Chemical Diversity and Biological Activity of Secondary Metabolites Isolated from Indonesian Marine Invertebrates

molecules

Review Chemical Diversity and Biological Activity of Secondary Metabolites Isolated from Indonesian Marine Invertebrates

Fauzia Izzati , Mega Ferdina Warsito, Asep Bayu * , Anggia Prasetyoputri , Akhirta Atikana, Linda Sukmarini, Siti Irma Rahmawati and Masteria Yunovilsa Putra *

Research Center for Biotechnology, Indonesian Institute of Sciences, Jl. Raya Jakarta-Bogor KM 46 Cibinong, Bogor, West Java 16911, Indonesia; [email protected] or [email protected] (F.I.); [email protected] (M.F.W.); [email protected] (A.P.); [email protected] (A.A.); [email protected] (L.S.); [email protected] (S.I.R.) * Correspondence: [email protected] or [email protected] (A.B.); [email protected] or [email protected] (M.Y.P.)

Abstract: Marine invertebrates have been reported to be an excellent resource of many novel bioactive compounds. Studies reported that Indonesia has remarkable yet underexplored marine natural products, with a high chemical diversity and a broad spectrum of biological activities. This review discusses recent updates on the exploration of marine natural products from Indonesian marine invertebrates (i.e., sponges, tunicates, and soft corals) throughout 2007–2020. This paper summa- rizes the structural diversity and biological function of the bioactive compounds isolated from Indonesian marine invertebrates as antimicrobial, antifungal, anticancer, and antiviral, while also presenting the opportunity for further investigation of novel compounds derived from Indonesian marine invertebrates. Citation: Izzati, F.; Warsito, M.F.; Bayu, A.; Prasetyoputri, A.; Atikana, Keywords: Indonesia; marine natural product; marine invertebrates; soft corals; sponges; tunicates; A.; Sukmarini, L.; Rahmawati, S.I.; biodiversity; biological activity Putra, M.Y. Chemical Diversity and Biological Activity of Secondary Metabolites Isolated from Indonesian Marine Invertebrates. Molecules 2021, 26, 1898. https://doi.org/10.3390/ 1. Introduction molecules26071898 A wide range of natural products (NPs) has been isolated from various marine organisms, especially marine invertebrates such as sponges, tunicates, soft corals, bryozoans, and Academic Editor: Anna Petruczynik nudibranchs. These marine invertebrates are excellent sources of NPs with vast chemical structures and potential biological activities [1–3]. During 2012–2017, no less than 550–700 Received: 1 March 2021 new compounds have been reported from marine invertebrates [4], in which half of these Accepted: 23 March 2021 compounds were isolated from marine sponges [5]. Among those, 4% and 22% of the Published: 27 March 2021 compounds were identified in 2017 and 2016, respectively [4,5]. Between 1998 to 2018, one hundred and fourteen secondary metabolites were isolated from the marine sponges of the Publisher’s Note: MDPI stays neutral genus Suberea [6]. Meanwhile, a hundred and seventy compounds were isolated from soft with regard to jurisdictional claims in corals of the genus Dendronephthya alone throughout 1999–2019 [7]. Soft corals belonging to published maps and institutional affil- the genus Xenia are rich in terpenoids, with 199 compounds isolated from 1977–2019 [8]. To iations. date, approximately 30,000–40,000 marine natural products (MNPs) have been identified, with the majority of the compounds exhibiting cytotoxic and anticancer properties [4,5,9]. The biological potential of MNPs from marine invertebrates has been proven to be a valuable source for drug discovery and development. Most of the approved commercial Copyright: © 2021 by the authors. marine-based drugs are of marine invertebrate origin. Eight marine drugs have been Licensee MDPI, Basel, Switzerland. approved by the US Food and Drug Administration (FDA) and European Medicines This article is an open access article Agency (EMA). The first approved marine drug is Ziconotide (Prialt®) discovered in the distributed under the terms and marine snail Conus magus. This peptide-derived marine drug is commonly used as an conditions of the Creative Commons analgesic drug for the management of severe chronic pain through the intrathecal route. Attribution (CC BY) license (https:// The second one is Omega-3-acid-ethyl esters (Lovaza®) derived from fish oil and used as creativecommons.org/licenses/by/ an anti-hypertriglyceridemia drug. The third is Vidarabine (Vira-A®) derived from the 4.0/).

Molecules 2021, 26, 1898. https://doi.org/10.3390/molecules26071898 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 1898 2 of 22

sponge Cryptotethya crypta, while the fourth is Iota-carrageenan (Carragelose®), derived from red macroalgae. These two were registered as antivirals. The other four drugs were approved for cancer treatment, i.e., (1) viz. Cytarabine (Cytosar-U® and Depocyt®) discovered in sponge Cryptotethya crypta, (2) Trabectedin (Yondelis®) isolated from the tunicate Ecteinascidia turbinata, (3) Eribulin mesylate (Halaven®) discovered from sponge Halichondria okadai, and (4) Brentuximab vedotin (Adcetris®) derived from the sea hare Dolabella auricularia. Additionally, approximately 30 MNPs were reported in different clinical trial stages, mainly derived from marine invertebrates [9–11]. Indonesia is the world’s largest archipelagic country with 17,500 islands and a long coastline of 81,000 km. This extraordinary geographic attribute offers a highly diverse variety of marine organisms, resulting in Indonesia being known as a mega-biodiversity of marine organisms. Like other living organisms, marine species synthesize metabolites, either primary or secondary, to support their lives. Living in an extreme environment often induces these organisms to synthesize multiple secondary metabolites with unique chemical properties. A part of their defense mechanism, these metabolites have also been reported to have diverse biological activities that are important for drug discovery and development [12]. The study of Indonesian MNPs was started in 1972 by Engelbrecht et al., who discovered a compound called 25-hydroxy-24ξ-methylcholesterol derived from a soft coral collected from Nias Island, Indonesia [13]. Following that, Cornery et al. reported two novel cytotoxic compounds from the Indonesian sponge Hyatella sp. called viz. lauli- malide and isolaulimalide, which were active against the KB cell line with an IC50 value of 15 ng/mL [14]. Since then, research on Indonesian MNPs has expanded signiﬁcantly. From the 1970s to the year 2017, about 732 MNPs were isolated from Indonesian sea waters. They were mainly produced by sponges (Porifera), tunicates (Chordata), and soft corals (Cnidaria) [15]. In the past decade, hundreds of novel compounds have been discovered from Indonesian marine organisms, many of which showing potent biological activity [16,17]. This review presents recent updates on Indonesian MNPs isolated from three marine invertebrates (sponges, tunicates, and soft corals), reported from 2007 to 2020, covering the chemical diversity and biological activity.

2. Marine Invertebrates 2.1. Sponges Among sponges, alkaloids were reported as the most isolated bioactive compounds, followed by terpenoids, peptides, and polyketides (Table1). Among the isolated alkaloids from sponges, manzamines are mostly reported to exhibit a broad spectrum of biological activities such as cytotoxic, antimicrobial, antimalarial, antiviral, anti-inﬂammatory, an- tiatherosclerotic, insecticidal, and proteasome inhibitor [18]. Their structure has a fused tetra- or pentacyclic ring attached to a carboline moiety.

Table 1. Summary of the marine natural products isolated from the marine sponges from Indonesian oceans.

Compound Compound Class Species Biological Activity Ref Acanthomanzamine A (1) Alkaloid Acanthostrongylophora Cytotoxic against human [18] ingens cervical HeLa cells; inhibition of proteasome; cholesterol ester accumulation inhibitor Acanthomanzamine B (2) Alkaloid A. ingens Cytotoxic against human [18] cervical HeLa cells; inhibition of proteasome; cholesterol ester accumulation inhibitor Molecules 2021, 26, 1898 3 of 22

Table 1. Cont.

Compound Compound Class Species Biological Activity Ref Acanthomanzamine C (3) Alkaloid A. ingens n.a. [18] Acanthomanzamine D (4) Alkaloid A. ingens Cytotoxic against human [18] cervical HeLa cells; inhibition of proteasome; cholesterol ester accumulation inhibitor Acanthomanzamine E (5) Alkaloid A. ingens Cytotoxic against human [18] cervical HeLa cells; inhibition of proteasome; cholesterol ester accumulation inhibitor Acantholactam (6) Alkaloid A. ingens Inhibition of proteasome [19] Pre-neo-kauluamine (7) Alkaloid A. ingens Inhibition of proteasome [19] Acanthocyclamine A (8) Alkaloid A. ingens Antimicrobial against E. [20,21] coli; inhibitor of amyloid β-42 production Epi-tetradehydrohalicyclamine B (9) Alkaloid A. ingens n.a. [21] Tetradehydrohalicyclamine B (10) Alkaloid A. ingens n.a. [21] Halicyclamine B (11) Alkaloid A. ingens Antimicrobial against S. [21] aureus Chloromethylhalicyclamine B (12) Alkaloid A. ingens Protein kinase CK1 δ/ε [21] inhibitor Cyclo (D-Pro-L-Phe) (13) Alkaloid A. ingens Protein kinase [21] CDK2/cyclin A inhibitor Cyclo (L-Pro-Gly) (14) Alkaloid A. ingens n.a. [21] Cyclo (L-Pro-L-Ala) (15) Alkaloid A. ingens n.a. [21] Cyclo (D-Pro-L-Val) (16) Alkaloid A. ingens n.a. [21] Cyclo (L-Pro-Ser) (17) Alkaloid A. ingens n.a. [21] Cyclo (D-Pro-L-Ile) (18) Alkaloid A. ingens n.a. [21] Cyclo (L-Pro-L-Tyr) (19) Alkaloid A. ingens n.a. [21] Ingenine C (20) Alkaloid A. ingens Cytotoxic against human [22] breast MCF-7 and colorectal HCT116 cancer cells Ingenine D (21) Alkaloid A. ingens Cytotoxic against human [22] breast MCF-7 and colorectal HCT116 cancer cells Dispacamide E (22) Alkaloid Stylissa massa Protein kinase inhibitor [23] (GSK-3, DYRK1A, and CK-1) Ethyl Alkaloid S. massa n.a. [23] 3,4-dibromo-1H-pyrrole-2-carboxylate (23) 12-N-methyl stevensine (24) Alkaloid Stylissa sp. Cytotoxic against mouse [24] lymphoma L5187Y cancer cell line 12-N-methyl-2-debromostevensine (25) Alkaloid Stylissa sp. n.a. [24] 3-debromolatonduine B methyl ester Alkaloid Stylissa sp. n.a. [24] (26) 3-debromolatonduine A (27) Alkaloid Stylissa sp. n.a. [24] Crambescidin 345 (28) Alkaloid Clathria bulbotoxa Cytotoxic against the [25] human epidermal A431 carcinoma cell line Crambescidin 361 (29) Alkaloid C. bulbotoxa Cytotoxic against the [25] human epidermal A431 carcinoma cell line Molecules 2021, 26, 1898 4 of 22

Table 1. Cont.

