(Arenochalina), Biemna and Clathria

marine drugs

Review Chemistry and Biological Activities of the Marine Sponges of the Genera Mycale (Arenochalina), Biemna and Clathria

Amr El-Demerdash 1,2,* ID , Mohamed A. Tammam 3,4, Atanas G. Atanasov 5,6 ID , John N. A. Hooper 7 ID , Ali Al-Mourabit 8 and Anake Kijjoa 9,* ID 1 Muséum National d’Histoire Naturelle, Molécules de Communication et Adaptation des Micro-organismes, Sorbonne Universités, UMR 7245 CNRS/MNHN, CP 54, 57 Rue Cuvier, 75005 Paris, France 2 Organic Chemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt 3 Department of Pharmacognosy and Chemistry of Natural products, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens 15771, Greece; [email protected] 4 Department of Biochemistry, Faculty of Agriculture, Fayoum University, 63514 Fayoum, Egypt 5 Department of Pharmacognosy, University of Vienna, 1090 Vienna, Austria; [email protected] 6 Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland 7 Queensland Museum, Biodiversity & Geosciences Program, P.O. Box 3300, South Brisbane BC, Queensland 4101, Australia; [email protected] 8 ICSN—Institut de Chimie des Substances Naturelles, CNRS UPR 2301, University of Paris-Saclay, 1, Avenue de la Terrasse, 91198 Gif-Sur-Yvette, France; [email protected] 9 ICBAS—Instituto de Ciências Biomédicas Abel Salazar & CIIMAR, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal * Correspondence: [email protected] (A.E.-D.); [email protected] (A.K.); Tel.: +33-7584-90229 (A.E.-D.); +351-2204-28331 (A.K.); Fax: +351-2206-2232 (A.K.) Received: 28 April 2018; Accepted: 13 June 2018; Published: 18 June 2018

Abstract: Over the past seven decades, particularly since the discovery of the ﬁrst marine-derived nucleosides, spongothymidine and spongouridine, from the Caribbean sponge Cryptotethya crypta in the early 1950s, marine natural products have emerged as unique, renewable and yet under-investigated pools for discovery of new drug leads with distinct structural features, and myriad interesting biological activities. Marine sponges are the most primitive and simplest multicellular animals, with approximately 8900 known described species, although more than 15,000 species are thought to exist worldwide today. These marine organisms potentially represent the richest pipeline for novel drug leads. Mycale (Arenochalina) and Clathria are recognized marine sponge genera belonging to the order Poecilosclerida, whereas Biemna was more recently reclassiﬁed, based on molecular genetics, as a new order Biemnida. Together, these sponge genera contribute to the production of physiologically active molecular entities with diverse structural features and a wide range of medicinal and therapeutic potentialities. In this review, we provide a comprehensive insight and up-to-date literature survey over the period of 1976–2018, focusing on the chemistry of the isolated compounds from members of these three genera, as well as their biological and pharmacological activities, whenever available.

Keywords: marine sponges; Poecilosclerida; Biemnida; Mycale (Arenochalina), Biemna; Clathria; crambescidins; batzelladines; guanidine alkaloids; pteridine alkaloids; terpenoids; thiopepetides; macrolides; polyketides; indole alkaloids; pyrrole-containing alkaloids; nucleotides; terpenoids; steroids; fatty acids

Mar. Drugs 2018, 16, 214; doi:10.3390/md16060214 www.mdpi.com/journal/marinedrugs Mar. Drugs 2018, 16, 214 2 of 26

1. Introduction Current medical risks, including diabetes, chronic pains, hepatitis, hypertension, microbial infection, together with the emergence of multidrug-resistant microbes and different types of carcinoma, have motivated and encouraged scientists to search for new bioactive compounds with novel modes of action [1]. Naturally occurring compounds derived from plants, marine invertebrates and microorganisms have provided important platforms and ideal validated starting materials for drug development and manufacturing [2]. Marine natural products represent a potent, promising and valuable source of supply for new chemical entities possessing unprecedented and novel mechanisms of action [2–7]. At present, marine-derived compounds or derivatives thereof have contributed to seven approved drugs for the market: cytarabine (Cytosar-U®, Depocyst®, approved by FDA in 1969 for cancer treatment), vidarabine (Vira-A®, approved by FDA in 1976 as antiviral), ziconotide (Prialt®, approved by FDA in in 2004 as analgesic for treatment of severe chronic pain), trabectedin (Yondelis®, ET-743, approved in the EU in 2007 as an anticancer), eribulin mesylate (Halaven®, approved by FDA in 2010 and by Heath Canada in 2011 for metastatic breast cancer treatment), brentuximab vidotin (Adcetris®, approved by FDA in 2011 for Hodgkin’s lymphoma cells, and in 2017 for cutaneous T-cell lymphoma) and omega-3 acid ethyl esters (Lovaza®, approved by FDA in 2004 for lowering blood triglyceride levels in adults with severe hypertriglyceridemia) [8,9]. Moreover, twelve marine natural products are being under exploration in different phases of clinical trials [8], and a number of them are in the preclinical pipeline. Despite being the most basal of metazoan animal phyla, marine sponges (Porifera) greatly contribute as prolific suppliers of potentially valuable novel compounds to the clinical pipeline, with almost 47% of all reported bioactive compounds from the marine environment. Several relevant reports have shown that almost 62.5% (i.e., 10 out of 16) of clinically approved medicines, or those in ongoing advanced clinical phases, are derived from marine invertebrates, including marine sponges [10,11]. Marine sponges of the genera Mycale (Arenochalina) (family Mycalidae), Clathria (family Microcionidae), and Biemna (family Desmacellidae) include diverse sponge species belonging to the orders Poecilosclerida and Biemnida. They are rich producers of diverse and physiologically active secondary metabolites [12,13] with a wide range of biological activities, including cytotoxic, antimalarial [14,15], anti-HIV [16], anti-inflammatory [17,18], enzyme inhibitors [19], antifungal and antibacterial properties [20,21]. Some of these compounds are chemotaxonomic markers, particularly for some Poecilosclerida marine sponges of the genera Batzella, Crambe and Monanchora [22]. The World Porifera Database [23] lists 14 valid species of Mycale (Arenochalina), 55 of Biemna, and 381 of Clathria. To the best of our knowledge, chemical investigations have previously been carried out only on nineteen species of the genus Mycale (Arenochalina), i.e., Mycale (Arenochalina) mirabilis and Mycale (Arenochalina) sp., M. rotalis, M. aff. graveleyi, M. laxxissima, M. izuensis, M. fibrexilis, M. ancorina, M. (carmia) cf. spongiosa, M. adhaerens, M. magellanica, M. hentscheli, M. micracanthoxea, M. tenuispiculata, M. cecilia, M. laevis, M. lissochela and M. plumos. For the genus Biemna, only four species, including Biemna laboutei, Biemna sp., B. ehrenbergi, and B. fortis, were chemically studied, while eleven species of the genus Clathria, i.e., Clathria hirsuta, C. gombawuiensis, C. cervicornis, C. compressa, C. araiosa, Clathia. sp., C. calla, C. reinwardtii, C. lissosclera, C. basilana, C. strepsitoxa and C. pyramida were chemically investigated (Table1). Due to our interest in the marine sponges of the order Poecilosclerida [ 22,24–26], we have reviewed the literature reporting the isolation of secondary metabolites from these three marine sponge genera, covering the period of 1976–2018. This up-to-date review focuses mainly on the chemistry of the isolated metabolites, although their biological and pharmacological properties are also discussed when they are available. Mar. Drugs 2018, 16, 214 3 of 26

Table 1. Summary of the secondary metabolites isolated from the marine sponges belonging to the genera Mycale (Arenochalina), Biemna and Clathria, their source organisms and biological activities.

Name Compound Class Marine Sponges Collection Bioactivities Ref. Crambescidin 800 (1) Pentacyclic guanidine Clathria (Thalysias) cervicornis - Antimicrobial 21 Crambescidins 1–6 Pentacyclic guanidine C. bulbotoxa Indonesia Cytotoxic, antifungal 28 Norbatzelladine L (7) Tricyclic guanidine C. (Microciona) calla Caribbean Cytotoxic 29 Clathriadic acid (8) Tricyclic guanidine C. (Microciona) calla Caribbean Cytotoxic, antimalarial 29 Mirabilins A–F (9–14) Tricyclic guanidine Mycale (Arenochalina) mirabilis Australia Nr 30 Netamines A–G (15–21) Tricyclic guanidine Biemna laboutei Madagascar Cytotoxicity 31 Netamines H–N (22–28) Tricyclic guanidine B. laboutei Madagascar Cytotoxic, antimalarial 14 Netamines O–S (29–33) Tricyclic guanidine B.laboutei Madagascar Cytotoxic, antimalarial 15 Mirabilin G (34) Tricyclic guanidine Clathria sp. Australia Antibacterial, antifungal 32 Mirabilins H–J (35–37) Tricyclic guanidine Clathria sp. Australia Cytotoxic 33 Araiosamines A–D (38–41) Indole cyclic guanidine C. (Thalysias) araiosa Vanuatu Antibacterial, Anti-HIV-1 34 42–45 Pyridoacridine Biemna sp. Okinawa Cytotoxicity 37 46 and 47 Pyridoacridine Biemna sp. Indonesia Enzyme inhibitor 38 48 and 49 Pyridoacridine Biemna sp. Japan Cytotoxic 39 50–53 Pyridoacridine Biemna sp. Japan Cytotoxic 40 Pseudoanchnazines A–C (54–56) Pteridine alkaloid Clathria sp. Argentina Antibacterial 41 Clathryimine A (57) Quinolizine alkaloid C. (Clathria) basilana Indo-Pacific Nr 42 N-methylpyrrolidone (58) Pyrrolodine Alkaloid C. frondifera India Nr 43 59–69 Indole alkaloids M. fibrexilis China Nr 44 70–83 Pyrrole alkaloids M. micracanthoxea Spain Cytotoxic 45 84–94 Pyrrole alkaloids M. micracanthoxea Venezuela Cytotoxic 46 95–97 Pyrrole alkaloids M. tenuispiculata India Nr 47 98–111 Pyrrole alkaloids M. cecilia California Cytotoxic 48 112 and 113 Pyrrole alkaloids M. lissochela China Enzyme inhibitor 49 Clathrynamides A–C (114–116) Bromine-containing amide Clathria sp. Sad-Misaki, Japan Cytotoxic, inhibitors of starfish eggs 50 Microcionamides A&B (117&118) Cyclic thiopeptide C. (Thalysias) abietina Philippines Cytotoxic, antibacterial 51 Gombamide A (119) Cyclic thiopeptide C. (Clathria) gombawuiensis Korea Cytotoxic, enzyme inhibitor 52 Azumamides (120–124) Cyclic peptides Mycale izuensis Japan Histone Deacetylase 53 Mycalisines (125–126) Nucleotides Mycale sp. Japan Inhibitors of starfish eggs 54 127 and 128 Nucleotides C.(Microciona) strepsitoxa Atlantic Nr 55 129 and 130 Fatty acid M. laevis Caribbean Nr 56 131 Fatty acid M. laxissima Caribbean Nr 57 132–134 Fatty acid M. euplectellioides Red Sea Cytotoxic 58 Mycalamides A&B (135&136) Polyketide Mycale sp. New Zealand Cytotoxic, antiviral 59–60 Mycalamide D (137) Polyketide Mycale sp. New Zealand Cytotoxic 61 Mar. Drugs 2018, 16, 214 4 of 26

Table 1. Cont.

