R2 =Me,R3 =

O 31 30 (+)-503b R1 = O OSO Na R1 OR 3 O 2 H OEt NH2 R2 =Me,R3 = O H O 31 R H 3 (+)-504a R1 = O OH NH OH 2 R2 =H,R3 = 31 O 30 (+)-504b R1 = O OSO3Na NH OH 2 R2 =H,R3 = NHSO3H O O HO (+)-505 R1 = OAc O O O R2 = Ac, R3 = O P NMe3 O O

B C D 12

10 9 8 7 6 5 4 3 2 1 0

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

Figure 31. Cont.

Mar. Drugs 2019, 17, x FOR PEER REVIEW 35 of 71

E Mar. Drugs 2019, 17, 364 35 of 69 Mar. Drugs 2019, 17, x FOR PEER REVIEW 35 of 71

Figure 31. Structures of marine serine-containing alkaloids from Indonesian waters found in 1970–

2017: (A) representative. Distribution of the alkaloids by year (B). Statistics of the alkaloids (C). DistributionFigureFigure 31. 31.ofStructures Structuresmarine of serine-containing marineof marine serine-containing serine-containing alkalo alkaloidsids alkaloids on fromthe from Indonesianbasis Indonesian of their waters waters chemical found found in 1970–2017:inskeleton 1970– (D), (A) representative. Distribution of the alkaloids by year (B). Statistics of the alkaloids (C). Distribution biological2017: source (A) representative. (E), and biogeography Distribution (ofF). the alkaloids by year (B). Statistics of the alkaloids (C). of marineDistribution serine-containing of marine serine-containing alkaloids on the basisalkalo ofids their on chemicalthe basis skeletonof their (Dchemical), biological skeleton source (D (),E ), andbiological biogeography source ( F(E).), and biogeography (F). 2.3.11. Other Marine Alkaloids 2.3.11. Other Marine Alkaloids A 2.3.11.total ofOther 33 Marinealkaloids Alkaloids do not belong to the above structural classes. They are comprised of a pyrroloimino-quinone,A totalA total of of 33 33 alkaloids alkaloids five ceramides, do do not not belongbelong 15 totetramicto the ab aboveove acids, structural structural two nucleosides,classes. classes. They They are two are comprised comprisedformamides, of a of one polycyclica pyrroloimino-quinone,pyrroloimino-quinone, diamine, one pterin, ﬁvefive ceramides,twoceramides, thiadiazoles, 15 tetramic one acids, pyrazole, two two nucleosides, nucleosides,one azirine, two twotwo formamides, formamides,simple amine/amide one one polycyclic diamine, one pterin, two thiadiazoles, one pyrazole, one azirine, two simple amine/amide alkaloidspolycyclic (2 molecules) diamine, (Figuresone pterin, 32A–C, two thiadiazoles, S18, Table one S18). pyrazole, Of 33 one molecules, azirine, two seven, simple amine/amide538, 540, 541 , 544, alkaloidsalkaloids (2 (2 molecules) molecules) (Figure (Figures 32 32A–C,A–C, Figure S18, Table S18, S18). Table Of S18). 33 molecules, Of 33 molecules, seven, 538 seven,, 540, 541538, 544, 540, , 548, 549, and 551, contain rare structural motifs. ACs of three molecules, 524, 525 and 538, were 541548, 544, 549, 548, ,and549 551, and, contain551, contain rare structural rare structural motifs. motifs. ACs of ACsthree of molecules, three molecules, 524, 525524 and, 525 538and, were538 , determinedweredetermined determined by ECD. by by ECD. With ECD. With Withregard regard regard to tobiological to biological biological activiactivi activities,ties,ties, cytotoxicity cytotoxicity cytotoxicity and and and antibacterial antibacterial antibacterial activity activity activity were were were seenseen seenin in 44 andin and 34 molecules, and3 3molecules, respectively,molecules, whereasrespectivelyrespectively antifungal,,, whereaswhereas immunosuppresive, antifungal,antifungal, immunosuppresive, immunomodulatory, immunosuppresive, immunomodulatory,neurological,immunomodulatory, and electrophysiologicalneurolog neurological,ical, and and electrophysiological activity electrophysiological were shown activity inactivity one were molecule were shown shown each in one (Figurein molecule one 32moleculeD). eachThe (Figureeach sources (Figure 32D). of the32D). The molecules Thesources sources are of 10ofthe spongethe molecules molecules species are and 1010 2sponge sponge tunicates species species (Figure and and 322 tunicatesE). 2 Thetunicates majority (Figure (Figure 32E). of the 32E). Thealkaloids majorityThe majority were of the found of alkaloids the from alkaloids specimens were were found fromfound SSWfrom from (19), specimensspecimens MLU (4), from from NSW SSW SSW (2), (19), EKM (19), MLU (2), MLU and(4), NSW BLI(4), (1 NSW(2), molecule) EKM (2), EKM (2), and BLI (1 molecule) (Figure 32F). (2), (Figureand BLI 32 (1F). molecule) (Figure 32F).