Compound Compound Class Species Biological Activity Ref Crambescidin 373 (30) Alkaloid C. bulbotoxa Cytotoxic against the [25] human epidermal A431 carcinoma cell line Methyldorimidazole (31) Alkaloid Leucetta chagosensis n.a. [26] Preclathridine B (32) Alkaloid L. chagosensis n.a. [26] Naamidine H (33) Alkaloid L. chagosensis Cytotoxic against human [27,28] cervical HeLa cells Naamidine I (34) Alkaloid L. chagosensis Cytotoxic against human [27] cervical HeLa cells Spironaamidine (35) Alkaloid Leucetta microraphis Antibacterial activity [28] against B. cereus Variabine A (36) Alkaloid Luffariella variabilis n.a. [29] Variabine B (37) Alkaloid L. variabilis Inhibition of proteasome [29] and Ubc13 (E2)–Uev1A interaction Sagitol C (38) Alkaloid Oceanapia sp. Cytotoxic against mouse [30] lymphoma L5187Y, human cervical HeLa, and rat pheochromocytoma PC12 cells Cortistatin E (39) Alkaloid Corticium complex n.a. [31] Cortistatin F (40) Alkaloid C. complex n.a. [31] Cortistatin G (41) Alkaloid C. complex n.a. [31] Cortistatin H (42) Alkaloid C. complex n.a. [31] Cortistatin J (43) Alkaloid C. complex Cytostatic antiproliferative [32] activity against human umbilical vein endothelial cells (HUVECs) Cortistatin K (44) Alkaloid C. complex n.a. [32] Cortistatin L (45) Alkaloid C. complex n.a. [32] 11-Methoxy-3H- Alkaloid Aaptos suberitoides n.a. [33] [1,6]naphthyridino[6,5,4- def ]quinoxalin-3-one (46) 2,11-Dimethoxy-3H- Alkaloid A. suberitoides n.a. [33] [1,6]naphthyridino[6,5,4- def ]quinoxalin-3-one (47) 5-Benzoydemethylaaptamine (48) Alkaloid A. suberitoides Cytotoxic against mouse [33] lymphoma L5187Y cancer cell line 3-Aminodemethyl(oxy)aaptamine (49) Alkaloid A. suberitoides n.a. [33] 2-methoxy-3-oxoaaptamine (50) Alkaloid Aaptos sp. Antibacterial against [34] Mycobacterium smegmatis 19-Hydroxypsammaplysin E (51) Alkaloid Aplysinella Antimalarial against P. [35] strongylata falciparum Psammaplysin K (52) Alkaloid A. strongylata n.a. [35] Psammaplysin K dimethoxy acetal (53) Alkaloid A. strongylata n.a. [35] Psammaplysin L (54) Alkaloid A. strongylata n.a. [35] Psammaplysin M (55) Alkaloid A. strongylata n.a. [35] Psammaplysin N (56) Alkaloid A. strongylata n.a. [35] Psammaplysin O (57) Alkaloid A. strongylata n.a. [35] Psammaplysin P (58) Alkaloid A. strongylata n.a. [35] 19-Hydroxypsammaplysin P (59) Alkaloid A. strongylata n.a. [35] Psammaplysin Q (60) Alkaloid A. strongylata n.a. [35] 19-Hydroxypsammaplysin Q (61) Alkaloid A. strongylata n.a. [35] Psammaplysin R (62) Alkaloid A. strongylata n.a. [35] Psammaplysin S (63) Alkaloid A. strongylata n.a. [35] Molecules 2021, 26, 1898 5 of 22

Table 1. Cont.

Compound Compound Class Species Biological Activity Ref 19-Hydroxypsammaplysin S (64) Alkaloid A. strongylata n.a. [35] Psammaplysin T (65) Alkaloid A. strongylata n.a. [35] 19-Hydroxypsammaplysin T (66) Alkaloid A. strongylata n.a. [35] Psammaplysin U (67) Alkaloid A. strongylata n.a. [35] 19-Hydroxypsammaplysin U (68) Alkaloid A. strongylata n.a. [35] Psammaplysin V (69) Alkaloid A. strongylata n.a. [35] Psammaplysin W (70) Alkaloid A. strongylata n.a. [35] 19-Hydroxypsammaplysin W (71) Alkaloid A. strongylata n.a. [35] Lamellodysidine A (72) Terpenoid Lamellodysidea n.a. [36] herbacea Lamellodysidine B (73) Terpenoid L. herbacea n.a. [36] O,O-dimethyllingshuiolide A (74) Terpenoid L. herbacea n.a. [36] 11-epi-O,O-dimethyllingshuiolide A (75) Terpenoid L. herbacea n.a. [36] 18-nor-3,17-dihydroxyspongia- Terpenoid Spongia sp. Inhibition of aromatase [37] 3,13(16),14-trien-2-one (76) 18-nor-3,5,17-trihydroxyspongia- Terpenoid Spongia sp. n.a. [37] 3,13(16),14-trien-2-one (77) Spongiapyridine (78) Terpenoid Spongia sp. n.a. [37] 20,24-bishomo-25-norscalarane 1 (79) Terpenoid Carteriospongia Antiproliferative activity [38] foliascens against human prostate PC3, colorectal LoVo, colorectal CACO-2, and breast MDA-468 cancer cells; inhibition of RCE-protease 20,24-bishomo-25-norscalarane 2 (80) Terpenoid C. foliascens n.a. [38] 20,24-bishomoscalarane ketals 3 (81) Terpenoid C. foliascens Antiproliferative activity [38] against human prostate PC3, colorectal LoVo, colorectal CACO-2, and breast MDA-468 cancer cells; inhibition of RCE-protease 20,24-bishomoscalarane ketals 4 (82) Terpenoid C. foliascens Antiproliferative activity [38] against human prostate PC3, colorectal LoVo, colorectal CACO-2, and breast MDA-468 cancer cells; inhibition of RCE-protease nakijiquinone V (83) Terpenoid Dactylospongia n.a. [39] elegans Halioxepine (84) Terpenoid Haliclona sp. Cytotoxic against rat [40] bladder tumour NBT-T2; antioxidant activity Melophluoside A (85) Terpenoid Melophlus Cytotoxic against human [41] sarasinorum cervical HeLa cells Melophluoside B (86) Terpenoid M. sarasinorum Cytotoxic against human [41] cervical HeLa cells Jaspamide Q (87) Peptide Jaspis splendens Cytotoxic against mouse [42] lymphoma L5187Y cancer cell line Jaspamide R (88) Peptide J. splendens Cytotoxic against mouse [42] lymphoma L5187Y cancer cell line Molecules 2021, 26, 1898 6 of 22

Table 1. Cont.

Compound Compound Class Species Biological Activity Ref Sulﬁnyltheonellapeptolide (89) Peptide Theonella swinhoei Antiproliferative activity [43] against human liver HepG2 cancer cell line Theonellapeptolide If (90) Peptide T. swinhoei Antiproliferative activity [43] against human liver HepG2 cancer cell line Celebeside A (91) Peptide Siliquariaspongia Cytotoxic against HCT116; [44] mirabilis anti-HIV Celebeside B (92) Peptide S. mirabilis n.a. [44] Celebeside C (93) Peptide S. mirabilis n.a. [44] Theopapuamide B (94) Peptide S. mirabilis Cytotoxic against human [44] colorectal HCT116 cancer cell line; anti-HIV Theopapuamide C (95) Peptide S. mirabilis Cytotoxic against human [44] colorectal HCT116 cancer cell line Theopapuamide D (96) Peptide S. mirabilis n.a. [44] Haloirciniamide A (97) Peptide Ircinia sp. n.a. [45] Seribunamide A (98) Peptide Ircinia sp. n.a. [45] Manadoperoxide A (99) Polyketide Plakortis cfr. simplex Antimalarial against P. [46] falciparum Manadoperoxide B (100) Polyketide Plakortis cfr. simplex Antimalarial against P. [46] falciparum Manadoperoxide C (101) Polyketide Plakortis cfr. simplex Antimalarial against P. [46] falciparum Manadoperoxide D (102) Polyketide Plakortis cfr. simplex Antimalarial against P. [46] falciparum Callyspongiolide (103) Macrolide Callyspongia sp. Cytotoxic against Jurkat [47] J16 T and Ramos B lymphocytes Clathruhoate (104) Steroid Clathria sp. n.a. [48] Saranoside S (105) Saponin Petrosia sp. n.a. [49]

To date, more than 80 menzamine-derived alkaloids have been isolated from sponges. This report showed 21 alkaloids were isolated from marine sponge A. ingens, five of which were identified as novel manzamine alkaloids, acanthomanzamines A-E (1–5). These five acanthomanzamines were isolated from the marine sponge A. ingens collected in Mantehage, North Sulawesi [18]. The acanthomanzamines A (1) and B (2) were the first compounds to contain the 1,2,3,4-tetrahydroisoquinoline-6,7-diol moiety instead of the β-carboline moiety, while the acanthomanzamine C (3) contains the hexahydrocy- clopenta[b]-pyrrol-4(2H)-one ring system, and the acanthomanzamines D (4) and E (5) have the oxazolidine and two methyloxazolidine rings, respectively (Figure1). In terms of biological activity, the acanthomanzamines 1 and 2 demonstrated more potent cytotoxic activity against cervical cancer HeLa cells (IC50 values 4.2 and 5.7 µM, respectively) than the acanthomanzamines 4 and 5 (IC50 values 15 and >20 µM, respectively). However, the acanthomanzamines 4 and 5 showed better proteasome inhibition against the proteasomal chymotrypsin-like activity (IC50 values of 0.63 and 1.5 µM, respectively). These findings suggested that the presence of 1,2,3,4-tetrahydroisoquinoline-6,7-diol probably enhanced the cytotoxicity. Meanwhile, compounds containing β-carboline perform better on chymotrypsin-like activity. Additionally, the acanthomanzamines 1, 2, 4, and 5 inhibited the accumulation of the cholesterol ester at 20 µM in macrophages with 48%, 73%, 73%, and 61%, respectively [18]. Molecules 2021, 26, x FOR PEER REVIEW 3 of 23

acanthomanzamines 4 and 5 showed better proteasome inhibition against the proteasomal chymotrypsin-like activity (IC5o values of 0.63 and 1.5 µM, respectively). These findings suggested that the presence of 1,2,3,4-tetrahydroisoquinoline-6,7-diol probably enhanced the cytotoxicity. Meanwhile, compounds containing β-carboline perform better on chymotrypsin-like activity. Additionally, the acanthomanzamines 1, 2, 4, and 5 inhibited the Molecules 2021, 26, 1898 7 of 22 accumulation of the cholesterol ester at 20 µM in macrophages with 48%, 73%, 73%, and 61%, respectively [18].