Name Compound Class Marine Sponges Collection Bioactivities Ref. 138–140 Polyketide M. rotalis Mediterranean Nr 62–63 141–146 Anthraquinone C. (Thalysias) hirsuta Australia Nr 64 147–149 Macrolide Mycale sp. Japan Antifungal, cytotoxic 65 150 Macrolide M. adhaerens Lamb Japan Cytotoxic 66 Pateamine (151) Macrolide Mycale sp. New Zealand Cytotoxic 67 152 and 153 Macrolide Mycale sp. Japan Cytotoxic 68 154–156 Macrolide M. magellanica Japan Cytotoxic 69–70 Peloruside A (157) Macrolide Mycale sp. New Zealand Cytotoxic 71 158 Macrolide M. izuensis Japan Cytotoxic 72 159 Macrolide Mycale sp. Japan Cytotoxic 73 Peloruside B (160) Macrolide M. hentscheli New Zealand Cytotoxic 74 161 and 162 Macrolide Mycale sp. Japan Cytotoxic 75 Peloruside C&D (163&164) Macrolide M. hentscheli New Zealand Cytotoxic 76 165-169 Sesquiterpene M. (Arenochalina) sp Australia Antitumor, antifungal 80–83 Clathrin A–C (170–172) Sesterterpene Clathria sp Australia - 84 Clathric acid (173)C21 terpenoid C. compressa Florida Antimicrobial 20 Clathrimide A&B (174&175)C21 -terpenoid C. compressa Florida Antimicrobial 20 Gombaspiroketal A–C (176–178) Sesterterpene C. gombawuiensis Korea Antibacterial, enzyme inhibitors 85 179 and 181 Norterpene/triterpene C. gombawuiensis Korea Antibacterial 86 Rotalins (182–183) Diterepene M. rotalis Mediterranean Nr 87 Mycgranol (184) Diterepene M. aff. graveleyi Kenya Nr 88 185–189 Cyclic norterpenoid peroxide M. ancorina Australia Nr 89 190 and 191 Cyclic norterpenoid peroxide M. (carmia) cf. spongiosa Australia Antimicrobial 90 192 and 193 Cyclic norterpenoid peroxide Mycale sp. Thailand Cytotoxic, antiviral 91 194–201 Cyclic peroxide/norditerepene Mycale sp. Australia Nr 92 202–204 Cyclic norterpenoid peroxide Mycale sp. Australia Nr 93 205 Cyclic norterpenoid peroxide Mycale sp. Thailand Cytotoxic 94 206 and 207 Tetraterpene C. frondifera (=C. (Thalysias vulpina) Japan Nr 95–96 Contignasterol (208) Steroid C. (Clathria) lissosclera New Zealand Histamine inhibitory 17–18 Clathriols A&B (209&210) Steroid C. (Clathria) lissosclera New Zealand Anti-inﬂammatory, histamine inhibitory 17–18 Clathsterol (211) Sulphated sterol Clathria sp. Red Sea Anti-HIV-1 16 Biemansterol (212) Sterol Biemna sp. Okinawa, Japan Cytotoxic 97 213 Sterol Biemna sp. Okinawa, Japan Cytotoxic 97 Foristerol (214) Sterol B. fortis China Nr 98 215 Sterol B. triraphis Madagascar Nr 99 Mar. Drugs 2018, 16, 214 5 of 26

Table 1. Cont.

Name Compound Class Marine Sponges Collection Bioactivities Ref. 216–224 Sterol B. fortis China Lymphocytes and hPTP1B inhibition 100 225 and 226 Sterol B. ehrenbergi Red Sea Cytotoxic, antibacterial 101 227–235 Sterol M. laxissima Caribbean Fertilized eggs inhibitors 102–103 Mycapolyols A–F (184–189) Mixed PKS/NPRS M. izuensis Japan Cytotoxic 104 242 Thio-sugar C. (Dendrocia) pyramida Australia Nr 105 243 Glycol C.reinwardtti India Nr 106 244 1,5-Diamine Mycale sp. Kenya Cytotoxic 107 Mar. Drugs 2018, 16, 214 6 of 26

2. Chemistry and Biological Activities of the Secondary Metabolites Isolated from the Marine Sponges of the Genera Mycale (Arenochalina), Biemna and Clathria In this section, we provide insights into the chemical classes and biological activities of the marine sponge-derived secondary metabolites obtained from these three genera. For convenience, the isolated compounds are divided into fourteen major groups, according to their skeleton as well as their biosynthetic origins. Additionally, their biological potentialities are also discussed whenever applicable.

Mar. Drugs 2018, 16, x 3 of 26 2.1. Guanidine-Containing Alkaloids Crambescidins,as their biosynthetic batzelladines, origins. Additionally, mirabilins their and biological ptilocaulins potentialities aredeﬁnite are also discussed groups ofwhenever marine cyclic applicable. guanidine-containing alkaloids that display potent biological activities, such as cytotoxic, antiviral, antifungal2.1. Guanidine and anti-HIV-1-Containing gp Alkaloids 120-human. These compounds were isolated from various marine sponge genera,Crambescidins, like Batzella batzelladines,, Crambe, Monanchoramirabilins andand ptilocaulinsPtilocaulis are, definite and are groups chemotaxonomic of marine cyclic markers for the marineguanidine sponges-containing belonging alkaloids tothat the display orders potent Poecilosclerida biological activities and Axinellida, such as cytotoxic, [22,27]. antiviral, Crambescidin 800 (1),antifungal a pentacyclic and anti guanidine-HIV-1 gp alkaloid, 120-human. was These isolated compounds from thewere marine isolated sponge from variousClathria marine(Thalysias ) cervicornissponge, and genera was, foundlike Batzella to display, Crambe, potent Monanchora antimicrobial and Ptilocaulis activity, and are against chemotaxonomicAcinetobacter markers baumannii, Klebsiellafor pneumoniae the marine spongesand Pseudomonas belonging to aeruginosa the orders, withPoecilosclerida MIC values and ofAxinellida 2, 1 and [22,27 1 µg/mL,]. Crambescidin respectively [21]. 800 (1), a pentacyclic guanidine alkaloid, was isolated from the marine sponge Clathria (Thalysias) Recently, three new crambescidin-type alkaloids, including crambescidin 345 (2), crambescidin 361 (3) cervicornis, and was found to display potent antimicrobial activity against Acinetobacter baumannii, and crambescidinKlebsiella pneumoniae 373 (4), and along Pseudomonas with the aeruginosa known congeners, with MIC values1, crambescidin of 2, 1 and 1 359μg/mL, (5) respectively and crambescidin 657 (6)[21]. (Figure Recently,1), were three isolatednew crambescidin from the-typ Indonesiane alkaloids, including marine crambescidin sponge C. 345 bulbotoxa (2), crambescidin. Interestingly, 3 was reported361 (3) and as a crambescidin new crambescidin 373 (4), along congener with which the known possesses congeners two 1, identical crambescidin saturated 359 (5) spiroaminal and six-memberedcrambescidin ring 657 on ( both6) (Figure sides, 1), which were isolated is considered from the to Indonesian be rare within marine sponge the crambescidin C. bulbotoxa. family. Additionally,Interestin3 bearsgly, 3 awas propyl reported group as as a newan alkyl crambescidin substituent congener of the which left-sided possesses tetrahydropyran two identical moiety. saturated spiroaminal six-membered ring on both sides, which is considered to be rare within the Compounds 2–5, possessing only the pentacyclic guanidinium core (vessel), exhibited moderate crambescidin family. Additionally, 3 bears a propyl group as an alkyl substituent of the left-sided cytotoxicitytetrahydropyran against the moiety. A431 Compounds cancer cell 2–5, linepossessing with only IC50 thevalues pentacyclic of 7.0, guanidinium 2.5, 0.94 core and (vessel 3.1),µ g/mL, respectively.exhibited However, moderate 1cytotoxicityand 6, featuring against the both A431 the cancervessel cell andline with the IC long-chain50 values of ω7.0,-hydroxy 2.5, 0.94 and fatty acid (anchor)3.1 motifs, μg/mL, displayed respectively. signiﬁcant However, 1 cytotoxicityand 6, featuring with both IC the50 vesselvalues and of the 48 long and-chain 12 nM,ω-hydroxy respectively. Such variationfatty acid in ( cytotoxicityanchor) motifs, highlighted displayed significant the importance cytotoxicity of the with spermidine IC50 values part, of 48 which and 12 could nM, act as a spacer linkingrespectively. two Such sites variation of interaction in cytotoxicity [24]. highlighted Furthermore, the importance2–4 demonstrated of the spermidine a strong part anti-oomycete, which activitycould against act as the a spacer plant linking pathogenic two sites fungus of interactionPhytophthora [24]. Furthermore, capsici with 2–4 a demonstrated minimum inhibitory a strong dose anti-oomycete activity against the plant pathogenic fungus Phytophthora capsici with a minimum (MID) of 50 µg/disk, while 1 and 6 showed a weak activity with MID 100 mg/disk or even higher [28]. inhibitory dose (MID) of 50 μg/disk, while 1 and 6 showed a weak activity with MID 100 mg/disk or Two batzelladineeven higher derivatives,[28]. Two batzelladine norbatzelladine derivatives, L norbatzelladine (7) and clathriadic L (7) and acid clathriadic (8) (Figure acid1 (),8) were(Figure isolated from the1), Caribbean were isolated marine from the sponge CaribbeanC. (Microciona marine sponge) calla C.. ( CompoundMicrociona) calla7 exhibited. Compound potent 7 exhibited cytotoxicity againstpotent a variety cytotoxicity of cancer against cell lines,a variety including of cancer breast cell lines, cancer including (MDA-MB-231), breast cancer (MDA non-small-MB-231), cell non lung- cancer small cell lung cancer (A549) and colon cancer (HT29), with GI50 = 0.7, 1.1 and 1.2 03BCg/mL, (A549) and colon cancer (HT29), with GI50 = 0.7, 1.1 and 1.2 03BCg/mL, respectively, whereas 8 showed respectively, whereas 8 showed a weak antitumor activity with GI50 = 13.5, >30 and >30 μM, a weak antitumor activity with GI50 = 13.5, >30 and >30 µM, respectively. Moreover, 7 displayed respectively. Moreover, 7 displayed stronger (IC50 = 0.4 μg/mL) antimalarial activity than 8 (IC50 = 2.3 µ 8 µ strongerμg/mL) (IC50 =[29]. 0.4 g/mL) antimalarial activity than (IC50 = 2.3 g/mL) [29].