A A

Figure 32. Cont.

Mar. Drugs 2019, 17, 364 36 of 69 Mar. Drugs 2019, 17, x FOR PEER REVIEW 36 of 71

13 12 B C

11 10 9 8 7 6 5 4 3

2 1 0

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016

D E

FigureFigure 32. 32. StructuresStructures of of other other marine marine alkaloids alkaloids from from Indonesian Indonesian waters waters found found in 1970–2017: in 1970–2017: (A) (Arepresentative.) representative. Distribution Distribution of other of othermarine marine alkaloids alkaloids by year by (B). year Statistics (B). Statistics of other marine of other alkaloids marine alkaloids(C). Distribution (C). Distribution of other marine of other alkaloid marines alkaloidson the basis on of the biological basis of activity biological (D), activity biological (D), source biological (E), sourceand biogeography (E), and biogeography (F). (F).

BioorganicBioorganic studies studies ofof melophlinmelophlin AA ((523)523) toto dynaminsdynamins IIII andand I-likeI-like proteins in cells, thereby thereby modulatingmodulating signal signal transduction transduction through through the the Ras Ras network,network, waswas conductedconducted by using a surface surface plasmon plasmon resonanceresonance (SPR) (SPR) [83 [83].]. Furthermore, Furthermore, Mg Mg oror ZnZn complexescomplexes ofof 523 are antiproliferative in various various cancer cancer cells,cells, while while they they areare lessless toxic to normal normal fibroblasts. ﬁbroblasts. The The complexes complexes dissolve dissolve more more in water in water than than Ca Caanalogue analogue [84]. [84 ].Melophlin Melophlin A A(523 (523) )also also exhibited exhibited anti-dormant anti-dormant mycobacterial mycobacterial activity activity [85] [85] and and cytotoxicitycytotoxicity against against L1210 L1210 cells cells [ 86[86].]. The The inﬂuenceinfluence ofof 523523 onon the colony formation of Chinese Chinese hamster hamster V79V79 lung lung cells cells and and of the of productionthe produc oftion interleukin of interleukin (IL)-8 in(IL)-8 phorbol in phorbol myristate myristate acetate (PMA)-stimulated acetate (PMA)- HL60stimulated cells were HL60 examined cells were [87 examined]. [87]. TwoTwo alkaloids alkaloids containingcontaining an uncommon 1,2,4-thiadiazole 1,2,4-thiadiazole ring ring named named polycarpathiamines polycarpathiamines A A((544544) and) and B ( B545 (545) (Figure) (Figure 32B) 32wereB) wereisolated isolated from the from ascidian the ascidian PolycarpaPolycarpa aurata collected aurata incollected MLU [46]. in MLUThe [structures46]. The structures of 544 and of 544 545and were545 wereelucidated elucidated by spectroscopic by spectroscopic methods methods and and by by synthesis. synthesis. PolycarpathiaminePolycarpathiamine A A ( 544(544)) showed showed cytotoxicity cytotoxicity toto L5178YL5178Y cells.cells. The biosynthetic relation relation of of 544544 andand 545545was was proposed proposed as as shown shown in in Figure Figure 33 33..

Mar. Drugs 2019, 17, 364 37 of 69 Mar.Mar. Drugs Drugs 2019 2019, 17, 17, x, xFOR FOR PEER PEER REVIEW REVIEW 3737 of of 71 71