Figure 1. Chemical structures of Figure1–19. 1. Chemical structures of 1–19.

The sponge A. ingensThe spongealso producesA. ingens otheralso producestypes of othernitrogen-containing types of nitrogen-containing molecules, molecules,i.e., i.e., acantholactam (6),acantholactam pre-neo-kauluamine (6), pre-neo (7-kauluamine), acathocyclamine (7), acathocyclamine A (8), epi-tetradehydrohali- A (8), epi-tetradehydrohalicyclamine B (9), tetradehydrohalicyclamine B (10), halicyclamine B (11), chloromethylhal- cyclamine B (9), tetradehydrohalicyclamine B (10), halicyclamine B (11), chloromethylhali- icyclamine B (12), cyclo (D-Pro-L-Phe) (13), cyclo (L-Pro-Gly) (14), cyclo (L-Pro-L-Ala) cyclamine B (12), cyclo (D-Pro-L-Phe) (13), cyclo (L-Pro-Gly) (14), cyclo (L-Pro-L-Ala) (15), (15), cyclo (D-Pro-L-Val) (16), cyclo (L-Pro-Ser) (17), cyclo (D-Pro-L-Ile) (18), and cyclo cyclo (D-Pro-L-Val)(L -Pro-(16),L cyclo-Tyr) ((19L-Pro-Ser)). Alkaloid (17 compounds), cyclo (D6-Pro-andL7-Ile)were (18 isolated), and fromcycloA. (L ingens-Pro-Lcollected- in Tyr) (19). AlkaloidBajotalawaan, compounds North 6 and Sulawesi 7 were isolated [19]. Compound from A.7 ingensexhibited collected proteasome in Bajotala- inhibitory activity waan, North Sulawesiwith an[19]. IC50 Compoundvalue of 0.34 7 µexhibitedM, whereas proteasome compound 6inhibitoryshowed little activity to no activitywith an [ 19]. These IC50 value of 0.34 ﬁndingsµM, whereas indicated compound that the eight-membered6 showed little ringto no in activity the manzamines [19]. These plays find- a key role in ings indicated thattheir the bioactivity. eight-membered ring in the manzamines plays a key role in their bioactivity. A novel 3-alkylpiperidine alkaloid (8) was also isolated from A. ingens collected from Wakatobi Marine National Park in Southeast Sulawesi [20]. Recently, the alkaloid A novel 3-alkylpiperidine alkaloid (8) was also isolated from A. ingens collected from compounds 9–19 were also isolated from A. ingens collected from South Sulawesi along Wakatobi Marinewith National compound Park8 in[21 Southeast]. Moreover, Sulawesi compound [20].8 was Recently, reported the to havealkaloid speciﬁc com- antimicrobial pounds 9–19 wereactivity also isolated against E. from coli and A. ingens showed collected an inhibitory from effect South on amyloidSulawesiβ-42 along production with induced compound 8 [21].by Moreover, aftin-5 without compound cytotoxicity 8 was atreported 26 µM. to Compounds have specific8 and antimicrobial11 exhibited ac- antibacterial tivity against E. coliactivity and showed at 100 µ g/discan inhibitory against effectE. coli onand amyloidS. aureus β.-42 In production addition to that,induced compound 12 by aftin-5 withoutwas cytotoxicity reported toat have26 µM. selective Compounds inhibitory 8 and activity 11 exhibited against the antibacterial protein kinase ac- CK1 δ/ε tivity at 100 µg/discwith against an IC50 E.value coli ofand 6 µ M,S. aureus while the. In diketopiperazine addition to that, compound compound13 showed 12 wasa selective reported to have kinaseselective inhibitory inhibitory activity activity against against CDK2/cyclin the protein A with kinase an IC50 CK1value δ/ ofε 1withµM. an However, no bioactivity was reported from compounds 14–19 [21]. IC50 value of 6 µM, while the diketopiperazine compound 13 showed a selective kinase A study reported two new pyrimidine-β-carboline alkaloids—namely, ingenines C (20) inhibitory activityand against D (21 CDK2/cyclin), successfully A isolated with an from ICA.50 value ingens ofobtained 1 µM. However, in Sulawesi no [22 bioac-]. The ingenines tivity was reported20 fromand 21 compoundsexhibited cytotoxic 14–19 [21]. activities towards the human breast MCF-7 and colorectal HCT116 cancer cells (IC values of 4.33 and 6.05 µM, and 2.90 and 3.35 µM, respectively) [22]. Two bromopyrrole alkaloids, dispacamide E (22) and ethyl 3,4-dibromo-1H-pyrrole-2- carboxylate (23), were isolated from methanolic extract of the marine sponge S. massa

Molecules 2021, 26, 1898 8 of 22

collected in Papua, Indonesia [23]. Compound 22 had significant protein kinase inhibitory activities against GSK-4, DYRKIA, and CK-1 with IC50 values of 2.1, 6.2, and 4.9 µM, respectively [23]. Another four new alkaloids were isolated from genus Stylissa in Derawan Island, Berau, Northeast Kalimantan—namely, 12-N-methylstevensine (24), 12-N-methyl-2-debromostevensine (25), 3-debromolatonduine B methyl ester (26), and 3-debromolatonduine A (27). Among these four compounds, however, only compound 24 showed significant in-vitro cytotoxic activity against the mouse lymphoma L5187Y cancer Molecules 2021, 26, x FOR PEER REVIEW 8 of 23 cell line with an EC50 value of 8.7 µM[24]. Recently, three new guanidine alkaloids, crambescidins 345 (28), 361 (29), and 373 (30), were isolated from C. bulbotoxa collected in Samalona Island, South Sulawesi [25]. tetrahydropyraneInterestingly, ring (Figure crambescidin2). Crambescidin28 was 29 the possesses first crambescidin a rare propyl analogue substituent with a and non-alkylated another tetrahydropyranetetrahydropyrane ring in place ring (Figure of the2 left-side). Crambescidin unsaturated29 possesses seven-membered a rare propyl ring. substituent and another tetrahydropyrane ring in place of the left-side unsaturated seven-membered ring. Meanwhile, crambescidin 30 was the first analogue with an ethyl group at the right-side Meanwhile, crambescidin 30 was the first analogue with an ethyl group at the right-side tetrahydropyranetetrahydropyrane ring, which possesses ring, which a methyl possesses group a methylin most group reported in most crambescidin- reported crambescidin- type alkaloids. Thesetype three alkaloids. guanidine These three alkaloids guanidine (28, 29, alkaloids and 30) (28, exhibited 29, and 30 moderate) exhibited cyto- moderate cytotoxicity against thetoxicity human against epidermoid the human A431 epidermoid carcinoma A431 cell carcinoma line with cell IC line50 values with ICof50 7.0,values of 7.0, 2.5, and 0.94 µM, 2.5,respectively and 0.94 µ M,[25]. respectively They also [ 25showed]. They anti-oomycete also showed anti-oomycete activity against activity the against the oomycete plant pathogenoomycete Phytophthora plant pathogen capsiciPhytophthora [25]. capsici [25].

Figure 2. Chemical structures ofFigure 20–30. 2. Chemical structures of 20–30.

Four new imidazoleFour alkaloids new imidazole were isolated alkaloids from were the isolated Indonesian from the sponge Indonesian L. chagosensi sponge L. chagosensi 31 32 (Table 1). The alkaloids(Table1 ).methyldorimidazole The alkaloids methyldorimidazole (31) and preclathridine ( ) and preclathridine B (32) were B isolated ( ) were isolated from Kapoposang Island, South Sulawesi [26], whereas the other two alkaloids, naamidines from Kapoposang Island, South Sulawesi [26], whereas the other two alkaloids, naami- H(33) and I (34), were isolated from L. chagosensi collected in North Sulawesi [27,28]. Com- dines H (33) and I (34), were isolated from L. chagosensi collected in North Sulawesi [27,28]. pounds 33 and 34 were reported to show cytotoxicity against HeLa cells with IC50 values Compounds 33 andof 11.334 were and 29.6 reportedµM, respectively to show cytotoxicity [27,28]. Another against new alkaloidHeLa cells was with isolated IC50 from L. mi- values of 11.3 andcroraphis, 29.6 µM,named respectively spironaamidine [27,28]. Another (35)[28]. Thenew spironaamidine alkaloid was isolated possessed from antimicrobial L. microraphis, namedactivity spironaamidine against B. cereus (35. However,) [28]. The the spironaamidine effect was slightly possessed lower than antimicro- that of naamidine bial activity against33 [B.27 cereus,28], probably. However, due tothe the effect presence was slightly of spiroquinone, lower than which that is exceptionallyof naami- rare in dine 33 [27,28], probablynatural sourcesdue to (Figurethe presence3). of spiroquinone, which is exceptionally rare in natural sources (Figure 3).

Figure 3. Chemical Structures of 31–38.

Two new β-carboline alkaloids, variabines A (36) and B (37), were isolated from In- donesian marine sponge Luffariealla variabilis collected in North Sulawesi [29]. Compound

Molecules 2021, 26, x FOR PEER REVIEW 8 of 23

tetrahydropyrane ring (Figure 2). Crambescidin 29 possesses a rare propyl substituent and another tetrahydropyrane ring in place of the left-side unsaturated seven-membered ring. Meanwhile, crambescidin 30 was the first analogue with an ethyl group at the right-side tetrahydropyrane ring, which possesses a methyl group in most reported crambescidin- type alkaloids. These three guanidine alkaloids (28, 29, and 30) exhibited moderate cytotoxicity against the human epidermoid A431 carcinoma cell line with IC50 values of 7.0, 2.5, and 0.94 µM, respectively [25]. They also showed anti-oomycete activity against the oomycete plant pathogen Phytophthora capsici [25].

Figure 2. Chemical structures of 20–30.