R H H H H O O O H H O O O N N N N N N O N O N N (CH2)12 X O OH 2, R = H 1, x = NH2 4, R = Et 3 N NH2 5, R = Me

6, x = OH

O H H H N O HO N H H N N (CH2)7 O N N N (CH2)6CH3 H H H N N (CH2)7CH3 8 7 H H Figure 1. Chemical structures of 1–8. Figure 1. Chemical structures of 1–8. Six tricyclic guanidine alkaloids, mirabilins A–F (9–14), were isolated from a Southern Australian marine sponge Mycale (Arenochalina) mirabilis [30]. Later on, seven further cytotoxic tricyclic guanidine alkaloids, netamines A–G (15–21), were reported from a Madagascar marine sponge Biemna laboutei. These compounds showed an in vitro cytotoxic activity against three human cancer cell lines, i.e., NSCL (A549), colon (HT29), and breast (MDA-MB-231). While netamine C (17)

Mar. Drugs 2018, 16, 214 7 of 26

Six tricyclic guanidine alkaloids, mirabilins A–F (9–14), were isolated from a Southern Australian marine sponge Mycale (Arenochalina) mirabilis [30]. Later on, seven further cytotoxic tricyclic guanidine alkaloids, netamines A–G (15–21), were reported from a Madagascar marine sponge Biemna laboutei. These compounds showed an in vitro cytotoxic activity against three human cancer cell lines, i.e., NSCL (A549), colon (HT29), and breast (MDA-MB-231). While netamine C (17) showed GI50 values of 4.3, 2.4 and 2.6 µg/mL, respectively, netamine D (18) exhibited slightly higher GI50 values of 6.6, 5.3 and 6.3 µg/mL against these cancer cell lines [31]. An additional seven tricyclic alkaloids, netamines H–N (22–28), along with the known congeners netamine G (21) and mirabilins A (9), C (11) and F (14),Mar. were Drugs isolated 2018, 16, x from the same marine sponge. These compounds displayed4 cytotoxic of 26 and antimalarialshowed activities. GI50 value Netamines of 4.3, 2.4 M and (27 2.6) exhibited μg/mL, respectively, cytotoxicity netamine against D (18 KB) exhibited cancer slightly cell line higher with the IC50 in a micromolarGI50 values range of 6.6, whereas 5.3 and 6.3 netamine μg/mL against K (25 these) showed cancer cell antiplasmodial lines [31]. An additional activity seven against tricyclicPlasmodium alkaloids, netamines H–N (22–28), along with the known congeners netamine G (21) and mirabilins falciparum with the IC50 value of 2.4 µg/mL [14]. Another ﬁve antimalarial tricyclic guanidine alkaloids, A (9), C (11) and F (14), were isolated from the same marine sponge. These compounds displayed 29 33 19 netaminescytotoxic O–S ( and– antimalarial), were also activities. isolated, Netamine together M (27) with exhibited the cytotoxicity previously against reported KB cancer netamine cell E ( ), from B. labouteiline with. Netamines the IC50 in a micro O–Qmolar (29– 31range) showed whereas anetamine promising K (25)in showed vitro antiplasmodialantimalarial activity activity against P. falciparumagainstwith Plasmodium IC50 values falciparum of 16.99with the± IC4.12,50 value 32.62 of 2.4 μg/mL± 3.44, [14]. and Another 8.37 five± antimalarial1.35 µg/mL, tricyclic respectively. Moreover,guanidine these compounds alkaloids, netamines also exhibited O–S (29–33), cytotoxic were also isolated, activity together against withthe the pr KBeviously cancer reported cell line in the netamine E (19), from B. laboutei. Netamines O–Q (29–31) showed a promising in vitro antimalarial range of 10−5 M[15]. A tricyclic guanidine alkaloid, mirabilin G (34), isolated from the Australian activity against P. falciparum with IC50 values of 16.99 ± 4.12, 32.62 ± 3.44, and 8.37 ± 1.35 μg/mL, sponge Clathriarespectively.sp., displayed Moreover, these a moderate compounds antibacterial also exhibited activity cytotoxic against activity Gram-negativeagainst the KB cancer bacterial cell strains, including lineEscherichia in the range coli ofand 10−5 SerratiaM [15]. A marcescens tricyclic guanidine, as well alkaloid, as antifungal mirabilin G activity (34), isolated against fromSaccharomyces the cerevisiae [Australian32]. Further sponge chemical Clathria investigationsp., displayed a of moderat the marinee antibacterial sponge activityClathria againstsp., Gram collected-negative from South bacterial strains, including Escherichia coli and Serratia marcescens, as well as antifungal activity against 11 14 34 Australia,Saccharomyces resulted in cerevisiae the isolation [32]. Further of mirabilins chemical investigation C ( ), F ( of the) and marine G ( sponge), along Clathria with sp., three new congeners,collected namely from mirabilins South Australia, H–J (35 resulted–37). Compoundsin the isolation of11 mirabilins, 14, 34–37 C (displayed11), F (14) and no Gcytotoxicity (34), along against neuroblastomawith three (SH-SY5Y), new congeners, gastric namely (AGS), mirabilins colorectal H–J (35 (HT29)–37). Compounds and intestinal 11, 14, 34 (Intestine-407)–37 displayed no cancer cell cytotoxicity against neuroblastoma (SH-SY5Y), gastric (AGS), colorectal (HT29) and intestinal lines, with LD50 > 30 µg/mL [33] (Figure2). (Intestine-407) cancer cell lines, with LD50 > 30 μg/mL [33] (Figure 2).

Figure 2. Chemical structures of 9–37. Figure 2. Chemical structures of 9–37. Another interesting group of marine cyclic guanidine alkaloids comprises those containing a bromoindole moiety. The tris-bromoindole cyclic guanidine alkaloids, araiosamine A–D (38–41)

Mar. Drugs 2018, 16, 214 8 of 26

Mar. DrugsAnother 2018, 16 interesting, x group of marine cyclic guanidine alkaloids comprises those containing5 of 26 a bromoindole moiety. The tris-bromoindole cyclic guanidine alkaloids, araiosamine A–D (38–41) (Figure3 3),), werewere isolatedisolated fromfrom thethe marinemarine spongesponge Clathria ((Thalysias)) araiosa,araiosa, collectedcollected from from Vanuatu. Vanuatu. These compounds originated from an unusual mode of linear polymerization of tryptamine units involving a C C–C–C bond formation. Compounds 3838–41 were evaluated for for their antimicrobial activity; however, none of them displayed signiﬁcantsignificant antibacterial activity against S. aureus or anti-HIVanti-HIV activity [[34].34].

Br ''' R' R' R''' R' R' R''' R H H H H MeO HN HO NH H '' NH NH HN R HN NH HN HN NH HN HN N NH ' NH NH HN R NH NH ' H ''' H 38 39 R R 40 41 H HN NH R = HN NH NH N Br H NH

Figure 3. Chemical structures of 38–41.

2.2. Pyridoacridine, Pteridine, Tetrahydroquinolizine and N-methylpyrrolidone Alkaloids 2.2. Pyridoacridine, Pteridine, Tetrahydroquinolizine and N-methylpyrrolidone Alkaloids Pyridoacridine alkaloids are a unique group of marine-derived metabolites and are one of the Pyridoacridine alkaloids are a unique group of marine-derived metabolites and are one of the largest marine alkaloid families. Chemically, they feature a common tetracyclic hetero-aromatic largest marine alkaloid families. Chemically, they feature a common tetracyclic hetero-aromatic parent-11H-pyrido[4,3,2nm] acridine or 4H-pyrido[2,3,4-kl] acridone [35,36]. Among the three marine parent-11H-pyrido[4,3,2nm] acridine or 4H-pyrido[2,3,4-kl] acridone [35,36]. Among the three sponge genera, pyridoacridine alkaloids were exclusively isolated from Biemna species. Biemnadin marine sponge genera, pyridoacridine alkaloids were exclusively isolated from Biemna species. (42), 8, 9-dihydro-11-hydroxyascididemin (43), 8-hydroxyisocystodamine (44) and 9- Biemnadin (42), 8, 9-dihydro-11-hydroxyascididemin (43), 8-hydroxyisocystodamine (44) and hydroxyisocystodamine (45) (Figure 4), were reported from the Okinawan Biemna sp. Compounds 42 9-hydroxyisocystodamine (45) (Figure4), were reported from the Okinawan Biemna sp. Compounds and 43 displayed a significant in vitro cytotoxicity against two tumor cell lines: human epidermoid 42 and 43 displayed a signiﬁcant in vitro cytotoxicity against two tumor cell lines: human epidermoid carcinoma KB (with IC50 values of 1.73 and 0.209 μg/mL, respectively) and murine lymphoma L1210 carcinoma KB (with IC50 values of 1.73 and 0.209 µg/mL, respectively) and murine lymphoma (with IC50 values of 4.29 and 0.675 μg/mL, respectively) [37]. Moreover, labuanine A (46) was isolated, L1210 (with IC50 values of 4.29 and 0.675 µg/mL, respectively) [37]. Moreover, labuanine A (46) along with three previously described congeners, i.e., 42, 45 and isocystodamine (47) (Figure 4), from was isolated, along with three previously described congeners, i.e., 42, 45 and isocystodamine the Indonesian sponge B. fortis. All of these compounds induced multipolar neuritogenesis in more (47) (Figure4), from the Indonesian sponge B. fortis. All of these compounds induced multipolar than 50% of Neuro 2A murine neuroblastoma cells at concentrations of 0.03–3 μM. Interestingly, 47 neuritogenesis in more than 50% of Neuro 2A murine neuroblastoma cells at concentrations of not only displayed the strongest neuritogenic activity but also activated an increase of the 0.03–3 µM. Interestingly, 47 not only displayed the strongest neuritogenic activity but also activated acetylcholinesterase level [38]. Matsunaga’s group [39] described the isolation of N- an increase of the acetylcholinesterase level [38]. Matsunaga’s group [39] described the isolation of methylisocystodamine (48) and methoxymethylisocystodamine (49) (Figure 4), together with 47, N-methylisocystodamine (48) and methoxymethylisocystodamine (49) (Figure4), together with 47, from the marine sponge Biemna sp., collected at Oshima-Shinsone, Southern Japan. Both 48 and 49 from the marine sponge Biemna sp., collected at Oshima-Shinsone, Southern Japan. Both 48 and 49 were found to activate the erythroid differentiation of human leukemia K562 cells, with an ED50 value were found to activate the erythroid differentiation of human leukemia K562 cells, with an ED value of 5 nM [39]. Later on, the same group [40] further isolated N-hydroxymethylisocystodamine (5050) and of 5 nM [39]. Later on, the same group [40] further isolated N-hydroxymethylisocystodamine (50) and neolabuaninen A (51), together with the previously reported congeners ecionines A (52) and B (53), neolabuaninen A (51), together with the previously reported congeners ecionines A (52) and B (53), 42, 42, 45 and 47 (Figure 4), from the same sponge. These compounds displayed cytotoxicity and 45 and 47 (Figure4), from the same sponge. These compounds displayed cytotoxicity and activated activated differentiation of K562 leukaemia cells into erythrocytes at a concentration of 5 μg/mL. differentiation of K562 leukaemia cells into erythrocytes at a concentration of 5 µg/mL. Furthermore, Furthermore, 47 and 50 were the most active in inducing neuronal differentiation when compared to 47 and 50 were the most active in inducing neuronal differentiation when compared to 42, 45 and 42, 45 and 51. Interestingly, while 51 and 52 lowered this activity, 42, 47 and 53 showed no notable 51. Interestingly, while 51 and 52 lowered this activity, 42, 47 and 53 showed no notable activity [40]. activity [40]. Another interesting group of marine-derived alkaloids are the pteridines, which Another interesting group of marine-derived alkaloids are the pteridines, which represent a widely represent a widely distributed family of naturally occurring alkaloids. Chemically, pteridine nucleus distributed family of naturally occurring alkaloids. Chemically, pteridine nucleus is composed of is composed of a pyrimidine ring fused with a pyrazine ring. Examples of this group are a pyrimidine ring fused with a pyrazine ring. Examples of this group are pseudoanchnazines A–C pseudoanchnazines A–C (54–56) (Figure 4), which were isolated from the marine sponge Clathria sp., (54–56) (Figure4), which were isolated from the marine sponge Clathria sp., collected near the coast of collected near the coast of Rio Negro, Argentina. Compound 54 showed a moderate inhibition against Rio Negro, Argentina. Compound 54 showed a moderate inhibition against E. coli at 50 µg/disk [41]. E. coli at 50 μg/disk [41]. Additionally, Sperry and Crews described isolation of a new Additionally, Sperry and Crews described isolation of a new tetrahydroquinolizinium ion, clathryimine tetrahydroquinolizinium ion, clathryimine A (57), which produced a decarboxylated derivative A (57), which produced a decarboxylated derivative clathryimine B upon heating in CDCl3 (Figure4), clathryimine B upon heating in CDCl3 (Figure 4), from the Indo-Pacific marine sponge C. basilana, collected in Indonesia [42]. Radhika et al. [43] reported the isolation of N-methylpyrrolidone (58) (Figure 4) from C. frondifera, collected from the East coast of India.