FigureFigure 33. 33. PlausiblePlausible Plausible biosynthetic biosynthetic relation relation of of polycarpathiamines polycarpathiamines A A 544 544 and and B B 545 545. . 2.4. Peptides 2.4.2.4. Peptides Peptides MarineMarine peptides peptides have have emerged emerged as as a a very very importantimport importantant class class of of bioactive bioactive compound compound in in Indonesian Indonesian MNPs.MNPs. The TheThe class class is is iscomprised comprised comprised of of 60 of60 natural 60natural natural and and 6 and 6 revised revised 6 revised MNPs MNPs MNPs(Figures (Figures (Figure 34A–C, 34A–C, 34 S19, A–C,S19, Table Table Figure 19). 19). S19,The The Tablenaturalnatural S19). peptides peptides The can naturalcan be be grou peptidesgroupedped into: into: can linear belinear grouped dipeptides, dipeptides, into: 552 552 linear––557557, , dipeptides,aa linear linear tridecapeptide, tridecapeptide,552–557, a 590 linear590, ,a a cyclotetrapeptide,tridecapeptide,cyclotetrapeptide,590 608 ,608 a, cyclotetrapeptide, ,two two cyclopentapeptides, cyclopentapeptides,608, two 604 604 cyclopentapeptides,––605605, ,cyclohexapeptides, cyclohexapeptides,604–605 558 ,558 cyclohexapeptides,––563563, ,cyclohepta- cyclohepta- peptides,558peptides,–563, cyclohepta-peptides,564 564––570570, ,a a cyclooctapeptide, cyclooctapeptide,564–570 ,571 571 a cyclooctapeptide,, ,cycloundecapeptides, cycloundecapeptides,571, cycloundecapeptides,572a 572a––575575, ,cyclopeptides cyclopeptides572a with with–575 a ,a linearcyclopeptideslinear peptidic peptidic withchain, chain, a 576a linear576a, ,577 577 peptidic––579579, ,580a 580a chain,, ,581 581576a, ,582b 582b, 577, ,583 –583579––588,588580a, ,and and, 581 606 606,–582b–607,607, ,and and583 –cyclodepsipeptide, cyclodepsipeptide,588, and 606–607, 591aand591a cyclodepsipeptide,––603603, , cyclodepsipeptidecyclodepsipeptide591a– 603 withwith, cyclodepsipeptide aa sideside chain,chain, 589 with589, , and aand side macrocyclicmacrocyclic chain, 589 , andpeptides,peptides, macrocyclic 609609––611611 peptides,. . NineNine molecules,609molecules,–611. Nine 553 553 molecules,, ,561 561, ,564 564, 553,589 589,, 561,590 590,,564 ,591a 591a, 589, ,593 ,593590, ,595 ,595591a, ,and and, 593 602 602, 595, ,are ,are and categorized categorized602, are categorized as as having having as rare rare having FG FG and rare and structuralFGstructural and structural motifs. motifs. motifs.After After their their After first first their discovery discovery ﬁrst discovery in in 199 1996, in6, the 1996,the number number the number of of Indonesian Indonesian of Indonesian marine marine marine peptides peptides peptides has has kepthaskept kept increasing increasing increasing until until until now. now. now. The The The ACs ACs ACs of of ofpeptides peptides peptides (41 (41 (41 molecules) molecules) molecules) have have have generally generally been beenbeen determined determineddetermined by by MarfeyMarfey analysis.analysis. analysis. OnlyOnly Only 3 3 peptides,3 peptides, peptides,553 553 ,553565, ,565 and565 and 566band 566b ,566b were, ,were solvedwere solved solved by X-ray by by X-ray crystallography. X-ray crystallography. crystallography. With respect With With respecttorespect biological to to biological biological activity, activity, 20activity, peptides 20 20 peptides peptides were reported were were repo repo to bertedrted cytotoxic, to to be be cytotoxic, cytotoxic, followed followed followed by 4 with by by antifungal,4 4 with with antifungal, antifungal, 3 each with33 eacheach antibacterial withwith antibacterialantibacterial and antiviral, andand antiviral,antiviral, and one and eachand one withone eacheach anti-inﬂammatory withwith anti-inflammatoryanti-inflammatory and antiparasitic andand antiparasiticantiparasitic activities (Figureactivitiesactivities 34 (Figure E).(Figure Indonesian 34E). 34E). Indonesian Indonesian marine peptides marine marine havepeptidespeptides been have have found been been from found found 4 phyla from from (Rhodophyta,4 4 phyla phyla (Rhodophyta, (Rhodophyta, Porifera, Porifera,Chordata,Porifera, Chordata, andChordata, Mollusca). andand OnMollusca).Mollusca). the biogeography, OnOn thethe biogeography,biogeography, MLU (18 molecules) MLUMLU and (18(18 NSW molecules)molecules) (14 molecules) andand NSWNSW are the(14(14 molecules)topmolecules) places forare are the the the discovery top top places places of for for Indonesian the the discovery discovery marine of of Indonesian peptidesIndonesian (Figure marine marine 34 peptidesF). peptides (Figure (Figure 34F). 34F).