Four new imidazole alkaloids were isolated from the Indonesian sponge L. chagosensi (Table 1). The alkaloids methyldorimidazole (31) and preclathridine B (32) were isolated from Kapoposang Island, South Sulawesi [26], whereas the other two alkaloids, naamidines H (33) and I (34), were isolated from L. chagosensi collected in North Sulawesi [27,28]. Compounds 33 and 34 were reported to show cytotoxicity against HeLa cells with IC50 values of 11.3 and 29.6 µM, respectively [27,28]. Another new alkaloid was isolated from Molecules 2021, 26, 1898L. microraphis, named spironaamidine (35) [28]. The spironaamidine possessed antimicro- 9 of 22 bial activity against B. cer

Figure 3. Chemical Structures of 31–38. Molecules 2021, 26, x FOR PEER REVIEW Figure 3. Chemical Structures of 31–38. 9 of 23

Two new β-carbolineTwo new alkaloids,β-carboline variabines alkaloids, A (36 variabines) and B (37 A), were (36) and isolated B (37 from), were In- isolated from donesian marineIndonesian sponge Luffariealla marine sponge variabilisLuffariealla collected variabilis in Northcollected Sulawesi in North [29]. Compound Sulawesi [29 ]. Compound 36 was the first 36sulfatedwas the β-carboline ﬁrst sulfated alkaloidβ-carboline and the alkaloid sulfonated and derivative the sulfonated of compound derivative of compound 37. A hydroxy group37. A in hydroxy compound group 37 inreplaces compound the sulfate37 replaces group theat C-6 sulfate in compound group at C-636. in compound Compound 37 was36. Compound found to inhibit37 was the found chymotrypsin-like to inhibit the activity chymotrypsin-like of the proteasome activity and of the proteasome Ubc13 (E2)-Uev1Aand interaction Ubc13 (E2)-Uev1A with IC50 interaction values of 16.5 with and IC50 20.6values µM, ofrespectively. 16.5 and 20.6 Inµ con-M, respectively. In trast, compoundcontrast, 36 showed compound a weak36 effectshowed on proteasome. a weak effect This on proteasome. result suggested This result that the suggested that the sulfate group insulfate variabines group decrease in variabiness chymotrypsin-like decreases chymotrypsin-like activity [29]. activity [29]. A novel pyridoacridineA novel pyridoacridinealkaloid, sagitol alkaloid, C (38), was sagitol isolated C (38 ),from was the isolated ethyl fromacetate the ethyl acetate fraction of Oceaniapiafraction sp. of collectedOceaniapia in sp.Ambon, collected Maluku in Ambon, Islands Maluku [30]. Alkaloid Islands 38 [30 was]. Alkaloid found 38 was found to exhibit cytotoxicto exhibit activity cytotoxic against activity the mo againstuse lymphoma the mouse L5187Y lymphoma canc L5187Yer cell line, cancer HeLa cell line, HeLa cell, cell, and the ratand pheochromocytoma the rat pheochromocytoma PC12 cell lines PC12 with cell linesED50 withvalues ED of50 0.7,values 0.9, ofand 0.7, 2.3 0.9, and 2.3 µM, µM, respectivelyrespectively [30]. [30]. Seven novel anti-angiogenicSeven novel anti-angiogenic steroidal alkaloids steroidal (Figure alkaloids 4) were (Figure isolated4) werefrom isolatedthe from the sponge Corticiumsponge simplexCorticium collected simplex in Florescollected Island, in East Flores Nusa Island, Tenggara East Nusa [31,32], Tenggara namely [ 31,32], namely cortistatins E-Hcortistatins (39–42) and E-H J-L ( 39(43–42–45)). and These J-L (compounds43–45). These have compounds unique abeo-9(10-19)- have unique abeo-9(10-19)- stigmastane-typestigmastane-type steroidal alkaloids. steroidal Compounds alkaloids. 38 Compounds–42 have oxabicyclo[3.2.1]octene38–42 have oxabicyclo[3.2.1]octene and and N-methyl piperidineN-methyl or 3-methylpyridine piperidine or 3-methylpyridine units in the side unitschain, in while the sidecompounds chain, while 43–45 compounds 43– have an isoquinoline45 have unit. an isoquinoline Compound unit. 43 showed Compound cytostatic43 showed antiproliferative cytostatic antiproliferative activity activity against human againstumbilical human vein endothelial umbilical vein cells endothelial (HUVECs) cells at 8 (HUVECs)nM [31,32]. at 8 nM [31,32].

Figure 4. Chemical structures ofFigure 39–50. 4. Chemical structures of 39–50.

The genus Aaptos is also an abundant source of novel aaptamine alkaloids (Table 1). Four new aaptamine derivates were isolated from A. suberitoides collected in Ambon, Ma- luku Islands [33]—namely, 11-methoxy-3H-[1,6]naphthyridino [6,5,4-def]quinoxalin-3- one (46), 2,11-dimethoxy-3H-[1,6]naphthyridino [6,5,4-def]quinoxalin-3-one (47), 5-benzo- yldemethylaaptamine (48), and 3-aminodemethyl(oxy)aaptamine (49). Compound 47 is the 11-methoxy derivative of compound 46 and represents a benzoyl-aaptamine skeleton that has not been previously identified [33]. Concerning the biological activity, compound 48 exhibited cytotoxic activity against the mouse lymphoma L5187Y cancer cell line with an IC50 value of 5.5 µM [33]. Another aaptamine derivate isolated from Aaptos sp. collected from Kupang, East Nusa Tenggara [34],—namely, 2-methoxy-3-oxoaaptamine (50), demonstrated an anti-mycobacterial activity under both aerobic and hypoxic conditions, both with a MIC value of 23 µM [34]. Twenty-one novel psammaplysin derivatives were successfully isolated from A. strongylata collected in Tulamben Bay, Bali [35]. Compounds 19-Hydroxypsammaplysin E (51), psammaplysin K (52), psammaplysin K dimethoxy acetal (53), psammaplysin L (54), and M (55), possess modified aromatic ring substituents. Meanwhile, psammaplysin N-P (56–58), 19-hydroxypsammaplysin P (59), psammaplysin Q (60), 19-hydroxypsammaplysin Q (61), psammaplysin R-S (62–63), 19-hydroxypsammaplysin S (64),

Molecules 2021, 26, 1898 10 of 22

The genus Aaptos is also an abundant source of novel aaptamine alkaloids (Table1). Four new aaptamine derivates were isolated from A. suberitoides collected in Ambon, Maluku Islands [33]—namely, 11-methoxy-3H-[1,6]naphthyridino [6,5,4-def ]quinoxalin-3- one (46), 2,11-dimethoxy-3H-[1,6]naphthyridino [6,5,4-def ]quinoxalin-3-one (47), 5-benzoyl- demethylaaptamine (48), and 3-aminodemethyl(oxy)aaptamine (49). Compound 47 is the 11-methoxy derivative of compound 46 and represents a benzoyl-aaptamine skeleton that has not been previously identified [33]. Concerning the biological activity, compound 48 exhibited cytotoxic activity against the mouse lymphoma L5187Y cancer cell line with an IC50 value of 5.5 µM[33]. Another aaptamine derivate isolated from Aaptos sp. collected from Kupang, East Nusa Tenggara [34],—namely, 2-methoxy-3-oxoaaptamine (50), demonstrated an anti-mycobacterial activity under both aerobic and hypoxic conditions, both with a MIC value of 23 µM[34]. Twenty-one novel psammaplysin derivatives were successfully isolated from A. strongylata collected in Tulamben Bay, Bali [35]. Compounds 19-Hydroxypsammaplysin E (51), psammaplysin K (52), psammaplysin K dimethoxy acetal (53), psammaplysin L (54), and M (55), possess modified aromatic ring substituents. Meanwhile, psammaplysin N-P (56–58), 19-hydroxypsammaplysin P (59), psammaplysin Q (60), 19-hydroxypsammaplysin Q (61), psammaplysin R-S (62–63), 19-hydroxypsammaplysin S (64), psammaplysin T (65), and 19-hydroxypsammaplysin T (66) exhibit various side chains that are saturated fatty acid side chains (Figure5). On the other hand, psammaplysin U ( 67), 19-hydroxypsammaplysin U(68), psammaplysin V-W (69–70), and 19-hydroxypsammaplysin W (71) have monoenoic fatty acid side chains. Among these 21 compounds, 19-hydroxypsammaplysin E (51), having the N-substitution of the ethylamino moiety, showed the best antimalarial activity with modest inhibition against P. falciparum (IC50 = 6.4 µM) [35]. Several new terpenes were isolated from Indonesian marine sponges from the Dic- tyoceratida order (Figure6), such as L. herbacea [36], Spongia sp. [37], and Carterospongia foliascens [38]. Four new sesquiterpenes were isolated from L. herbacea collected in Manado, North Sulawesi—namely, lamellodysidines A (72) and B (73), O,O-dimethyllingshuiolide A(74), and 11-epi-O,O-dimethyllingshuiolide A (75)[36]. Compound 72 was the first compound identified with a unique bridged polycyclic framework, and compound 73 is a novel nitrogenous sesquiterpene, while compounds 74 and 75 were obtained as an inseparable mixture due to their 11-epimeric nature [36]. Sponges from the genus Spongia are known as a rich source of unique terpenoids (Table1). This is evident in the successful isolation of three novel terpenoids from Spongia sp. collected in Bunaken Marine Park, North Sulawesi [37]. These three compounds were identified as diterpene—namely, 18-nor-3,17-dihydroxyspongia-3,13(16),14-trien-2-one (76), 18-nor-3,5,17-trihydroxyspongia-3,13(16),14-trien-2-one (77), and spongiapyridine (78). Compound 77 possesses an unusual D-ring substitute, a pyridyl ring system, in the place of δ-lactone (Figure6). In terms of the biological activity of these four compounds, only compound 76 possessed moderate activity on aromatase inhibition with an IC50 of 34 µM and quinone reductase 1 induction with the concentration needed to double the enzymatic response of 11.2 µM[37]. Four new scalarane-based sesterterpenoids were isolated from C. foliascens associated with the coral reefs of Palau Barang Lompo, near Makasar, South Sulawesi [38]. The closely related compounds were identified as 20,24-bishomo-25-norscalaranes 1 (79) and 2 (80), and 20,24-bishomoscalaranes ketals 3 (81) and 4 (82) (Figure6). Compounds 81 and 82 were isolated as an inseparable mixture. Compound 80 showed little to no activity toward RCE-protease inhibition compared to 79. Meanwhile, a combination of 80 and 82 (plus 81, as its inseparable mixture) had inhibition activity with IC50 values of 38 and 4.2 µg/mL, respectively [38]. Compound 79 and the mixture of 81 and 82 also showed inhibition against tumour cell lines (human prostate PC3, colorectal LoVo, colorectal adenocarcinoma CACO-2, and breast MDA-468 cancer cell lines) with IC50 values ranging from 2.9–9.5 µg/mL [38]. Molecules 2021, 26, x FOR PEER REVIEW 10 of 23

psammaplysin T (65), and 19-hydroxypsammaplysin T (66) exhibit various side chains that are saturated fatty acid side chains (Figure 5). On the other hand, psammaplysin U (67), 19-hydroxypsammaplysin U (68), psammaplysin V-W (69–70), and 19-hydroxypsammaplysin W (71) have monoenoic fatty acid side chains. Among these 21 compounds, 19-hydroxypsammaplysin E (51), having the N-substitution of the ethylamino Molecules 2021, 26, 1898 11 of 22 moiety, showed the best antimalarial activity with modest inhibition against P. falciparum (IC50 = 6.4 µM) [35].