Mar. Drugs 2018, 16, 214 9 of 26 from the Indo-Paciﬁc marine sponge C. basilana, collected in Indonesia [42]. Radhika et al. [43] reported the isolation of N-methylpyrrolidone (58) (Figure4) from C. frondifera, collected from the East coast ofMar. India. Drugs 2018, 16, x 6 of 26 Mar. Drugs 2018, 16, x 6 of 26

Figure 4.4. Chemical structures ofof 4242––58.58. Figure 4. Chemical structures of 42–58. 2.3. Monoindole Alkaloids 2.3.2.3. Monoindole Alkaloids Wang et al. [44] reported the isolation of eleven brominated indole alkaloids, 59–69 (Figure 5), Wang et al. [[44]44] reported the isolation of eleven brominated indole alkaloids, 59–6969 (Figure 55),), from the marine sponge M. fibrexilis. Since monoindole alkaloids were less common for this sponge from the marine sponge M. ﬁbrexilis.fibrexilis. Since monoindole alkaloids were less common for this sponge family, the authors proposed that they could be specific for this species. family, thethe authorsauthors proposedproposed thatthat theythey couldcould bebe speciﬁcspecific forfor thisthis species.species.

Figure 5. Chemical structures of 59–69. Figure 5. Chemical structures of 59–69. 2.4. Pyrrole-Containing Alkaloids 2.4. Pyrrole-Containing Alkaloids Fourteen pyrrole-containing metabolites, named mycalazols (70–81) and mycalazals (82–83) Fourteen pyrrole-containing metabolites, named mycalazols (70–81) and mycalazals (82–83) (Figures 6 and 7), were isolated from M. micracanthoxea, collected at the Southern coast of Spain. (Figures 6 and 7), were isolated from M. micracanthoxea, collected at the Southern coast of Spain. Compounds 70–83 displayed a potent in vitro cytotoxicity with ED50 values in the micromolar rang, Compounds 70–83 displayed a potent in vitro cytotoxicity with ED50 values in the micromolar rang, against five cancer cell lines: P388, SCHABEL mice lymphoma, A549 human lung carcinoma, HT29 againsthuman five colon cancer carcinoma cell lines: and P388, MEL28 SCHABEL human mice melanoma, lymphoma, and 75A549–76 humanand 81 lung were carcinoma, the most HT29 active human colon carcinoma and MEL28 human melanoma, and 75–76 and 81 were the most active analogues [45]. analogues [45].

Mar. Drugs 2018, 16, 214 10 of 26

2.4. Pyrrole-Containing Alkaloids Fourteen pyrrole-containing metabolites, named mycalazols (70–81) and mycalazals (82–83) (Figures6 and7), were isolated from M. micracanthoxea, collected at the Southern coast of Spain. Compounds 70–83 displayed a potent in vitro cytotoxicity with ED50 values in the micromolar rang, against ﬁve cancer cell lines: P388, SCHABEL mice lymphoma, A549 human lung carcinoma, HT29 human colon carcinoma and MEL28 human melanoma, and 75–76 and 81 were the most active analogues [45]. Mar. Drugs 2018, 16, x 7 of 26 Mar. Drugs 2018, 16, x 7 of 26

Figure 6. Chemical structures 70–76. Figure 6. Chemical structures 70–76. Figure 6. Chemical structures 70–76.

Figure 7. Chemical structures 77–83. Figure 7. Chemical structures 77–83. Figure 7. Chemical structures 77–83. A further eleven pyrrole-containing metabolites, 84–94 (Figure 8), were isolated from the same sponge,A further collected eleven in thepyrrole Caribbean-containing Sea metabolites, in Venezuela. 84 –The94 (Figure structures 8), were of these isolated compounds from the same were elucidatedsponge, collected by analys in is the of Caribbeantheir NMR, Sea HRMS in Venezuela. and GC-MS The data. structures Compound of these84 was compounds the most active were againstelucidated Leishmania by analys mexicanais of their promastigotes, NMR, HRMS with and LD GC50 value-MS data.of 12 Compoundµg/mL [46]. 84Three was 5 -thealkylpyrrole most active-2- carbaldehydesagainst Leishmania (95 –mexicana97) (Figure promastigotes, 8) were reported with LDfrom50 value M. tenuispiculata of 12 µg/mL, [46].collected Three in 5 -Soalkylpyrroleuthern India-2- [47],carbaldehydes while an additional (95–97) (Figure fourteen 8) were5-alkylpyrrole reported -from2-carbaldehyde M. tenuispiculata analogues,, collected with varyingin Southern alkyl India side chains,[47], while named an additional mycalazals fourteen (98–108) 5- alkylpyrroleand mycalenitriles-2-carbaldehyde (109–111) analogues, (Figure 8) withwere varying isolated alkyl from side M. Ceciliachains,, collectednamed mycalazals in California. (98 –These108) and compoun mycalenitrilesds displayed (109 –growth111) (Figure inhibition 8) were activity isolated against from nine M. Cecilia, collected in California. These compounds displayed growth inhibition activity against nine

Mar. Drugs 2018, 16, 214 11 of 26

A further eleven pyrrole-containing metabolites, 84–94 (Figure8), were isolated from the same sponge, collected in the Caribbean Sea in Venezuela. The structures of these compounds were elucidated by analysis of their NMR, HRMS and GC-MS data. Compound 84 was the most active against Leishmania mexicana promastigotes, with LD50 value of 12 µg/mL [46]. Three 5-alkylpyrrole-2-carbaldehydes (95–97) (Figure8) were reported from M. tenuispiculata, collected in Southern India [47], while an additional fourteen 5-alkylpyrrole-2-carbaldehyde analogues, with varying alkyl side chains, named mycalazals (98–108) and mycalenitriles (109–111) (Figure8) Mar. Drugs 2018, 16, x 8 of 26 were isolated from M. Cecilia, collected in California. These compounds displayed growth inhibition µ canceractivity cell against lines, ninewith cancer GI50 values cell lines, below with 5 µg/mL, GI50 values being below103 the 5 mostg/mL, cytotoxic being 103againstthe mostthe LNcaP cytotoxic cell µ line,against with the a LNcaP GI50 value cell line,of 0.2 with µg/mL. a GI 50 Compoundsvalue of 0.2 98,g/mL. 99 and Compounds 102 displayed98, remarkable99 and 102 displayed cytostatic activityremarkable on this cytostatic tumor cell activity line, onwith this TGI tumor (Total cell Growth line, with Inhibition) TGI (Total values Growth of 3.3, Inhibition) 2.6 and 2.8 values µg/mL, of respectively.3.3, 2.6 and 2.8 Compoundsµg/mL, respectively. 109–111 exhibited Compounds potent cytotoxicity109–111 exhibited with high potent selectivity cytotoxicity against with PANC1 high humanselectivity pancreas, against LOVO PANC1 human human colon, pancreas, and HELA LOVO human human lymphoma colon, and HELAcell lines human [48]. It lymphoma is interesting cell tolines point [48]. out It is that interesting the cytotoxicity to point out exhibited that the cytotoxicity by mycalazals exhibited and mycalenitriles by mycalazals is and affected mycalenitriles by the structuralis affected features by the structural of the alkyl features side chains, of the alkyl including side chains, their length, including the theirnumber length, and the pos numberition of andthe unsaturationsposition of the unsaturations [48]. Recently, [48 Xue]. Recently, et al. [49]Xue et described al. [49] described isolation isolation of mycalenitrile of mycalenitrile-15-15 (112) (112 and) mycalenitrileand mycalenitrile-16-16 (113) (from113) fromthe Chinese the Chinese M. lissochelaM. lissochela. Compound. Compound 112 displayed112 displayed a remarkable a remarkable PTP1B µ (ProteinPTP1B (Protein-tyrosine-tyrosine phosphatase phosphatase 1B) inhibitory 1B) inhibitory activity activity with an with IC50 anvalue IC50 ofvalue 8.6 µM. of8.6 M.