OO NHNH2 AA SS 2 OO HNHN NHNH ClCl ClCl NH OO NN Cl NH NH Cl OO NH NHNH OO OO NN OO HH NN OO NN HN N O HN SS N H O H OO OMeOMe N O O N ClCl N N O O N N OSOOSONa3Na HNHN OO 3 OO ClCl OO HOHO NHNH (+)-553(+)-553 SS NHNH OO ( ()-561)-561 HH NN OO OO NH NH O SS OO O O ( ()-564)-564 OH NNNN O OH NN H HH H O N NN O N NN HH NN OO OO OO

( ()-565)-565

Figure 34. Cont. FigureFigure 34A. 34A. Cont. Cont.

Mar. Drugs 2019, 17, 364 38 of 69 Mar. Drugs 2019, 17, x FOR PEER REVIEW 38 of 71

H N O NH2

SO H O O O O O 3 O H H H H H N N N N N H N N N N N N H H H H Me O O O O O O O OH H N N NH O HO O Br H2N NH (+)-589 Cl O

O O O Me Me Me O N N N S Me O N N N S O N NH Me Me H O O NH O NMe OMeN H N O 2 H O O N HN O NH HO NH MeN O O ( )-590 O O H O O OH H OH HN N N O NMe H O O O Me H N N O N N Me O O Me ( )-591a

O O NH Me 2 N N H O SOMe O H O NH O O N Me H N NH N O H O N NH O Me HO O O O HN O H H N NH O NH HO NH O O O O H O O NMe O HN H H H H O MeN N N N N O N N H H H Me O O O O ( )-591b Cl ( )-593

O NH2 OPO H O 3 2 H NH N O N HN H NH HO O MeN O O CONH2 S O HN HN OH O O O S HN O Et H2N HN O NH HN ( )-595 O O

( )-604

Figure 34. Cont.

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B C D 10 60 9 20 8 7 6 3 4 3 5 1 1 4 3

6 Antiviral

2 Cytotoxic

Antifungal Antiparasite 1 Antibacterial Original new MNPs 0 Anti-inflammatory

Revised MNPs (New)

1976 1981 1986 1991 1996 2001 2006 2011 2016 1971 E Ceratodictyon spongiosum 2 Diazona sp. 3 Lissoclinum bistratum 2 Pleurobranchus forskalii 1 Daedalopelta sp. 1 Jaspis splendens 2 Siliquariaspongia mirabilis 6 Sidonops microspinosa 1 Callyspongia aerizussa 14 Ircinia dendroides 1 Stylissa sp. 1 Stylissa carteri 2 Clathria basilana 5 Theonella cupola 1 Theonella swinhoei 8 Haliclona sp. 1 Dysidea sp. 7

F 18 14

5 6 4 3 4

2 1 1 2

BLI

BBI

EJV

JMI JMI

SES

SST

CJV

SRY

UEP

LPG

SRA

ENT

NST

BTN

PUA

WJV

BKU

SSW

RAU

WST

CSW GTO

EKM

SKM

MLU

JSCR

NSW

CKM

WNT

NKM NMU

WSW

WKM SRWP

Figure 34. Structures of marine peptides from Indonesian waters found in 1970–2017: (A) representative. Distribution of marine peptides by year (B). Statistics of marine peptides (C). Distribution of marine Figure 34. Structures of marine peptides from Indonesian waters found in 1970–2017: (A) peptides on the basis of biological activity (D), biological source (E), and biogeography (F). representative. Distribution of marine peptides by year (B). Statistics of marine peptides (C). 2.5. FattyDistribution Acids and of Linear marine Molecules peptides on the basis of biological activity (D), biological source (E), and biogeography (F). A total of 13 (or 12) Indonesian marine fatty acids or linear molecules, probably biosynthesized through2.5. Fatty acetate Acids pathways,and Linear Molecules have been reported, and they were characterized by the presence of double or triple bonds or their combination, ranging from 1 to 7 (Figure 35A, Figure S20, Table S20). After the A total of 13 (or 12) Indonesian marine fatty acids or linear molecules, probably biosynthesized first discovery of (–)-elenic acid (612) in 1995, this group of metabolites has been reported continuously through acetate pathways, have been reported, and they were characterized by the presence of (Figure 35B). Of 13 molecules, one showed cytotoxicity, three showed neurological, and five showed double or triple bonds or their combination, ranging from 1 to 7 (Figures 35A, S20, Table S20). After antihyperlipidemic activity (Figure 35D). The ACs of the metabolites were determined by modified the first discovery of (–)-elenic acid (612) in 1995, this group of metabolites has been reported Mosher’s method for 615–619, and by total synthesis for 613 and 615–617. With respect to biological continuously (Figure 35B). Of 13 molecules, one showed cytotoxicity, three showed neurological, and sources, 12 molecules were found from Porifera and 1 from Ascomycota (Figure 35E). All the molecules five showed antihyperlipidemic activity (Figure 35D). The ACs of the metabolites were determined wereby modified isolated Mosher’s from specimens method for collected 615–619 in, and NSW by (5),total MLU synthesis (3), SSWfor 613 and and ENT 615– (2617 each),. With and respect UEP (1to molecule). biological sources, 12 molecules were found from Porifera and 1 from Ascomycota (Figure 35E). All the molecules were isolated from specimens collected in NSW (5), MLU (3), SSW and ENT (2 each), and UEP (1 molecule).