Figure 5. Chemical structuresFigure of 51– 5.71.Chemical structures of 51–71.

Other compounds isolated from Sulawesi included nakijiquinone V (83), isolated Several new terpenes were isolated from Indonesian marine sponges from the Dicty- from Dactylospongia elegans from Tahuna, Sangihe Islands, North Sulawesi [39]. It has oceratida orderthree (Figure methyl 6), such groups as L. attached herbacea to [36], a decalin Spongia system sp. [37], with and an exocyclicCarterospongia double foli- bond [39] ascens [38]. Four(Figure new 6sesquiterpenes). Another was were a new isolated meroditerpene—namely, from L. herbacea collected Halioxepine in Manado, ( 84), which was North Sulawesi—namely,isolated from lamellodysidines an Indonesian marine A (72 sponge) and B from (73 the), O genus,O-dimethyllingshuiolideHaliclona collected in Baubau, A (74), and 11-epiSoutheast-O,O-dimethyllingshuiolide Sulawesi [40]. This compound A (75) [36] showed. Compound moderate 72 cytotoxicitywas the first against com- the rat pound identifiedbladder with tumoura unique NBT-T2 bridged cells polycyclic with IC50 of framework, 11.6 µM and and antioxidant compound activity 73 is against a 1,1- novel nitrogenousdiphenyl-2-picrylhydrazyl sesquiterpene, while (DPPH)compounds with IC 7450 andof 7.7 75µ M[were40 ].obtained Recently, as two an new insep- terpenoids, arable mixture melophluosidesdue to their 11-epimeric A (85) and nature B (86), were[36]. successfully isolated from Melophlus sarassinorum collected in Siladen, North Sulawesi. These new compounds belong to the triterpene galactosides of the pouoside class, with compound 85 as the ﬁrst without an oxygenated

Molecules 2021, 26, x FOR PEER REVIEW 11 of 23

Sponges from the genus Spongia are known as a rich source of unique terpenoids (Table 1). This is evident in the successful isolation of three novel terpenoids from Spongia sp. collected in Bunaken Marine Park, North Sulawesi [37]. These three compounds were identified as diterpene—namely, 18-nor-3,17-dihydroxyspongia-3,13(16),14-trien-2-one Molecules 2021, 26,( 189876), 18-nor-3,5,17-trihydroxyspongia-3,13(16),14-trien-2-one (77), and spongiapyridine 12 of 22 (78). Compound 77 possesses an unusual D-ring substitute, a pyridyl ring system, in the place of δ-lactone (Figure 6). In terms of the biological activity of these four compounds, only compound 76 possessed moderate activity on aromatase inhibition with an IC50 of 34 µM and quinonegroup reductase at C-11. 1 induction Both compounds with the exhibited concentration moderate needed cytotoxic to double activity the againsten- HeLa cells zymatic responsewith of IC5011.2 µM values [37]. of 11.6 and 9.7 mM, respectively [41].

Figure 6. Chemical structures Figureof 72–86. 6. Chemical structures of 72–86.

Four new scalarane-basedTwo new cycoldepsipeptide sesterterpenoids were jaspamide isolated derivatives, from C. foliascens jaspamide associated Q (87) and jaspamide with the coral R(reefs88 ),of were Palau identified Barang Lompo, from the near marine Makasar, sponge SoutJ. splendensh Sulawesicollected [38]. The in neighbouring closely related islandscompounds near were East Kalimantanidentified as[ 20,24-bishomo-25-norscalaranes42]. They exhibited potent cytotoxic 1 (79) activity and against the 2 (80), and 20,24-bishomoscalaranesmouse lymphoma L5187Y ketals cancer3 (81) and cell 4line (82) with(Figure IC50 6).values Compounds of <126.8 81 andµM and <203 µM, 82 were isolatedrespectively as an inseparable [42]. mixture. Compound 80 showed little to no activity toward RCE-proteaseNovel inhibition tridecapeptides compared to of the79. theonellapeptolideMeanwhile, a combination family were of 80 isolated and 82 from T. swinhoei (plus 81, as its collectedinseparable from mixture) Bunaken ha Marined inhibition Park activity in Manado, with North IC50 values Sulawesi—namely, of 38 and 4.2 sulfinyltheonel- µg/mL, respectivelylapeptolide [38]. Compound (89) and theonellapeptolide 79 and the mixture If of (90 81)[ 43and]. These82 also compounds showed inhibi- differ in the abrine tion against tumourmoiety. cell Compound lines (human89 prostateis a theonellapeptolide PC3, colorectal LoVo, with a colorectal methylsulfinylacetyl adenocar- group at the cinoma CACO-2,N-terminus, and breast while MDA-468 compound cancer90 cellwas lines) the with first theonellapeptolideIC50 values ranging withfrom four 2.9– valine residues 9.5 µg/mL [38].(Figure 7). Both compounds showed significant antiproliferative activity against human Other compoundsliver HepG2 isolated cancer from cells Sula withwesi the sameincluded IC50 nakijiquinonevalue of 3 µM[ V43 (].83), isolated from DactylospongiaS. elegans mirabilis fromis also Tahuna, one of Sangihe the rich Islands, sources ofNorth diverse Sulawesi secondary [39]. metabolites, It has as exempli- three methyl groupsfied by attached the isolation to a decalin of six newsystem depsipeptides with an exocyclic with two double different bond structural [39] (Fig- classes named ure 6). Anothercelebesides was a new A-Cmeroditerpene—namely, (91–93) from the species Halioxepine collected in(84 Sulawesi), which [was44]. isolated Compounds 91–93 are from an Indonesiancyclic marine depsipeptides sponge withfrom a the polyketide genus Haliclona moiety and collected five amino in Baubau, acid residues South- (Figure7). The east Sulawesi [40].celebesides This compound A and B (showed91, 92) possess moderate a 3-carbamoyl cytotoxicity threonine against the and rat a phosphoserinebladder residue, which is quite uncommon. S. mirabilis also produced the peptides theopapuamides B–D (94– tumour NBT-T2 cells with IC50 of 11.6 µM and antioxidant activity against 1,1-diphenyl- 96), which are undecapeptides with an N-terminal fatty acid moiety, with theopapuamide 2-picrylhydrazyl (DPPH) with IC50 of 7.7 µM [40]. Recently, two new terpenoids, melo- D(96) containing a rare homoisoleucine residue (Figure7). These compounds exhibited phluosides A (85) and B (86), were successfully isolated from Melophlus sarassinorum col- several bioactivities. Theopapuamides B and C (94, 95) were found to have relatively lected in Siladen, North Sulawesi. These new compounds belong to the triterpene galac- strong antifungal activity against amphotericin B-resistant C. albicans [44]. Additionally, tosides of the pouoside class, with compound 85 as the first without an oxygenated group celebeside A (91) and theopapuamide B (94) neutralized HIV-1 in a single-round infectivity assay with an IC50 value of 2.1 ± 0.4 µM and 499.7 ± 0.3 µg/mL [44]. Celebeside 91 and theopapuamides 94 and 95 also demonstrated cytotoxicity against human colon carcinoma cells with IC values 9.9 µM, 1.3 µM, and 2.5 µM, respectively [44]. Although they were 50 potent against human colon HCT116 carcinoma cells, celebesides A, B, and C (91-93) were also found to be cytotoxic for healthy cell lines [44]. Molecules 2021, 26, x FOR PEER REVIEW 12 of 23

at C-11. Both compounds exhibited moderate cytotoxic activity against HeLa cells with IC50 values of 11.6 and 9.7 mM, respectively [41]. Two new cycoldepsipeptide jaspamide derivatives, jaspamide Q (87) and jaspamide R (88), were identified from the marine sponge J. splendens collected in neighbouring islands near East Kalimantan [42]. They exhibited potent cytotoxic activity against the mouse lymphoma L5187Y cancer cell line with IC50 values of <126.8 µM and <203 µM, respectively [42]. Novel tridecapeptides of the theonellapeptolide family were isolated from T. swinhoei collected from Bunaken Marine Park in Manado, North Sulawesi—namely, sulfinylthe- onellapeptolide (89) and theonellapeptolide If (90) [43]. These compounds differ in the abrine moiety. Compound 89 is a theonellapeptolide with a methylsulfinylacetyl group at Molecules 2021, 26, 1898 the N-terminus, while compound 90 was the first theonellapeptolide with four valine res-13 of 22 idues (Figure 7). Both compounds showed significant antiproliferative activity against human liver HepG2 cancer cells with the same IC50 value of 3 µM [43].