Figure 8. Chemical structures 84–113. Figure 8. Chemical structures 84–113.

2.5. Bromine-Containing Amides Three brominated acetylenic amides, clathrynamides A–C (114–116) (Figure 9), were isolated from the Japanese marine sponge Clathria sp., collected from the Sad-misaki coast. Compound 114 displayed potent inhibitory activity against the mitotic cell division of starfish eggs at a very low concentration, with an IC50 value of 6 ng/mL, and cytotoxicity against the human myeloid K-562 cell line with an IC50 value of 0.2 μg/mL. Compounds 115 and 116 were less active than 114 against the mitotic cell division of starfish eggs, with IC50 values of 0.2 and 1 μg/mL, respectively. Based on the IC50 values of 114–116, it is clear that the presence of a primary amide in the molecule plays an important role in the inhibitory activity of the mitotic cell division of starfish eggs [50].

Mar. Drugs 2018, 16, 214 12 of 26

2.5. Bromine-Containing Amides Three brominated acetylenic amides, clathrynamides A–C (114–116) (Figure9), were isolated from the Japanese marine sponge Clathria sp., collected from the Sad-misaki coast. Compound 114 displayed potent inhibitory activity against the mitotic cell division of starfish eggs at a very low concentration, with an IC50 value of 6 ng/mL, and cytotoxicity against the human myeloid K-562 cell line with an IC50 value of 0.2 µg/mL. Compounds 115 and 116 were less active than 114 against the mitotic cell division of starfish eggs, with IC50 values of 0.2 and 1 µg/mL, respectively. Based on the IC50 values of 114–116, it is clear that the presence of a primary amide in the molecule plays an Mar.important Drugs 2018 role, 16 in, x the inhibitory activity of the mitotic cell division of starfish eggs [50]. 9 of 26

Mar. Drugs 2018, 16, x Br OH O 9 of 26

Br OH O NHR OH NHR 114, R =OH H 115, R = CH(CH3)CH2CH2CH(OH)CH3 111164, ,R R = = CHH(CH3)CH2CH2COCH3 115, R = CH(CH3)CH2CH2CH(OH)CH3 Figure11 69. , ChemicalR = CH(CH structures 3)CH2CH2 COCHof 1143–116. Figure 9. Chemical structures of 114–116. 2.62.6.. Cyclic Peptides/Thiopeptides 2.6. Cyclic Peptides/Thiopeptides Two cyclic thiopeptides, microcionamides A ( (117) and B B ( (111818), were isolated from from C. ((Thalysias)) abietina,Two, collected collected cyclic from fromthiopeptides, the Philippines. microcionamides Compounds Compounds A (117 117117) and and B 118(118 displayed), were isolated a significant signiﬁcant from C. (cytotoxicity Thalysias) against the human breast tumor cell lines, MCF-7 and SKBR-3, with the IC50 values of 125/98 nM and againstabietina the, collected human from breast the tumor Philippines. cell lines, Compounds MCF-7 and 117 SKBR-3,and 118 displayed with the ICa significant50 values ofcytotoxicity 125/98 nM 177/172 nM, respectively. Furthermore, 117 and 118 also displayed inhibitory activity against andagainst 177/172 the human nM, respectively. breast tumor Furthermore, cell lines, MCF117-7 and SKBR118 also-3, with displayed the IC50 inhibitory values of 125/98 activity nM against and Mycobacterium177/172 nM, tuberculosis respectively. (H Furthermore,37Ra), with MIC 117 valueand 118of 5.7also μg/mL displayed [51]. inhibitoryAnother cyclic activity thiopep againsttide, Mycobacterium tuberculosis (H37Ra), with MIC value of 5.7 µg/mL [51]. Another cyclic thiopeptide, gombamideMycobacterium A A (119 ( 119tuberculosis) )(Figure (Figure (H10) 1037 Ra),)was was withisola isolated tedMIC from value from the of the Korean5.7 Korean μg/mL marine marine[51]. spongeAnother sponge C. cyclic gombawuiensisC. gombawuiensisthiopeptide,. 119 . exhibitedgombamide a weak A ( 119cytotoxicity) (Figure 10) against was isola K562ted and from A549 the Koreancell lines marine with spongethe IC50 C. values gombawuiensis of 6.9 and. 119 7.1 119 exhibited a weak cytotoxicity against K562 and A549 cell lines with the IC50 values of 6.9 and + + μ7.1g/mLexhibitedµg/mL,, respectively. a respectively.weak cytotoxicity Moreover, Moreover, against 119 also K562119 exhibitedalso and exhibitedA549 a moderatecell lines a moderate with inhibitory the inhibitoryIC 50 activity values activity againstof 6.9 and Na against 7.1/K - + + ATPasμ+g/mLe+ with, respectively. IC50 of 17.8 Moreover, μg/mL [52].119 also Five exhibited cyclic tetrapeptides, a moderate inhibitory azumamides activity A– E against (120–124 Na),/K were- Na /K -ATPase with IC50 of 17.8 µg/mL [52]. Five cyclic tetrapeptides, azumamides A–E (120–124), ATPase with IC50 of 17.8 μg/mL [52]. Five cyclic tetrapeptides, azumamides A–E (120–124), were wereisolated isolated from the from marine the marine sponge sponge M. izuensis.M. izuensis. These compoundsThese compounds displayed displayed a potent aHDAC potent (Histone HDAC Deacetylase)isolated from inhibitory the marine activity sponge with M. the izuensis. IC50 values These ofcompounds 0.045 to 1.3 displayed µM, using a potent enzymes HDAC obtained (Histone from (Histone Deacetylase) inhibitory activity with the IC50 values of 0.045 to 1.3 µM, using enzymes K562Deacetylase) human leukemia inhibitory cells. activity Compounds with the IC 12050 values–124 represented of 0.045 to 1.3 the µM first, using examples enzymes of obtained cyclic peptides from obtained from K562 human leukemia cells. Compounds 120–124 represented the ﬁrst examples of withK562 HDAC human inhibition leukemia activity cells. Compounds recorded from 120 marine–124 represented invertebrates the first[53]. examples of cyclic peptides cyclicwith peptides HDAC inhibition with HDAC activity inhibition recorded activity from recordedmarine invertebrates from marine [53]. invertebrates [53].

FigureFigure 10. 10. Chemical Chemical structures ofof 117117––124.124.124 .

2.72.7. Nucleotides. Nucleotides TwoTwo guanine guanine-nucleotides,-nucleotides, mycalisines mycalisines A A ((125125)) and B (126)) (Figure(Figure 11), 11), from from the the Japanese Japanese sponge sponge MycaleMycale sp., sp., were were found found to to inhibit inhibit a a cell cell division division ofof thethe fertilized starfishstarfish ( Asterina(Asterina pectinifera pectinifera) eggs) eggs with with MIC50 of 0.5 and 200 µg/mL, respectively [54]. Two 8-oxoisoguanine-nucleotides, 127 and 128 (Figure MIC50 of 0.5 and 200 µg/mL, respectively [54]. Two 8-oxoisoguanine-nucleotides, 127 and 128 (Figure 11), were isolated from Clathria (Microciona) strepsitoxa, collected from the Northeastern Atlantic. 11), were isolated from Clathria (Microciona) strepsitoxa, collected from the Northeastern Atlantic. These compounds did not exhibit any significant antimicrobial or cytotoxic activity [55]. These compounds did not exhibit any significant antimicrobial or cytotoxic activity [55].

Mar. Drugs 2018, 16, 214 13 of 26

2.7. Nucleotides Two guanine-nucleotides, mycalisines A (125) and B (126) (Figure 11), from the Japanese sponge Mycale sp., were found to inhibit a cell division of the fertilized starﬁsh (Asterina pectinifera) eggs with MIC50 of 0.5 and 200 µg/mL, respectively [54]. Two 8-oxoisoguanine-nucleotides, 127 and 128 (Figure 11), were isolated from Clathria (Microciona) strepsitoxa, collected from the Northeastern

Atlantic.Mar. Drugs These2018, 16 compounds, x did not exhibit any signiﬁcant antimicrobial or cytotoxic activity [5510]. of 26 Mar. Drugs 2018, 16, x 10 of 26

Figure 11. Chemical structures of 125–128. FFigureigure 11. Chemical structures of 125–128. 2.8. Fatty Acids 2.82.8.. Fatty Acids (Z)-16-pentacosenoic acid (129) and (Z)-18-pentacosenoic acid (130) were isolated from the (Z))-16-pentacosenoic-16-pentacosenoic acid acid ( (129129)) and (Z))-18-pentacosenoic-18-pentacosenoic acid acid ( (130)) were isolated from the hydrolyzed phospholipids of the Caribbean sponge M. laevis [56], while (5Z)-2-methoxy-5- hydrolyzed phospholipidsphospholipids of theof Caribbeanthe Caribbean sponge spongeM. laevis M.[56 laevis], while [56], (5Z )-2-methoxy-5-hexadeconicwhile (5Z)-2-methoxy-5- hexadeconic acid (131) (Figure 12) was reported from M. laxissima [57]. Chemical investigation of the hexadeconicacid (131) (Figure acid (131 12) (Figure was reported 12) was fromreportedM. laxissimafrom M. laxissima[57]. Chemical [57]. Chemical investigation investigation of the of Red the Red Sea M. euplectellioides led to the identification of hexacosa-(6Z,10Z)-dienoic acid methyl ester RedSea M. Sea euplectellioidesM. euplectellioidesled led to tothe the identiﬁcation identification of of hexacosa-(6 hexacosa-(6ZZ,10,10ZZ)-dienoic)-dienoic acid acid methyl methyl ester (132), hexacosa-(6Z,10Z)-dienoic acid (133) and icosa-(8Z,11Z)-dienoic acid methyl ester (134) (Figure (132), hexacosa hexacosa-(6-(6ZZ,10,10ZZ)-)-dienoicdienoic acid acid (133 (133) and) and icosa icosa-(8-(8Z,11Z),11-dienoicZ)-dienoic acid methyl acid methyl ester (134 ester) (Figure (134) 12). Compounds 132–134 displayed weak cytotoxicity against A549 human lung carcinoma, U373 (Figure12). Compounds 12). Compounds 132–134132 displayed–134 displayed weak cytotoxicity weak cytotoxicity against againstA549 human A549 human lung carcinoma, lung carcinoma, U373 glioblastoma and PC-3 prostate cancer cell lines [58]. glioblastomaU373 glioblastoma and PC and-3 prostate PC-3 prostate cancer cancer cell lines cell [58]. lines [58].