Mar. Drugs 2019, 17, x FOR PEER REVIEW 40 of 71

Mar. Drugs 2019, 17, 364 40 of 69

(+)-620

B C

3 D 4 3

2 1 11111

swinhoei

Theonella

0 sp. Haliclona Callyspongia Lendenfeldia sp. Cinachyrella sp. (Ascomycota) pseudoreticulata sp. Callyspongia Plakinastrella sp. Plakinastrella Uknown unknown Uknown 1971 1976 1981 1986 1991 1996 2001 2006 2011 2016 E

FigureFigure 35. 35.Structures Structures of of fatty fatty acidsacids andand linearlinear molecules from Indonesian Indonesian waters waters found found in in 1970–2017: 1970–2017: (A(A) representative.) representative. Distribution Distribution ofof thisthis groupgroup ofof metabolitesmetabolites by by year year ( (BB).). Distribution Distribution of of marine marine fatty fatty acidacid on on the the basis basis of of their their biological biological activity activity ((CC),), biologicalbiological sourcesource (D), and biogeography biogeography ( (EE).).

2.6.2.6. Polyketides Polyketides SeveralSeveral polyketidespolyketides have been been discovered discovered in inIndonesian Indonesian waters, waters, particularly particularly since since1995. The 1995. Themolecules molecules can can be begrouped grouped into into 121 121 natural, natural, 13 13mixtures, mixtures, and and 10 10revised revised molecules molecules (Figures (Figure 36A–C, 36A–C, FigureS21 and S21 Table and S21). Table Of S21). 121 Ofpolyketides, 121 polyketides, significant significant biological biological activities activitieswere observed, were observed,with 11 withcytotoxic, 11 cytotoxic, 9 antiparasitic, 9 antiparasitic, 8 antibacteria 8 antibacterial,l, 7 anticancer 7 without anticancer cytotoxicity, without 4 cytotoxicity, cytostatic, and 4 cytostatic,3 each of andantifungal 3 each of and antifungal growth andrestoring growth activity restoring (Figure activity 36D). (Figure Polyketides 36D). can Polyketides be classified can beinto classified 9 different into 9structural different structuralgroups, consisting groups, consistingof 2 polyols, of 18 2 polyols,cyclic peroxides, 18 cyclic 34 peroxides, aromatic 34polyketides, aromatic polyketides,1 vertinoid 1polyketide, vertinoid polyketide, 6 γ-lactones, 6 γ10-lactones, δ-lactones, 10 16δ-lactones, macrolides, 16 33 macrolides, quinones, 33and quinones, 4 halogenated and 4 polyketides. halogenated polyketides.Stereo or regiochemist Stereo or regiochemistryry of four molecules of four molecules659b, 687–659b688 ,and687 –705688 andwere705 determinedwere determined by X-ray by X-raycrystallography, crystallography, while while the theACs ACs of 21 of molecule 21 moleculess were were determined determined by byECD. ECD. Seven Seven structures, structures, 659a659a, , 663a663a, 664a, 664a, 689a, 689a, ,692a 692a, ,693a 693a,, and and 701a701a,, werewere revisedrevised to to 659b659b,, 663b663b, ,664b664b, ,689b689b, ,692b692b, 693b, 693b, and, and 701b701b. . InIn addition, addition, fourfour molecules, 661a661a, ,662a662a, 665a, 665a, 666a, 666a, were, were revised revised twice twice as 661b as 661b1 to 661b1 to2,661b 662b21, to662b 662b1 2to, 662b2, 665b1 to 665b2, and 666b1 to 666b2. The revision was made by reisolation work, total synthesis, and X-ray analysis. For large molecules, such as 625 and 626, structure elucidation was aided by chemical Mar.Mar. Drugs Drugs2019 2019,,17 17,, 364 x FOR PEER REVIEW 41 ofof 6971

In addition, four molecules, 661a, 662a, 665a, 666a, were revised twice as 661b1 to 661b2, 662b1 to 662b2, degradation. The polyketides were isolated from specimens of 5 phyla: Ascomycota (35 molecules), 665b1 to 665b2, , Porifera (78 molecules), and Chordata (2 molecules). Ciliophora (2 molecules), Rhodophyta (1 molecule), Porifera (78 molecules), and Chordata (2 molecules).