Molecules 2021, 26, x FOR PEER REVIEW 13 of 23

[44]. Additionally, celebeside A (91) and theopapuamide B (94) neutralized HIV-1 in a single-round infectivity assay with an IC50 value of 2.1 ± 0.4 µM and 499.7 ± 0.3 µg/mL [44]. Celebeside 91 and theopapuamides 94 and 95 also demonstrated cytotoxicity against human colon carcinoma cells with IC50 values 9.9 µM, 1.3 µM, and 2.5 µM, respectively [44]. Although they were potent against human colon HCT116 carcinoma cells, celebesides A, B, and C (91-93) were also found to be cytotoxic for healthy cell lines [44]. FigureFigure 7. 7.Chemical Chemical structures of of 87-98.87–98. Haloirciniamide A (97) and seribunamide A (98), new polyhalogenated peptides, haveHaloirciniamide S.been mirabilis isolated is also A from one (97) of and Ircinia the seribunamide rich sp. sources collected of A diverse (98 from), new secondary the polyhalogenated coas metabolites,t of Thousand peptides, as exem- Islands. have Com- beenpoundplified isolated 97by thewas from isolation theIrcinia first ofsp. dibromopyrrolesix collected new depsipeptides from the cyclopeptide coast with of two Thousand different with Islands.a structural chlorohistidine Compound classes ring,97 while wasnamed the ﬁrst celebesides dibromopyrrole A-C (91-93 cyclopeptide) from the species with collected a chlorohistidine in Sulawesi ring, [44]. while Compounds compound compound91–93 are cyclic 98 depsipeptidespossess a rare with tribromopyrrole a polyketide moiety ring. and five Unfortunately, amino acid residues both (Fig- compounds did 98 possess a rare tribromopyrrole ring. Unfortunately, both compounds did not show noture show 7). The significant celebesides A cytotoxicity and B (91, 92) againspossess ta four3-carbamoyl human threonine tumour and cell a phosphoser-lines [45]. signiﬁcant cytotoxicity against four human tumour cell lines [45]. ine residue,Four new which endoperoxyketal is quite uncommon. polyketides, S. mirabilis also manadoperoxides produced the peptides A-D theopa-(99–102), were iso- Four new endoperoxyketal polyketides, manadoperoxides A-D (99–102), were isolated puamides B–D (94–96), which are undecapeptides with an N-terminal fatty acid moiety, fromlated the from sponge thePlakortis spongecfr. Plakortissimplex cfr.obtained simplex from obtained the Bunaken from Marine the Bunaken Park of Manado, Marine Park of Manado,with theopapuamide North Sulawesi D (96) containing[46]. In these a rare compou homoisoleunds,cine the residue methoxy (Figure group 7). These at C-6 is replaced Northcompounds Sulawesi exhibited [46]. In several these compounds,bioactivities. Theopapuamides the methoxy group B and at C C-6 (94, is 95 replaced) were found by either aby methylto eitherhave orrelatively a ethylmethyl group strong or ethyl insteadantifungal group of aac peroxyketal-type tivityinstead against of a amphotericin peroxyketal-type (Figure8 B-resistant), making (Figure themC. albicans 8), slightly making them differentslightly fromdifferent those from previously those previously isolated from isol theated same from species the same in the species Caribbean. in the All Caribbean. compoundsAll compounds isolated isolated from that from sponge that Plakortissponge cfr.Plakortissimplex cfr.showed simplex moderate showed antimalarial moderate antima- activitylarial activity against D10against and D10 W2 strains and W2 of Plasmodiumstrains of Plasmodium falciparum [46 falciparum]. [46].

FigureFigure 8. 8.Chemical Chemical structures structures of 99 of–102. 99–102.

A novel cytotoxic macrolide, namely Callyspongiolide (103), was isolated from the Indonesian marine sponge Calyspongia sp [47]. This compound has a notable feature of a conjugated diene-ynic sidechain ending at a benzene ring with bromine, which was not found in the previously isolated marine macrolides (Figure 9). Its cytotoxicity against human acute T cell leukaemia Jurkat J16 T and human Burkitt's lymphoma Ramos B lymphocytes showed remarkable IC50 values of 70 and 60 nM, respectively, as well as EC50 values of 80 and 50 nM, respectively [47].

Figure 9. Chemical structures of 103–105.

A novel A-nor steroid, namely clathruhoate (104), was isolated from a marine sponge Clathria sp., collected from Bintang Samudra Marine Education Park, Southeast Sulawesi

Molecules 2021, 26, x FOR PEER REVIEW 13 of 23

Molecules 2021Figure, 26, 1898 8. Chemical structures of 99–102. 14 of 22

A novel cytotoxic macrolide, namely Callyspongiolide (103), was isolated from the Indonesian marine spongeA novel Calyspongia cytotoxic macrolide, sp [47]. namelyThis compound Callyspongiolide has a ( 103notable), was isolatedfeature fromof a the conjugated diene-ynicIndonesian sidechain marine ending sponge Calyspongiaat a benzenesp [ 47ring]. This with compound bromine, has which a notable was feature not of a found in the previouslyconjugated isolated diene-ynic marine sidechain macrolides ending (Figure at a benzene 9). Its ring cytotoxicity with bromine, against which washu- not found in the previously isolated marine macrolides (Figure9). Its cytotoxicity against man acute T cell leukaemiahuman acute Jurkat T cell leukaemiaJ16 T and Jurkat human J16 Burkitt's T and human lymphoma Burkitt’s lymphomaRamos B Ramoslym- B 50 50 phocytes showed lymphocytesremarkable showed IC values remarkable of 70 IC 50andvalues 60 ofnM, 70 andrespectively, 60 nM, respectively, as well as as well EC as EC50 values of 80 and 50values nM, ofrespectively 80 and 50 nM, [47]. respectively [47].

Figure 9. Chemical structures Figureof 103– 9.105.Chemical structures of 103–105.

A novel A-nor steroid, namely clathruhoate (104), was isolated from a marine sponge A novel A-norClathria steroid,sp., collectednamely fromclathruhoate Bintang Samudra (104), Marine was isolated Education from Park, a Southeast marine Sulawesi sponge [ 48]. Clathria sp., collectedMoreover, from aBintang new nortriterpenoid Samudra saponin,Marine namelyEducation sarasinoside Park, SSoutheast (105), was identifiedSulawesi from the marine sponge Petrosia sp. obtained in North Sulawesi [49]. Compound 105 was the first among the nortriterpenes in the saranoside family with a degraded side chain (Figure9).

2.2. Tunicates Tryptamine-derived alkaloids named leptoclinidamide (106) and (-)-leptoclinidamine B(107) were isolated from tunicate L. dubius collected from Lembeh Strait, North Su- lawesi [50]. Compound 107 is the enantiomer of the previously isolated compound, (+)- leptoclinidamine B. These compounds have a unique amide moiety with two β-alanine units and D-arginine moiety, respectively [50]. Eleven compounds were identiﬁed from tunicate Lissoclinum cf. badium collected in Manado, Indonesia. Among these 11 compounds, there were four new polysulfur aromatic alkaloids named lissoclibadins 4–7 (108–111) (Figure 10), isolated with seven known alkaloids called lissoclibadins 1–3, lissoclinotoxins E and F, 3,4-dimethoxy6-(20- N,N-dimethylaminoethyl)-5-(methylthio)benzotrithiane, and N,N-dimethyl-5-(methylthio)- varacin [51]. Bioactivities of these compounds included inhibition against yeast Saccha- romyces cerevisiae demonstrated by compounds 109–111, and antimicrobial activity against S. aureus and E. coli evident from compounds 108–111 [51]. Other alkaloids polycarpathiamines A and B (112 and 113), were isolated from tunicate Polycarpa aurata (Table2). Both alkaloid compounds have a rare 1,2,4-thiadiazole ring (Figure 10). Compound 112 demonstrated potent cytotoxic activity against mouse lymphoma L5187Y cancer cell line with an IC50 value of 0.41 µM[52]. Molecules 2021, 26, x FOR PEER REVIEW 14 of 23

[48]. Moreover, a new nortriterpenoid saponin, namely sarasinoside S (105), was identified from the marine sponge Petrosia sp. obtained in North Sulawesi [49]. Compound 105 was the first among the nortriterpenes in the saranoside family with a degraded side chain (Figure 9).

2.2. Tunicates Tryptamine-derived alkaloids named leptoclinidamide (106) and (-)-leptoclinidamine B (107) were isolated from tunicate L. dubius collected from Lembeh Strait, North Sulawesi [50]. Compound 107 is the enantiomer of the previously isolated compound, (+)-leptoclinidamine B. These compounds have a unique amide moiety with two β-alanine units and D-arginine moiety, respectively [50]. Eleven compounds were identified from tunicate Lissoclinum cf. badium collected in Manado, Indonesia. Among these 11 compounds, there were four new polysulfur aromatic alkaloids named lissoclibadins 4–7 (108–111) (Figure 10), isolated with seven known alkaloids called lissoclibadins 1–3, lissoclinotoxins E and F, 3,4-dimethoxy6-(2′-N,N-dimethylaminoethyl)-5-(methylthio)benzotrithiane, and N,N-dimethyl-5-(methylthio)varacin [51]. Bioactivities of these compounds included inhibition against yeast Saccharomyces cere- Molecules 2021, 26, 1898 15 of 22 visiae demonstrated by compounds 109–111, and antimicrobial activity against S. aureus and E. coli evident from compounds 108–111 [51].

Figure 10. Chemical structuresFigure of 10. 106Chemical–111. structures of 106–111.

Table 2. SummaryOther alkaloids of the marine polycarpathiamines natural products isolated A fromand theB (112 marine and tunicates 113), were fromIndonesian isolated from oceans. tunicate Polycarpa aurata (Table 2). Both alkaloid compounds have a rare 1,2,4-thiadiazole ring Compound Compound Class Species Biological Activity Ref (Figure 10). Compound 112 demonstrated potent cytotoxic activity against mouse lym- Leptoclinidamide (106) Alkaloid Leptoclinides dubius n.a. [50] (-)-leptoclinidaminephoma B (107 L5187Y) cancer Alkaloid cell line with an ICL.50 value dubius of 0.41 µM [52].n.a. [50] Lissoclibadin 4 (108) Alkaloid Lissoclinum cf. badium Antibacterial against S. [51] Table 2. Summary of the marine natural products isolated from the marine tunicates from Indonesianaureus and oceans.E. coli Lissoclibadin 5 (109) Alkaloid Lissoclinum cf. badium Antibacterial against S. [51] Compound Compound Species Biological Activityaureus and E. coli; anti-yeast Ref Class activity against S. cerevisiae Lissoclibadin 6 (110) Alkaloid Lissoclinum cf. badium Antibacterial against S. [51] Leptoclinidamide (106) Alkaloid Leptoclinides dubius n.a. aureus and E. coli; anti-yeast[50] (-)-leptoclinidamine B (107) Alkaloid L. dubius n.a. activity against S. cerevisiae[50] Lissoclibadin 4 (108Lissoclibadin) 7 (111)Alkaloid Lissoclinum Alkaloid cf. badiumLissoclinum Antibacterialcf. badium againstAntibacterial S. aureus against andS. [51] [51] aureus and E. coli; anti-yeast E. coli activity against S. cerevisiae Lissoclibadin 5 (109Polycarpathiamine) A (Alkaloid112) Lissoclinum Alkaloid cf. badiumPolycarpa Antibacterial aurata againstCytotoxic S. aureus against and mouse [51] [52,53] E. coli; anti-yeastlymphoma activity against L5187Y cancerS. cell line Polycarpathiamine B (113) Alkaloid P. auratacerevisiae n.a. [52] Polyaurine A (114) Alkaloid P. aurata Egg deformation of [53] Schistosoma mansoni Polyaurine B (115) Alkaloid P. aurata n.a. [53] Ethyl benzoyl derivatives P. aurata n.a [53] 2-(4-methoxyphenyl)-2-oxoacetate (116) Methyl benzoyl derivatives P. aurata n.a. [53] 2-(4-hydroxyphenyl)-2-oxoacetate (117) Mollamide B (118) Peptide Didemnum molle Cytotoxic against human [54] non-small cell lung H460, breast MCF-7, and glioblastoma SF268 cells; antimalarial against P. falciparum; antiparasitic against Leishmania donovani; antiviral against HIV-1 Molecules 2021, 26, x FOR PEER REVIEW 15 of 23