Figure 12. Chemical structures 129–134. Figure 12. Chemical structures 129–134. 2.9. Polyketides Derivatives 2.92.9.. Polyketides D Derivativeserivatives Mycalamides A (135) and B (136) (Figure 13) were isolated from Mycale sp., collected from Otago Mycalamides A (135) and B (136) (Figure 13) were isolated from Mycale sp., collected from Otago Harbour,Mycalamides New Zealand. A (135 Both) and compounds B (136) (Figure exhibited 13) a were potent isolated in vitro from anti-MycaleHSV-1 activity.sp., collected Compound from Harbour, New Zealand. Both compounds exhibited a potent in vitro anti-HSV-1 activity. Compound Otago136 was Harbour, a more potent New Zealand.antiviral agent Both than compounds 135, with exhibited the Minimum a potent Activein vitroDosesanti-HSV-1 (MAD) of 1 activity.–2 and 136 was a more potent antiviral agent than 135, with the Minimum Active Doses (MAD) of 1–2 and Compound3.5–5.0 ng/disk,136 respectively.was a more Furthermore, potent antiviral 136 exhibited agent than stronger135, with(IC50 = the 0.7 Minimum± 0.3 ng/mL) Active cytotoxicity Doses 3.5–5.0 ng/disk, respectively. Furthermore, 136 exhibited stronger (IC50 = 0.7 ± 0.3 ng/mL) cytotoxicity (MAD)than 135 of (IC 1–250 = and 3.0 ± 3.5–5.0 1.3 ng/mL) ng/disk, against respectively. P-388 cancer Furthermore, line [59,60]. 136Additionally,exhibited strongermycalamide (IC 50D =(137 0.7) than 135 (IC50 = 3.0 ± 1.3 ng/mL) against P-388 cancer line [59,60]. Additionally, mycalamide D (137) ±(Figure0.3 ng/mL) 13), along cytotoxicity with 135 and than 136135, were(IC 50also= reported 3.0 ± 1.3 from ng/mL) Mycale against sp., collected P-388 cancerfrom New line Zealand [59,60]. (Figure 13), along with 135 and 136, were also reported from Mycale sp., collected from New Zealand Additionally,[61]. Compounds mycalamide 135 and D (137137) (Figuredisplayed 13), significant along with 135 cytotoxicityand 136, were against also three reported cell from lines:Mycale non- [61]. Compounds 135 and 137 displayed significant cytotoxicity against three cell lines: non- sp.,tumorigenic collected pig from kidney New (LLC Zealand-PK1), [61 human]. Compounds lung carcinoma135 and (H441)137 displayed and human signiﬁcant neuroblast cytotoxicityoma (SH- tumorigenic pig kidney (LLC-PK1), human lung carcinoma (H441) and human neuroblastoma (SH- againstSY5Y) cell three lines. cell lines: Furthermore, non-tumorigenic 135–137 pigexhibited kidney remarkable (LLC-PK1), cytotoxicityhuman lung in carcinoma a nanomolar (H441) range and SY5Y) cell lines. Furthermore, 135–137 exhibited remarkable cytotoxicity in a nanomolar range humanagainst neuroblastomalymphoma P-388 (SH-SY5Y) cells with cell IC lines.50 values Furthermore, of 5.2, 1.3135 and–137 65.5exhibited ± 5.5 nM, remarkable respectively. cytotoxicity From a against lymphoma P-388 cells with IC50 values of 5.2, 1.3 and 65.5 ± 5.5 nM, respectively. From a instructure a nanomolar-activity range point against of view, lymphoma the cytotoxic P-388 potency cells with is inversely IC50 values proportional of 5.2, 1.3 to and the 65.5number± 5.5 of nM, the structure-activity point of view, the cytotoxic potency is inversely proportional to the number of the respectively.methoxy groups From as a structure-activitywell as the polarity point of ofthe view, compounds the cytotoxic (Figure potency 13) [61]. is inversely Within proportionalthe polyketide to methoxy groups as well as the polarity of the compounds (Figure 13) [61]. Within the polyketide thegroup, number acetogenins of the methoxy were als groupso isolated as wellfrom as the the marine polarity sponge of the of compounds the genus (FigureMycale. 13Giordano)[61]. Within et al. group, acetogenins were also isolated from the marine sponge of the genus Mycale. Giordano et al. the[62] polyketide reported the group, isolation acetogenins of two werepolybrominated also isolated C15 from acetogenins the marine (138 sponge–139) offrom the M. genus rotalisMycale, and. [62] reported the isolation of two polybrominated C15 acetogenins (138–139) from M. rotalis, and subsequently, Notaro et al. isolated the C15 nonrterpenoid brominated ether (140) from the same subsequently, Notaro et al. isolated the C15 nonrterpenoid brominated ether (140) from the same sponge [63]. sponge [63].

Mar. Drugs 2018, 16, 214 14 of 26

Giordano et al. [62] reported the isolation of two polybrominated C15 acetogenins (138–139) from M. rotalis, and subsequently, Notaro et al. isolated the C15 nonrterpenoid brominated ether (140) from the sameMar. Drugs sponge 2018, [1663, x]. 11 of 26

Mar. Drugs 2018, 16, x 11 of 26

Figure 13. Chemical structures of 135–140. Figure 13. Chemical structures of 135–140. 2.10. Anthraquinones Figure 13. Chemical structures of 135–140. 2.10. Anthraquinones Six rhodocomatulin-type anthraquinones, including the previously reported rhodocomatulin 5, 2.10. Anthraquinones Six7-dimethyl rhodocomatulin-type ether (141) and anthraquinones, rhodocomatulin including 7-methyl ether the previously (142), together reported with rhodocomatulinthe new 6- 5, 7-dimethylmethoxyrhodocomatulinSix rhodocomatulin ether (141)- type and 7-methyl anthraquinones, rhodocomatulin ether (143 ),including 3- 7-methylbromo the-6- methoxypreviously ether- (12142 reported-deethylrhodocomatulin), together rhodocomatulin with the 75,- new 6-methoxyrhodocomatulin7methyl-dimethyl ether ether (144 (141), )7-methyl and 3-bromo rhodocomatulin ether-6-methoxyrhodocomatulin (143), 3-bromo-6-methoxy-12-deethylrhodocomatulin 7-methyl ether 7 (-142methyl), together ether with (155 the) and new 7-methyl 63- methoxyrhodocomatulin 7-methyl ether (143), 3-bromo-6-methoxy-12-deethylrhodocomatulin 7- etherbromorhodocomatulin (144), 3-bromo-6-methoxyrhodocomatulin 7-methyl ether (146) (Figure 7-methyl 14), were ether isolated (155) from and the 3-bromorhodocomatulin marine sponge C. methylhirsuta, collected ether from (144), the 3Great-bromo Barrier-6-methoxyrhodocomatulin Reef, Australia. Compounds 7-methyl 141 and ether 142 were (155 also) andisolated 3- 7-methyl ether (146) (Figure 14), were isolated from the marine sponge C. hirsuta, collected from the Great bromorhodocomatulinfrom the marine sponge 7 Comatula-methyl etherrotalaria (146 [64].) (Figure 14), were isolated from the marine sponge C. Barrierhirsuta, Reef, collected Australia. from Compounds the Great Barrier141 and Reef,142 Australia.were also Compounds isolated from141 and the 142 marine were spongealso isolatedComatula rotalariafrom[64 the]. marine spongeO ComatulaO OH rotalaria [64].OH O OH OH O OH O O O OH OH O OH O OH O OH O OH OH O OH O O O O O O O

O 141 OH O 142 OH O 143 OH O O O O O O OH O OH OH O OH OH 141 142 143O OH O Br O Br Br OH O OH OH O OH O OH O OH O OH O OH OH O Br O Br O O O Br O O O O 144 OH O 145 OH O 146 OH O O O O O Figure 14. Chemical structures of 141–146. O 144 145 146 2.11. Macrolides Figure 14. Chemical structures of 141–146. Figure 14. Chemical structures of 141–146. Three trioxazole containing macrolides, mycalolides A–C (147–149) (Figure 15), isolated from 2.11. Macrolides 2.11.the Macrolides Japanese Mycale sp., displayed antifungal activity against some pathogenic fungi. These compoundsThree trioxazole also showed containing a promising macrolides, cytotoxicity mycalolides against Athe–C B (-14716 cancer–149) (Figurecell line 15),, with isolated IC50 values from Threetheranging Japanese trioxazole from 0.5Mycale to containing 1.0 sp., ng/mL displayed macrolides,[65]. 13 - antifungalDeoxytedanolide mycalolides activity ( A–C150 against) (Figure (147 – some149 15),) (Figure pathogenicalong with 15), 147 fungi.isolated–148, These were from the Japanesecompoundsalso isolatedMycale alsofromsp., showed displayed the Japanese a promising antifungal sponge cytotoxicityM. activity adhaerens against .against Compound somethe B 150-16 pathogenic exhibitedcancer cell significant fungi. line, with These cytotoxicity IC50 compounds values ranging from 0.5 to 1.0 ng/mL [65]. 13-Deoxytedanolide (150) (Figure 15), along with 147–148, were also showedagainst P388 a promising leukemia cells, cytotoxicity with an IC against50 value of the 94 pg/mL B-16 cancer [66]. The cell chemical line, withinvestigation IC50 values of Mycale ranging fromalsosp., 0.5 isolated tocollected 1.0 ng/mL from from the [ NewJapanese65]. 13-Deoxytedanolide Zealand, sponge afforded M. adhaerens a potent. ( 150Compound) (Figure cytotoxic 150 15 exhibited thiazole), along- containingsignificant with 147 –cytotoxicity148, macrolide,were also isolatedagainstpateamine from P388 the(151 leukemia Japanese) (Figure cells, 15). sponge with Compound anM. IC adhaerens50 value151 displayed of. 94 Compound pg/mL significant [66]. The150 and chemicalexhibited selective investigation signiﬁcantcytotoxicity of cytotoxicity againstMycale sp.,P38 8 collectedcells with froman IC New50 value Zealand, of 0.15 ng/mL afforded [67]. a Thiomycalolides potent cytotoxic A thiazole (152) and-containing B (153) (Figure macrolide, 15), against P388 leukemia cells, with an IC50 value of 94 pg/mL [66]. The chemical investigation of pateamineanother two (151 trioxazole) (Figure-containing 15). Compound macrolides, 151 displayed were reported significant from and Mycale selective sp., collected cytotoxicity at Gokasho against Mycale sp., collected from New Zealand, afforded a potent cytotoxic thiazole-containing macrolide, P38Bay,8 Japan.cells with Both an compounds IC50 value wereof 0.15 cytotoxic ng/mL [67].against Thiomycalolides human leukae miaA (152 P388) and cells B with(153) an (Figure IC50 of 15), 18 151 151 pateamineanotherng/mL ([68]. two) Further (Figuretrioxazole analogues, 15-containing). Compound including macrolides, 30displayed-hydroxymycalolide were reported signiﬁcant from A Mycale and(154), selective 32sp.,-hydroxymycalolide collected cytotoxicity at Gokasho againstA P388Bay,( cells155) Japan.and with 38 Both an-hydroxymycalolide IC compounds50 value of were 0.15 B cytotoxic( ng/mL156) (Figure [against67 ].15), Thiomycalolides humanwere isolated, leukae miatogether A P388 (152 withcells) and 147with B– (149,153an IC )from (Figure50 of the 18 15), anotherng/mLJapanese two [68].trioxazole-containing M . Furthermagellanica analogues,. Comp oundsincluding macrolides, 154 30–156-hydroxymycalolide were showed reported cytotoxicity from A ( 154Mycale against), 32 -sp., L1210hydroxymycalolide collected cells, with at Gokasho IC A50 Bay, Japan.(values155) and of Both 380.019,-hydroxymycalolide compounds 0.013 and 0.015 were µg/mL,B cytotoxic(156) (Figurerespectively against 15), were [69 human,70]. isolated, Peloruside leukaemia together A ( P388with157), 147 cellsanother–149, with cytotoxicfrom an the IC 50 of 18 ng/mLJapanesemacrolide, [68 ].M was Further. magellanica isolated analogues, .from Comp Mycaleounds including sp., 154 collected– 30-hydroxymycalolide156 showed from New cytotoxicity Zealand. A against (This154), compound L1210 32-hydroxymycalolide cells exhibite, with ICd 50a A (155)valuesremarkable and 38-hydroxymycalolide of 0.019, cytotoxicity 0.013 and against0.015 B µg/mL, (156 P388) (Figure withrespectively IC 1550 ),value were[69,70]. ofisolated, Peloruside 18 nM together [71]. A (157 Additionally, with), another147– 149,cytotoxic 30, from 32- the macrolide, was isolated from Mycale sp., collected from New Zealand. This compound exhibited a remarkable cytotoxicity against P388 with IC50 value of 18 nM [71]. Additionally, 30, 32-