19 B C 18 17 121 16 15 14 13 12 11 10 9 8 13 10 7 5 6 5 4 Isolated as a mixture of MNPs 3 2 Original new MNPs 1 0 Revised MNPs (New)

2016 1976 1981 1986 1991 1996 2001 2006 2011 1971 Revised MNPs (Known)

Figure 36. Cont.

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Cont. Figure 36.

Mar. Drugs 2019, 17, 364 43 of 69 Mar. Drugs 2019, 17, x FOR PEER REVIEW 43 of 71 Mar. Drugs 2019, 17, x FOR PEER REVIEW 43 of 71

F F

FigureFigure 36. 36. StructuresStructuresStructures ofof ofmarinemarine marine polyketides polyketides from from Indonesian Indonesian waterswaters waters foundfound found inin 1970–2017:1970–2017: in 1970–2017: (A(A) ) (representative.Arepresentative.) representative. DistributionDistribution Distribution ofof marine ofmarine marine polyketides polyketides by by year year (BB ().).B ).StatisticsStatistics Statistics ofof of marinemarine marine polyketidespolyketides polyketides ( C( (CC).). ). DistributionDistribution ofof marinemarine polyketidepolyketide on th thee basis of their biological activityactivity (( DD),), biologicalbiological source source ( E( E),), andand biogeography biogeography (F(F).).).

2.7.2.7. Carbohydrates Carbohydrates OneOne eacheach each of ofof carbohydrates carbohydratescarbohydrates746 746746and andand747 747(Figure (Figure 37 37))37) was waswas isolated isolatedisolated from fromfrom a soft aa softsoft coral coralcoralSinularia Sinularia Sinulariasp. sp. and sp. fromandand from from the tunicatethe the tunicate tunicateDidemnum Didemnum Didemnum molle mollemollecollected collected in in NSW. NSW. Sinularioside Sinularioside ( 746 ((746746),),), a a a triacetylatedtriacetylated triacetylated glycolipid, glycolipid,glycolipid, containscontains two two α α-D-arabinopyranoses-D-arabinopyranoses and and a myristyl alcohol [88].[88]. [88]. TheThe The structurestructure structure ofof 747 747 was was solved solved by by interpretationinterpretation ofof of MSMS MS andand and NMRNMRNMR data,data,data, alongalongalong withwith ECD analysis of of degradation products. products. Molecule Molecule 746 746 waswas provedproved proved toto to inhibit inhibitinhibit LPS-inducedLPS-inducedLPS-induced nitricnitricnitric oxideoxide (NO)(NO) release.release. A A polysaccharide, polysaccharide, kakelokelosekakelokelose ( 747( 747),), 1 13 inhibitedinhibited thethe proliferationproliferatioproliferationn ofof HIV.HIV. AnalysisAnalysisAnalysis ofof 1HH andand 1313CC NMR NMR data data of of the the polysaccharide polysaccharidepolysaccharide and and its its desulfateddesulfated derivativederivative revealedrevealed thatthat itit consistedconsisted of a sequence of of 2,3-disulfated 2,3-disulfated mannose mannose units units joined joined throughthrough β β-1,6-1,6 glycosidicglycosidic linkages.linkageslinkages..

O OO NaNa SS O O OO Na OO OO Na OH OO SS OH HO OO O O O OO O O O OONa O OAc HO O S Na OAc HOO OO O S O O O O O OAc O S O O O O Na O S OO HO O O S O Na O HOO O O S O O O O O O OO S O O O OH Na S O HO O OH Na O HOO O O O OAc Na O O S O OAc Na SO O O ( )-747 O (+)-746 ( )-747 Na O (+)-746 Na Figure 37. Structures of marine carbohydrates from Indonesian waters in 1970–2017. Figure 37. Structures of marine carbohydrates from Indonesian waters in 1970–2017.