Lissoclibadin 6 (110) Alkaloid Lissoclinum cf. badium Antibacterial against S. aureus and [51] E. coli; anti-yeast activity against S. cerevisiae Lissoclibadin 7 (111) Alkaloid Lissoclinum cf. badium Antibacterial against S. aureus and [51] E. coli; anti-yeast activity against S. cerevisiae Polycarpathiamine A (112) Alkaloid Polycarpa aurata Cytotoxic against mouse lymphoma [52,53] L5187Y cancer cell line Polycarpathiamine B (113) Alkaloid P. aurata n.a. [52] Polyaurine A (114) Alkaloid P. aurata Egg deformation of Schistosoma [53] mansoni Polyaurine B (115) Alkaloid P. aurata n.a. [53] Ethyl 2-(4-methoxyphenyl)-2- benzoyl de- P. aurata n.a [53] oxoacetate (116) rivatives MoleculesMethyl2021 2-(4-hydroxyphenyl)-2-, 26, 1898 benzoyl de- P. aurata n.a. 16[53] of 22 oxoacetate (117) rivatives Mollamide B (118) Peptide Didemnum molle Cytotoxic against human non-small [54] Table 2. Cont. cell lung H460, breast MCF-7, and glioblastoma SF268 cells; antimalar- Compound Compound Class Speciesial against Biological P. falciparum Activity; antipara- Ref Mollamide C (119) Peptide D. molle sitic againstCytotoxic Leis againsthmania mouse donovani; [54] antivirallymphocytic against HIV-1 leukaemia L1210, human colorectal Mollamide C (119) Peptide D. molle CytotoxicHCT116, against lung mouse H125, lympho- and [54] cytic leukaemiamurine colon L1210, MC human 38 colorectal HCT116,cancer cells lung H125, and murine colon MC 38 cancer cells AnotherAnother twotwo novelnovel alkaloidsalkaloids havehave recentlyrecently beenbeen isolatedisolated fromfrom anotheranother P.P. aurata aurata from from thethe coastcoast of Siladen, Siladen, North North Sulawesi Sulawesi [53]. [53 ].Featuring Featuring a p-methoxyphenyl a p-methoxyphenyl group, group, these these com- compoundspounds were were named named polyaurines polyaurines A ( A114 (114) and) and B ( B115 (115). Compound). Compound 114114 deformeddeformed eggs eggs of ofparasite parasite SchistosomaSchistosoma mansoni mansoni, yet, yet it was it was not not toxic toxic to mammalian to mammalian cells cells [53]. [ 53Two]. Two new newben- benzoylzoyl derivatives derivatives from from this this species, species, ethyl ethyl 2-(4-methoxyphenyl)-2-oxoacetate 2-(4-methoxyphenyl)-2-oxoacetate (116 ()116 and) and me- methylthyl 2-(4-hydroxyphenyl)-2-oxoacetate 2-(4-hydroxyphenyl)-2-oxoacetate (117 (117), were), were also also isolated isolated (Figure (Figure 11). 11 ).

FigureFigure 11.11.Chemical Chemical structuresstructures ofof112 112––119.119.

Two new cyclic hexapeptides, mollamides B (118) and C (119) (Figure 11), were isolated from D. mole found in Manado Bay, Indonesia. Compound 118 was found to

have an antiparasitic activity against Plasmodium falciparum D6 clone (IC50 = 2.9 µM), P. falciparum W2 clone (IC50 = 3 µM), and Leishmania donovani (IC50 = 25.9 µM and IC90 = 50.3 µM) [54]. Compound 118 also displayed antiviral activity against HIV-1 in human PBM cells with an EC50 value of 48.7 µM and anticancer activity against the non-small lung H460, the breast MCF-7, and the human glioblastoma CNS SF268 cancer cell lines [54]. Furthermore, compound 119 showed anticancer activity with a unit zone differential value of 100 against mouse lymphocytic leukaemia L1210, human colon HCT116, and human lung H125 cells. This compound also showed a differential value of 250 against murine colon 38 [54]. However, compounds 118 and 119 did not show anti-inﬂammatory activity either in vitro in a cell-based assay through a cyclooxygenase enzyme (COX-2) activity assay or in vivo in rat neonatal microglia [54]. Furthermore, compounds 118 and 119 did not show antimicrobial activity against MRSA, Mycobacterium intracellulaire, Candida albicans, C. glabrata, C. krusei, nor Cryptococcus neoformans [54]. Molecules 2021, 26, 1898 17 of 22

2.3. Soft Corals Terpenoids were often isolated from soft corals, with varying degrees of bioactivities (Table3). Sarcofuranocembrenolides A ( 120) and B (121) were isolated from the soft coral Molecules 2021, 26, x FOR PEER REVIEW 16 of 23 Sarcophyton sp. collected in North Sulawesi [55]. Cembranoid 120 is a bisnorcembrenolide featuring a unique carbon skeleton of 8,19-bisnorfuranocembrenolide (Figure 12). On the other hand, cembranoid 121 is a furanocembrenolide with a C1 unit (C-20) attached to C-10. Two newIn the cyclic ordinary hexapeptides, cembrenolides, mollamides the C1 Bunit (118 is) and attached C (119 to) C-12(Figure [55 ].11), were isolated from D. mole found in Manado Bay, Indonesia. Compound 118 was found to have Table 3. Summaryan antiparasitic of the marine activity natural against products Plasmodium isolated from falciparum the marine D6 clone soft corals (IC50 from = 2.9 Indonesian µM), P. falcipa- oceans. rum W2 clone (IC50 = 3 µM), and Leishmania donovani (IC50 = 25.9 µM and IC90 = 50.3 µM) Compound[54]. Compound 118 also Compound displayed Class antiviral Species activity against BiologicalHIV-1 in human Activity PBM cells Ref Sarcofuranocembrenolidewith an A (EC12050) value of Terpenoid48.7 µM and anticancerSarcophyton activitysp. against n.a. the non-small lung H460, [55] Sarcofuranocembrenolidethe breast B (121 MCF-7,) and Terpenoidthe human glioblastomaSarcophyton CNSsp. SF268 cancer n.a. cell lines [54]. Further- [55] Chloroscabrolide A (122) Terpenoid Sinularia sp. n.a. [56] more, compound 119 showed anticancer activity with a unit zone differential value of 100 Chloroscabrolide B (123) Terpenoid Sinularia sp. n.a. [56] Prescabrolide (124)against mouse lymphocytic Terpenoid leukaemia L1210,Sinularia humansp. colon n.a.HCT116, and human lung [56] Cladielloide A (125)H125 cells. This compound Terpenoid also showed Cladiellaa differentialsp. value of n.a. 250 against murine colon [57] Cladielloide B (126)38 [54]. However, compounds Terpenoid 118 and 119Cladiella did notsp. show anti-inflammatory Cytotoxic against activity lymphocytic either [57] in vitro in a cell-based assay through a cyclooxygenase enzymeleukaemia (COX-2) CCRF-CEM activity assay cells; or in vivo in rat neonatal microglia [54]. Furthermore, compoundsinhibition 118 and of 119 superoxide did not show anion generation; inhibition of antimicrobial activity against MRSA, Mycobacterium intracellulaire, Candida albicans, C. gla- elastase release 3,4-epoxy-nephthenolbrata, acetate C. krusei (127), nor Cryptococcus Terpenoid neoformansNephthea [54]. sp. Antiproliferative activity against [58] human glioblastoma SF268, 2.3. Soft Corals breast MCF-7, and non-small cell Terpenoids were often isolated from soft corals, with varyinglung degrees H460 cancer of bioactivities cells Sangiangol A (128) Terpenoid Anthelia sp. Cytotoxic rat bladder tumour [59] (Table 3). Sarcofuranocembrenolides A (120) and B (121) wereNBT-T2 isolated cell from line the soft coral Sangiangol B (129)Sarcophyton sp. collected Terpenoid in North SulawesiAnthelia [55]. Cembranoidsp. 120 Cytotoxic is a bisnorcembrenolide rat bladder tumour [59] featuring a unique carbon skeleton of 8,19-bisnorfuranocembrNBT-T2enolide cell (Figure line 12). On the Lobozoanthamine (130other) hand, cembranoid Alkaloid 121 is a furanocembrenolideLobophytum sp. with a C n.a.1 unit (C-20) attached to C- [60] 10. In the ordinary cembrenolides, the C1 unit is attached to C-12 [55].

Figure 12. Chemical structuresFigure 12.of 120Chemical–130. structures of 120–130.

Three C-4 norcembranoids-typeThree C-4 norcembranoids-type macrocyclic macrocyclic diterpenoids, diterpenoids, namely chloroscabrolide namely chloroscabrolide A (122), chloroscabrolideA(122), chloroscabrolide B (123), and B prescarbolide (123), and prescarbolide (124), were ( 124isolated), were from isolated Sinularia from sp.Sinularia sp. collected fromcollected Bunaken from Marine Bunaken Park, Marine Manado, Park, North Manado, Sulawesi North [56]. Sulawesi Compounds [56]. Compounds 122 and 122 and 123 are two123 of veryare two few of chlorinated very few chlorinated compounds compounds from soft coral from metabolites soft coral metabolites and the second and the second example within the class of cembranoids (Figure 12). These two compounds also feature an oxygen bridge connecting C-13 and C-15, which is quite unusual. Meanwhile, the terpenoid prescarbolide (124) is believed to be the precursor of the scabrolide/leptocladolide family of cembranoids [56]. Two new isomeric eunicellin-type diterpenoids were isolated from an Indonesian octocoral Cladiella sp. in the West Pacific Ocean [57]. Cladielloide A (125) and cladielloide B

Molecules 2021, 26, 1898 18 of 22

example within the class of cembranoids (Figure 12). These two compounds also feature an oxygen bridge connecting C-13 and C-15, which is quite unusual. Meanwhile, the terpenoid prescarbolide (124) is believed to be the precursor of the scabrolide/leptocladolide family Molecules 2021, 26, x FOR PEER REVIEW 17 of 23 of cembranoids [56]. Two new isomeric eunicellin-type diterpenoids were isolated from an Indonesian octocoral Cladiella sp. in the West Paciﬁc Ocean [57]. Cladielloide A (125) and cladielloide B((126126) )both both possess possess a a 2-hydroxybutyroxy 2-hydroxybutyroxy group group in their structures (Figure(Figure 13 13).). CompoundCompound 126126exhibited exhibited a a potent potent inhibitory inhibitory effect effect on on superoxide superoxide anion anion generation generation and and elastase elastase release re- bylease human by human neutrophils neutrophils at 22 µ atM. 22 It µM. also showedIt also showed moderate moderate cytotoxicity cytotoxicity against against the acute the lymphocytic leukaemia CCRF-CEM tumour cells with an IC value of 10.1 µM[57]. acute lymphocytic leukaemia CCRF-CEM tumour cells with50 an IC50 value of 10.1 µM [57].