Mar. Drugs 2018, 16, 214 15 of 26

Japanese M. magellanica. Compounds 154–156 showed cytotoxicity against L1210 cells, with IC50 values of 0.019, 0.013 and 0.015 µg/mL, respectively [69,70]. Peloruside A (157), another cytotoxic macrolide, was isolated from Mycale sp., collected from New Zealand. This compound exhibited a remarkable Mar. Drugs 2018, 16, x 12 of 26 cytotoxicity against P388 with IC50 value of 18 nM [71]. Additionally, 30, 32-dihydroxymycaloloide A (158) (Figure 15) was isolated from the Japanese sponge M. izuensis as a cytotoxic compound against dihydroxymycaloloide A (158) (Figure 15) was isolated from the Japanese sponge M. izuensis as a HeLa cells with IC50 value of 2.6 ng/mL [72]. cytotoxic compound against HeLa cells with IC50 value of 2.6 ng/mL [72].

H Me Me Me Me O O N OH Me Me N Me O O R OMe O OMe O OH O O N O OMe O Me OH Me Me Me Me H Me 147, R = O Me N Me O O O OH O O H 148, R = OMe O OMe O 150 OMe O H 149, R = O OMe H Me Me Me Me O

Me O N S N Me Me O O R OMe O OMe N O O Me N Me OH N O Me Me HO NH H2N N O 151 O Me O S O O Me NH2 HO O O OMe O O Me

152, R = O O H 153, R = H Me Me Me Me O OMe O 31 OMe O N 32 30 N Me O O O OMe O OMe O O N Me OH Me OH X HO O Me N O Me O OMe H Me Me MeO O 31 HO 154, X = O OMe O N 32 30 HO OMe Me O O OH OH

Me 157

155, X = H Me Me 31 H Me Me Me Me O N 32 30 O Me OH O O N N Me OH OH OMe O OMe 156, X = H Me Me O O N 31 OH O N 32 30 Me O O O O 158 N Me O Me OH MeO O OMe Figure 15. Chemical structures of 147–158. Figure 15. Chemical structures of 147–158. A bisoxazole-containing macrolide, secomycalolide A (159) (Figure 16), was isolated from a AJapanese bisoxazole-containing Mycale sp., together macrolide, with 147 and secomycalolide 154. By using a chymotrypsin A (159) (Figure-like substrate,16), was 159, isolated 147 and from a Japanese154 displayedMycale sp., a promising together withproteasome147 and inhibition154. By activity using a, with chymotrypsin-like IC50 values of 11, substrate, 30 and 45 159µg/mL,, 147 and respectively [73]. Later on, peloruside B (160) (Figure 16), another potent cytotoxic macrolide, was 154 displayed a promising proteasome inhibition activity, with IC50 values of 11, 30 and 45 µg/mL, isolated from the New Zealand sponge M. hentscheli. Compound 160 showed strong cytotoxicity respectively [73]. Later on, peloruside B (160) (Figure 16), another potent cytotoxic macrolide, against human myeloid leukemia cells (HL-60) and human ovarian carcinoma 1A9 cells with IC50 was isolatedvalues of from 33 ± the10 and New 71 Zealand ± 6 nM, spongerespectivelyM. hentscheli[74]. Additionally,. Compound miuramides160 showed A (161 strong) and cytotoxicityB (162) against(Figure human 16) myeloid were identi leukemiafied from cells Mycale (HL-60) sp., and collected human from ovarian Japan. carcinoma Both compounds 1A9 cells showed with IC50 valuessignificant of 33 ± cytotoxicity10 and 71 ± against6 nM, 3YI respectively cells with IC [7450]. value Additionally, of 7 nM [75]. miuramides Very recently, A (161 Suo) and et al., B (162) (Figuredescribed 16) were the identiﬁed isolation of from pelorusidesMycale sp., C (163 collected) and D from (164) Japan. (Figure Both 16), compoundsalso from the showed New Zealand signiﬁcant cytotoxicitysponge M. against hentscheli. 3YI Both cells compounds with IC50 showedvalue cytotoxicity of 7 nM [75 against]. Very HL- recently,60 cell line Suo, with et IC al.,50 values described of more than 2 and 15 µM, respectively [76]. A structure-activity analysis revealed that pelorusides

Mar. Drugs 2018, 16, 214 16 of 26 the isolation of pelorusides C (163) and D (164) (Figure 16), also from the New Zealand sponge M. hentscheli. Both compounds showed cytotoxicity against HL-60 cell line, with IC50 values of more than 2Mar. and Drugs 15 2018µM,, 16 respectively, x [76]. A structure-activity analysis revealed that pelorusides13 A–D of 26 (157, 160, 163 and 164) (Figures 15 and 16) stabilize microtubules by binding to β-tubulin, similar to the A–D (157, 160, 163 and 164) (Figures 15 and 16) stabilize microtubules by binding to β-tubulin, similar antitumor drug paclitaxel, highlighting the potential of these compounds as promising anticancer to the antitumor drug paclitaxel, highlighting the potential of these compounds as promising drug candidates [74,75,77–79]. anticancer drug candidates [74,75,77–79].

Figure 16. Chemical structures of 159–164. Figure 16. Chemical structures of 159–164. 2.12. Terpenoids 2.12. Terpenoids Five sesquiterpenes, including two sesquiterpene phenols (+)-curcuphenol (165) and (+)- Fivecurcudiol sesquiterpenes, (166), along including with three two minor sesquiterpene compounds, phenols 167–169 (+)-curcuphenol (Figure 17), were (165 reported) and (+)-curcudiol from an (166),Australian along with marine three sponge minor compounds,Mycale (Arenochalina167–169) sp.(Figure [80]. 17 Compound), were reported 165 displayed from an in Australian vitro marinecytotoxicity sponge Mycale against P388(Arenochalina murine leukemia) sp. [80 and]. Compound human tumor165 celldisplayed lines (IC50 =in 7 vitroμg/mL),cytotoxicity HCT-8 (colon; against MIC = 0.1 μg/mL), mammary (MDAMB; MIC = 0.1 μg/mL) [80] and NSLC (A549; MIC =10 μM) [81], P388 murine leukemia and human tumor cell lines (IC50 = 7 µg/mL), HCT-8 (colon; MIC = 0.1 µg/mL), as well as antifungal activity against Candida albicans and Cryptococcus neoformans (MIC = 15 μM) mammary (MDAMB; MIC = 0.1 µg/mL) [80] and NSLC (A549; MIC = 10 µM) [81], as well as antifungal [81,82]. Moreover, 165 also showed antibacterial activity against both Staphylococcus aureus and µ activitymethicillin against-Candidaresistant albicansS. aureusand, withCryptococcus MIC value below neoformans 20 μM (MIC[82]. On = 15the contrary,M) [81,82 166]. Moreover,only exhibited165 also showedweak antibacterial antifungal activity activity against against filamentous both Staphylococcus fungi and Candida aureus albicansand with methicillin-resistant MIC = 250 μg/mL [81,83S. aureus]. , withThree MIC value terpenoid below metabolites, 20 µM[ clathrins82]. On A the–C contrary,(170–172) 166(Figureonly 17), exhibited were isolated weak from antifungal the marine activity againstsponge ﬁlamentous Clathria sp., fungi collected and Candidafrom the albicansGreat Australianwith MIC Bight. = 250Compoundµg/mL 170 [81 ,represents83]. Three the terpenoid first metabolites,example clathrins of a marine A–C sesquiterpene/benzenoid (170–172) (Figure 17), in were which isolated the “benzenoid” from the marine residue sponge retainedClathria a sp., collectednonaromatic from shikimate the Great character, Australian while 171 Bight. and 172 Compound are rearranged170 norditerpenes.represents the Howe ﬁrstver, example 172 was of a marinethought sesquiterpene/benzenoid to be an artefact, which in represents which the the “benzenoid” oxidized form residue of 171retained [84]. The aunusual nonaromatic bicyclic shikimate C21- diterpenoids, including clathric acid (173) and two acyl taurine derivatives, clathrimides A (174) and character, while 171 and 172 are rearranged norditerpenes. However, 172 was thought to be an B (175) (Figure 17), were isolated from the marine sponge C. compressa, which was collected in Florida artefact, which represents the oxidized form of 171 [84]. The unusual bicyclic C -diterpenoids, [20]. These compounds were tested for antibacterial activity against several Gram-positive21 and Gram- includingnegative clathric bacteria. acid However, (173) only and 173 two was acylfound taurine to exhibit derivatives, weak antibacterial clathrimides activity, with A M (174IC )= 32 and B (175)μ (Figureg/mL against 17), S. were aureus isolated (ATTC 6538P) from, the and marinewith MIC sponge = 64 μg/mLC. compressa against both, which methicillin was-resistant collected in FloridaS. aureus [20]. These(ATTC compounds33591) and vancomycin were tested-resistant for antibacterial S. aureus (VRSA), activity while against 174 and several 175 exhibited Gram-positive no and Gram-negativeactivity at the highest bacteria. concentration However, tested only (128173 μg/mwasL). foundMoreover, to exhibit none of weakthe compounds antibacterial showed activity, withactivity MIC = against 32 µg/mL Gram against-negativeS. bacteria aureus [20].(ATTC Three 6538P) tetracyclic, and sesterterpenes, with MIC = gombaspiroketals 64 µg/mL against A–C both methicillin-resistant(176–178) (Figure S.18) aureus, were isolated(ATTC 33591)from the and Korean vancomycin-resistant sponge C. gombawuiensisS. aureus, and showed(VRSA), in whilevitro 174 and 175cytotoxicityexhibited against no activity K562 and at theA549 highest cell lines concentration, with IC50 values tested of (1281.45, µ2.02,g/mL). 0.85 and Moreover, 0.77, 1.87, none 4.65 of the μg/mL, respectively. Furthermore, 176 and 178 also exhibited antibacterial activity against several compounds showed activity against Gram-negative bacteria [20]. Three tetracyclic sesterterpenes, strains of Gram-positive bacteria, including S. aureus, Bacillus subtilis and Kocuria rhizophila, with MIC gombaspiroketals A–C (176–178) (Figure 18), were isolated from the Korean sponge C. gombawuiensis, values of 25.0, 6.25, 12.5 and 25.0, 6.25, 25.0 μg/mL, respectively, and against Gram-negative bacteria and showedSalmonelain enterica vitro andcytotoxicity Proteus hauseri against, withK562 MIC values and A549 of 12.5, cell 6.25 lines, and 25.0, with 12.5 IC μg/mL,50 values respectiv of 1.45,ely. 2.02, Moreover, 176–178 also inhibited the enzymes Na+/K+-ATPase and isocitrate lyase (ICL) with IC50 =