3. Conclusions 3. Conclusions Over the past 47 years (from January 1970 to December 2017), 732 new natural products, 4 Over the past 47 47 years years (from (from January January 1970 1970 to to December December 2017), 2017), 732 732 new new natural natural products, products, 4 compounds isolated for the first time as natural products but known previously as synthetic entities, 4compounds compounds isolated isolated for for the the first first time time as as natural natural prod productsucts but but known known previously previously as as synthetic synthetic entities, entities, 34 compounds with structural revision, and 9 derivative compounds have appeared in 270 papers. 34 compounds with structural revision, and 9 derivative compounds have appeared in 270 papers. Currently, have been over 29,000 MNPs [89] discovered since the first report of spongothymidine in Currently, havehave beenbeen overover 29,00029,000 MNPsMNPs [[89]89] discovereddiscovered sincesince the firstfirst reportreport ofof spongothymidinespongothymidine in 1950 [90,91]. Original Indonesian MNPs have largely been found in Porifera, Cnidaria and Chordata, 1950 [[90,91].90,91]. Original Indonesian MNPs have largely been found in Porifera, Cnidaria and Chordata, while the global trends are Porifera, Cnidaria, and Ascomycota [89]. In addition to the three phyla, while the globalglobal trends areare Porifera,Porifera, Cnidaria,Cnidaria, and Ascomycota [[89].89]. In addition to the three phyla, Indonesian MNPs have been found in 94 species, 106 genera, 64 families, 32 orders, and 14 classes. Indonesian MNPs have been found in 94 species, 106 genera, 64 64 families, 32 32 orders, orders, and and 14 14 classes. classes. The chemical diversity of Indonesian MNPs has been substantiated on the basis of 28 compounds The chemical diversity of IndonesianIndonesian MNPs has been substantiated on the basis of 2828 compoundscompounds with new skeletons and 62 molecules with rare structural motifs and FGs, while atomic diversity is with new skeletonsskeletons and 62 moleculesmolecules with rare structuralstructural motifs and FGs, while atomic diversity is manifestedmanifested inin 2727 moleculesmolecules withwith 66 didifferentfferent atomsatoms inin 11 molecule.molecule. Of Of 732 732 molecules, molecules, 373 373 (51.0%) (51.0%) are are manifestednitrogenous. in In27 addition, molecules 122 with molecules 6 different (16.7%) atoms possess in 1ed molecule. a ratio of Of H/C 732 < 1.molecules, Of 34 defined 373 provinces,(51.0%) are nitrogenous.18 (NST, WST, In addition,BTN, JSCR, 122 WJV, molecules CJV, BLI,(16.7%) ENT, possess EKM,ed NSW, a ratio GTO, of H/C CSW, < 1. SSW,Of 34 SES,defined NMU, provinces, MLU, 18 (NST, WST, BTN, JSCR, WJV, CJV, BLI, ENT, EKM, NSW, GTO, CSW, SSW, SES, NMU, MLU,

Mar. Drugs 2019, 17, 364 44 of 69 nitrogenous. In addition, 122 molecules (16.7%) possessed a ratio of H/C < 1. Of 34 defined provinces, 18 (NST, WST, BTN, JSCR, WJV, CJV, BLI, ENT, EKM, NSW, GTO, CSW, SSW, SES, NMU, MLU, SRWP, and PUA) have been reported as collection sites for new MNPs. Among these, NSW, MLU, SSW, BLI, and EKM were the major regions for specimens, while there still remain underexplored regions with vast areas, like MLU, even though a certain number of MNPs have already been discovered. A large number of Indonesian marine macro- and microorganisms are still underexplored, and they may provide inspiration for many chemical entities. The significant biological activity of Indonesian MNPs is dominated by cytotoxicity (16.7%), followed by antibacterial activity (5.9%). By exploring untapped novel groups of organisms and by proposing newer biological targets, MNP researchers may be able to enhance the search for new marine drugs to treat human diseases. Moreover, careful and innovative techniques for the MNPs isolation are required for identification of new structures and activities including unstable intermediates [92]. The establishment of the Nagoya Protocols on the Convention on Biological Diversity (CBD) in 2010 has had a positive impact on global biodiversity especially in Indonesia by encouraging productive interaction between biodiversity-rich source countries and the more science and technology-advanced countries. International natural product researchers are strongly urged to be guided by the CBD principles in a fair and equitable framework that includes access and benefit-sharing [93]. These interactions will be crucial for conserving our global biodiversity [94] and providing valuable new MNPs for humankind. Therefore, the current primary issues in marine conservation, such as the loss of biodiversity through over-exploitation and habitat degradation, can be overcome. Additional information can be found in the Supplementary Materials [95–488].