FigureFigure 13.13.The The distributiondistribution ofof samplesample originorigin andand thethe division division of of compound compound class class by by genus. genus.

AA terpenoidterpenoid compound,compound, 3,4-epoxy-nephtenol3,4-epoxy-nephtenol ((127127),), waswas isolatedisolated fromfrom thethe soft soft coral coral NephtheaNephthea sp.sp. found found in in Seribu Seribu Islands, Islands, DKI DKI Jakarta Jakarta [58]. [58 ].Compound Compound 127127 showedshowed weak weak in- inhibitoryhibitory growth growth against against three three human human tumour tumour cell cell lines, i.e., humanhuman glioblastomaglioblastoma SF268,SF268, humanhuman breastbreast MCF-7,MCF-7, and and human human non-small non-small cell cell lung lung H460 H460 cancer cancer cells cells [ 58[58].]. TheThe latestlatest finding ﬁnding on on terpenoids terpenoids from from soft soft coral coral was was discovered discovered from from AntheliaAnthelia sp. col-sp. collectedlected at atBanten, Banten, West West Java, Java, which which successf successfullyully isolated isolated two two new new dolabellane dolabellane diterpe- diter- penoids,noids, sangiangol sangiangol A A(128 (128) and) and sangiangol sangiangol B B(129 (129). ).These These two two compounds compounds were were found found to toshow show weak weak toxicity toxicity against against NBT-T2 NBT-T2 rat ratbladder bladder epithelial epithelial cells cells (BRC-1370) (BRC-1370) at 18 at and 18 and 28.2 28.2µM,µ respectivelyM, respectively [59]. [The59]. first The reported ﬁrst reported zoanthamine-type zoanthamine-type alkaloid alkaloid from froma marine a marine inver- invertebratetebrate other other than thanzoanthids zoanthids was named was named lobozoanthamine lobozoanthamine (130), ( 130isolated), isolated from fromthe Indo- the Indonesiannesian soft coral soft coral LobophytumLobophytum sp. collectedsp. collected from fromthe Bunake the Bunakenn Marine Marine Park, Park,Manado, Manado, North NorthSulawesi Sulawesi [60]. However, [60]. However, there is there no report is no on report the bioactivity on the bioactivity of the compounds of the compounds 120–125 120and–125 130and (Table130 3).(Table 3).

Table 3. Summary of the marine3. Conclusions natural products isolated from the marine soft corals from Indonesian oceans. Indonesian marine biodiversity holds immense potential for drug discovery and Compound bioprospecting,Compound supporting Species the continuous explorationBiological Activity and investigation of Indonesian Ref MNPsClass from marine invertebrates such as sponges, tunicates, and soft corals. This is further Sarcofuranocembrenolide A (justiﬁed120) Terpenoid by no less thanSarcophyton a hundred sp. and thirtyn.a. novel compounds reported in this review[55] Sarcofuranocembrenolide B (from121) 43Terpenoid publications Sarcophyton throughout sp. 2007–2020, then.a. majority of which were isolated from[55] the Chloroscabrolide A (122) IndonesianTerpenoid marine invertebratesSinularia sp. collected fromn.a. the North region of Sulawesi, Indonesia[56] (Figure 13). Chloroscabrolide B (123) Terpenoid Sinularia sp. n.a. [56] Prescabrolide (124) Terpenoid Sinularia sp. n.a. [56] Cladielloide A (125) Terpenoid Cladiella sp. n.a. [57] Cladielloide B (126) Terpenoid Cladiella sp. Cytotoxic against lymphocytic leu- [57] kaemia CCRF-CEM cells; inhibition of superoxide anion generation; inhibition of elastase release

Molecules 2021, 26, x FOR PEER REVIEW 18 of 23

3,4-epoxy-nephthenol acetate Terpenoid Nephthea sp. Antiproliferative activity against [58] (127) human glioblastoma SF268, breast MCF-7, and non-small cell lung H460 cancer cells Sangiangol A (128) Terpenoid Anthelia sp. Cytotoxic rat bladder tumour [59] NBT-T2 cell line Sangiangol B (129) Terpenoid Anthelia sp. Cytotoxic rat bladder tumour [59] NBT-T2 cell line Lobozoanthamine (130) Alkaloid Lobophytum sp. n.a. [60]

3. Conclusions Indonesian marine biodiversity holds immense potential for drug discovery and bioprospecting, supporting the continuous exploration and investigation of Indonesian MNPs from marine invertebrates such as sponges, tunicates, and soft corals. This is further justified by no less than a hundred and thirty novel compounds reported in this review from 43 publications throughout 2007–2020, the majority of which were isolated

Molecules 2021from, 26, 1898the Indonesian marine invertebrates collected from the North region of Sulawesi,19 of 22 Indonesia (Figure 13). Indonesian sponges have been known as a major source of many novel MNPs. In this review, sponges wereIndonesian found to sponges contribute have beento 105 known novel as a compounds major source ofreported many novel between MNPs. In 2007-2020, the majoritythis review, being sponges alkaloids were found (Figure to contribute 14). Most to 105 of novelthe sponge compounds alkaloids reported were between isolated from the 2007–2020,genera Aplysinella the majority and being Acanthostrongulophora alkaloids (Figure 14). Most. The of next the sponge large alkaloidsgroups of were metabolites isolatedisolated from from Indonesian the genera spongesAplysinella wereand Acanthostrongulophora terpenes and peptides.. The next Nearly large all groups the of metabolites isolated from Indonesian sponges were terpenes and peptides. Nearly all the sponge terpenoidssponge were terpenoids isolated werefrom isolated the order from Dictyoceratida, the order Dictyoceratida, in which in which the dominant the dominant genera were Lamellodysideagenera were andLamellodysidea Carteriospongiaand Carteriospongia. .

FigureFigure 14. Biological 14. Biological activities activities of compounds of compounds isolated from Indonesianisolated from marine Indonesian invertebrates marine (left) and invertebrates the division of genus(left) by compoundand the division class (right). of genus by compound class (right). Meanwhile, all the peptides, with the exception of two peptides from Ircinia sp., were isolated from the order Tetractinellida. On the other hand, macrolides, steroids, and saponins were the least frequently isolated metabolites from Indonesian sponges. The sponge Plakortis simplex was the sole contributor of the polyketides isolated from Indonesia (Table1). During 2007–2020, ten alkaloids were reported from Indonesian tunicates, mainly from the family Didemnidae and Styelidae. Soft corals are also a good source of novel metabolites and are well-known as a producer of terpenoids, particularly the group of terpenes and cembranoid diterpenes. Soft coral-derived terpenoids have received signiﬁcant attention in Indonesian MNPs research (Table3). Compared to other invertebrates with alkaloids as the most abundant secondary metabolites, only one alkaloid was found in Indonesian soft coral species in this review. Indonesian soft corals and tunicates yielded far lower novel secondary metabolites than sponges reported throughout 2007–2020. Therefore, this review highlighted the opportunity to explore further the chemical diversity and the biological activity of tunicates from Indonesian waters. Molecules 2021, 26, 1898 20 of 22

Diverse biological activities were shown by ﬁfty per cent of the compounds isolated from the three Indonesian marine invertebrates discussed (Figure 14). The majority of compounds in this review were reported to possess cytotoxic or antiproliferative activity against various cancer cell lines. Four of these compounds showed a remarkable cytotoxic activity with IC50 values of less than 1 µM, namely compounds 30, 38, 103 and 112. Further- more, four compounds showed IC50 values between 1–4 µM, and another eight showed moderate cytotoxic with an IC50 value of less than 10 µM. Most of these compounds belong to the alkaloid group, followed by peptides and terpenoids. It is, therefore, evident that the exploration of potential anticancer drugs from Indonesian marine resources warrants further investigation. The bioactivity of compounds isolated from the Indonesian marine invertebrates (sponges, tunicates, and soft corals) as antimicrobial, antifungal, or antiviral was also described in this review. Unfortunately, little or no such activities were yet to be found from many compounds derived from the three Indonesian marine invertebrates, demon- strating the gap in the knowledge of their beneﬁcial biological activity other than their cytotoxic activity. This knowledge gap opens up the opportunity for further research focusing on exploring and harnessing the potential of Indonesian marine invertebrates as sources of compounds with antimicrobial, antifungal, or antiviral activities, as well as further exploration of Indonesian marine biodiversity for the discovery of novel bioactive compounds.

Author Contributions: Conceptualization, M.Y.P., A.B. and F.I.; resources, F.I., A.B. and M.F.W.; writing—original draft preparation, F.I. and A.B.; writing—review and editing, F.I., A.B., M.F.W., S.I.R., L.S., A.A., A.P., M.Y.P.; visualization, F.I., A.B. and M.F.W.; supervision, M.Y.P. and A.B.; project administration, A.B. and F.I.; All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the Indonesian Institute of Sciences (LIPI) through the DIPA 2021 Research Fund B-10405/IPH/HK.01.03/XI/2020. Institutional Review Board Statement: Not Applicable. Informed Consent Statement: Not Applicable. Data Availability Statement: Not Applicable. Acknowledgments: We would like to thank the Head of Research Center for Biotechnology, Indone- sian Institute of Sciences, as well as the research and administration staff members for their support. All authors are supported by the DIPA 2021 Research Fund. Conﬂicts of Interest: The authors declare there is no conﬂict of interest. Sample Availability: Not Applicable.

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