Supplementary Materials: The following are available online at http://www.mdpi.com/1660-3397/17/6/364/s1, Figure S1: Structures of marine sesquiterpenoids from Indonesian waters found in 1970–2017, Table S1: Marine sesquiterpenoids from Indonesian waters found in 1970–2017, Figure S2: Structures of marine diterpenoids from Indonesian waters found in 1970–2017, Table S2: Marine diterpenoids from Indonesian waters found in 1970–2017, Figure S3: Structures of marine sesterterpenoids from Indonesian waters found in 1970–2017, Table S3: Marine sesterterpenoids from Indonesian waters found in 1970–2017, Figure S4: Structures of marine triterpenoids from Indonesian waters found in 1970–2017, Table S4: Marine triterpenoids from Indonesian waters found in 1970–2017, Figure S5: Structures of marine steroids from Indonesian waters found in 1970–2017, Table S5: Marine steroids from Indonesian waters found in 1970–2017, Figure S6: Structures of marine saponins from Indonesian waters found in 1970–2017, Table S6: Marine saponins from Indonesian waters found in 1970–2017, Figure S7: Structures of marine meroterpenoids from Indonesian waters found in 1970–2017, Table S7: Marine meroterpe-noids from Indonesian waters found in 1970–2017, Figure S8: Structures of marine piperidine alkaloids from Indonesian waters found in 1970–2017, Table S8: Marine piperidine alkaloids from Indonesian waters found in 1970–2017, Figure S9: Structures of marine pyridine alkaloids from Indonesian waters found in 1970–2017, Table S9: Marine pyridine alkaloids from Indonesian waters found in 1970–2017, Figure S10: Structures of marine indole alkaloids from Indonesian waters found in 1970–2017, Table S10: Marine indole alkaloids from Indonesian waters found in 1970–2017, Figure S11: Structures of marine acridine alkaloids from Indonesian waters found in 1970–2017, Table S11: Marine acridine alkaloids from Indonesian waters found in 1970–2017, Figure S12: Structures of marine quinoline and isoquinoline alkaloids from Indonesian waters found in 1970–2017,Table S12: Marine quinoline and isoquinoline alkaloids from Indonesian waters found in 1970–2017, Figure S13: Structures of marine tyrosine alkaloids from Indonesian waters found in 1970–2017, Table S13: Marine tyrosine alkaloids from Indonesian waters found in 1970–2017, Figure S14: Structures of marine pyrrole alkaloids from Indonesian waters found in 1970–2017, Table S14: Marine pyrrole alkaloids from Indonesian waters found in 1970–2017, Figure S15: Structures of marine imidazole alkaloids from Indonesian waters found in 1970–2017, Table S15: Marine imidazole alkaloids from Indonesian waters found in 1970–2017, Figure S16: Structures of marine polysulfur aromatic alkaloids from Indonesian waters found in 1970–2017, Table S16: Marine polysulfur aromatic alkaloids from Indonesian waters found in 1970–2017, Figure S17: Structures of marine serine-derived alkaloids from Indonesian waters found in 1970–2017, Table S17: Marine serine-derived alkaloids from Indonesian waters found in 1970–2017, Figure S18: Structures of other marine alkaloids from Indonesian waters found in 1970–2017, Table S18: Other marine alkaloids from Indonesian waters found in 1970–2017, Figure S19: Structures of marine peptides from Indonesian waters found in 1970–2017, Table S19: Marine peptides from Indonesian waters found in 1970–2017, Figure S20: Structures of marine fatty acids and linear molecules from Indonesian waters found in 1970–2017, Table S20: Marine fatty acids and linear molecules from Indonesian waters found in 1970–2017, Figure S21: Structures of polyketides from Indonesian waters found in 1970–2017, Table S21: Marine polyketides from Indonesian waters found in 1970–2017, Figure S22: Structures of carbohydrates from Indonesian waters found in 1970–2017, Table S22: Marine carbohydrates from Indonesian waters found in 1970–2017. Funding: This research was funded by Indonesian Ministry of Research, Technology, and Higher Education, Indonesia awarded to N.H. Mar. Drugs 2019, 17, 364 45 of 69

Acknowledgments: This work was supported by the National Research Foundation, Indonesian Ministry of Research, Technology, and Higher Education, Indonesia under its excellence basic research university program (1769/IT3.11/PN/2018 and 4175/IT3.L1/PN/2019) awarded to N.H. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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