Mar. Drugs 2018, 16, 214 17 of 26

0.85 and 0.77, 1.87, 4.65 µg/mL, respectively. Furthermore, 176 and 178 also exhibited antibacterial activity against several strains of Gram-positive bacteria, including S. aureus, Bacillus subtilis and Kocuria rhizophila, with MIC values of 25.0, 6.25, 12.5 and 25.0, 6.25, 25.0 µg/mL, respectively, and against Gram-negative bacteria Salmonela enterica and Proteus hauseri, with MIC values of 12.5, 6.25 and 25.0, 12.5 µg/mL, respectively. Moreover, 176–178 also inhibited the enzymes Na+/K+-ATPase and isocitrate lyase (ICL) with IC50 = 10.9, 77.9, 18.7 and 57.4, >100, 66.3 µg/mL, respectively, and theirMar. Drugs inhibitory 2018, 16, x activity was hypothesized to be due to the three-dimensional structure14 of 26 of the Mar. Drugs 2018, 16, x 14 of 26 spiroketal10.9, 77.9, motif 18.7 [85 and]. Phorone57.4, >100, B66.3 (179 μg/mL,) and respectively, ansellone C and (180 their) (Figure inhibitory 18 ),activity along was with hypothesized a nortriterpene sodiumto10.9, O- be 77.9, sulfonato-glucuronide due 18.7 to and the 57.4, three >-dimensional100, 66.3 saponin μg/mL, structure respectively, gombaside of the and spiroketal A their (181 )inhibitory (Figure motif [85]. activity18), Phorone were was also hypothesized B (179 isolated) and from C. gombawuiensisanselloneto be due C to .(180 Compound the) (Figure three-dimensional 18),181 alongfeatures with structure a a nortriterpene rare of 4,4,14-trimethylthe spiroketal sodium O motif-sulfonato pregnane [85]. Phorone-glucuronide skeleton. B (179 saponin Compounds) and ansellone C (180) (Figure 18), along with a nortriterpene sodium O-sulfonato-glucuronide saponin 179–181gombasideexhibited A moderate(181) (Figure cytotoxicity 18), were also against isolated A549 from andC. gombawuiensis k562 cancer. Compound cell lines with 181 features IC50 values a of 4.7/3.9,raregombaside 5.4/4.5 4,4,14 and -Atrimethyl (181 2.1/1.8) (Figure pregnaneµg/mL, 18), were skeleton. respectively. also isolated Compounds Interestingly, from C.179 gombawuiensis–181 while exhibited181. Compoundshowed moderate antibacterial 181 cytotoxicity features activitya rare 4,4,14-trimethyl pregnane skeleton. Compounds50 179–181 exhibited moderate cytotoxicity againstagainstB. subtilis A549 and and P. k562 hauseri cancerwith cell MIC lines values with IC of values 1.6 and of 3.14.7/3.9,µg/mL, 5.4/4.5 respectively, and 2.1/1.8 μ179g/mLand, 180 respectively.against A549 Interestingly, and k562 cancer while cell181 linesshowed with antibacteri IC50 valuesal activity of 4.7/3.9, against 5.4/4.5 B. subtilis and 2.1/1.8and P. μhauserig/mL, were inactive (MIC > 100 µg/mL) [86]. Rotalins A (182) and B (183) are two diterpenes reported from withrespectively. MIC values Interestingly, of 1.6 and while 3.1 μg/mL, 181 showed respectively, antibacteri 179 aland activity 180 were against inactive B. subtilis (MIC and> 100 P. μg/mL) hauseri the Mediterranean[86].with RotalinsMIC values AM. (182 of rotalis )1.6 and and B[87 (3.1183] while μg/mL,) are two mycgranol respectively, diterpenes (184 reported 179) (Figureand from180 were18 the) isMediterranean inactive a diterpene, (MIC >M. isolated 100 rotalis μg/mL) [87] from the Kenyanwhile[86].M .Rotalins mycgranol aff. graveleyi A (182 (184)[ 88and) (Figure]. B (183 18)) are is a two diterpene, diterpenes isolated reported from from the Kenyan the Mediterranean M. aff. graveleyi M. rotalis [88]. [87] while mycgranol (184) (Figure 18) is a diterpene, isolated from the Kenyan M. aff. graveleyi [88].

Figure 17. Chemical structures 165–175. Figure 17. Chemical structures 165–175. Figure 17. Chemical structures 165–175.

Figure 18. Chemical structures of 176–184. FigureFigure 18. 18.Chemical Chemical structures of of 176176–184–184. . Norsesterterpene cyclic peroxides are a distinct class of marine sponges-derived metabolites. Five norsesterterpeneNorsesterterpene cyclic cyclic peroxides, peroxides 185 are– 189a distinct (Figure class 19), wereof marine isolated sponges from the-derived Australian metabolites. marine NorsesterterpenespongeFive norsesterterpene M. ancorina cyclic[89] cyclic. Capon peroxides peroxides, et al. [90] are185 reported– a189 distinct (Figure the isolation class19), were of of marineisolated further twofrom sponges-derived norsesterterpene the Australian marine metabolites. cyclic Five norsesterterpeneperoxides,sponge M. ancorina190–191 cyclic [89](Figure. Capon peroxides, 19), et from al. [90]185 M. reported– (189Carmia(Figure )the cf. isolation spongiosa 19), were of, collectedfurther isolated two from from norsesterterpene New the Australian South Wales, cyclic marine Australia.peroxides, Compounds190–191 (Figure 190 – 19),191 fromwere M. isolated (Carmia from) cf. thespongiosa CH2Cl, 2 collectedsoluble fraction, from New which South exhibited Wales, antimicrobialAustralia. Compounds activity against 190–191 B. subtiliswere isolated and Saccharomyces from the CH cerevisae2Cl2 soluble. Mycaperoxides fraction, which A (192 exhibited) and B (antimicrobial193) (Figure 19), activity isolated against from B. the subtilis Thai Mycale and Saccharomyces sp., were found cerevisae to display. Mycaperoxides in vitro potent A (cytotoxicity192) and B (193) (Figure 19), isolated from the Thai Mycale sp., were found to display in vitro potent cytotoxicity

Mar. Drugs 2018, 16, 214 18 of 26 sponge M. ancorina [89]. Capon et al. [90] reported the isolation of further two norsesterterpene cyclic peroxides, 190–191 (Figure 19), from M. (Carmia) cf. spongiosa, collected from New South Wales, Australia. Compounds 190–191 were isolated from the CH2Cl2 soluble fraction, which exhibited antimicrobial activity against B. subtilis and Saccharomyces cerevisae. Mycaperoxides A (192) and B (193) (Figure 19), isolated from the Thai Mycale sp., were found to display in vitro potent cytotoxicity against Mar. Drugs 2018, 16, x 15 of 26 three cancer cell lines, P-388, A-549 and HT.29 with IC50 of 0.5-1.0 µg/mL, and antiviral activity against Mar. Drugs 2018, 16, x 15 of 26 severalagainst viruses, three includingcancer cell lines, HSV-1. P-388, Moreover, A-549 and theseHT.29 compoundswith IC50 of 0.5 also-1.0 µg/mL, showed and antibacterial antiviral activity activity againstagainstB. subtilis several and viruses, S. aureus including[91]. HSV A further-1. Moreover, ﬁve cyclic these peroxides, compounds185 also, 186 showed, 189 , antibacterial mycaperoxides against three cancer cell lines, P-388, A-549 and HT.29 with IC50 of 0.5-1.0 µg/mL, and antiviral activity activity against B. subtilis and S. aureus [91]. A further five cyclic peroxides, 185, 186, 189, C(194against) and several D (195 viruses,), along inclu withding six HSV norterpenes,-1. Moreover,196 these–201 compounds(Figure 20 ), also were showed isolated antibacterial from M. sp. mycaperoxides C (194) and D (195), along with six norterpenes, 196–201 (Figure 20), were isolated Fromactivity Australia against [92]. B. A subtilis re-investigation and S. aureus of Mycale[91]. Asp., further collected five cyclicfrom New peroxides, South 185 Wales,, 186, Australia,189, from M. sp. From Australia [92]. A re-investigation of Mycale sp., collected from New South Wales, allowedmycaperoxides the identiﬁcation C (194) ofand two D ( further195), along mycaperoxides with six norterpenes, F (202) and196– G201 (203 (Figure) and 20), a norterpene were isolated ketone Australia, allowed the identification of two further mycaperoxides F (202) and G (203) and a (204)from (Figure M. 20sp.)[ From93]. Similarly,Australia [92]. re-examination A re-investigation of the of Thai MycaleMycale sp., sp.,collected by Phuwapraisirisan from New South etWales, al., led to norterpene ketone (204) (Figure 20) [93]. Similarly, re-examination of the Thai Mycale sp., by Australia, allowed the identification of two further mycaperoxides F (202) and G (203) and a the isolationPhuwapraisirisan of mycaperoxide et al., led to H the (205 isolation) (Figure of mycaperoxide20), which was H (205 cytotoxic) (Figure against 20), which the was HeLa cytotoxic cancer cell norterpene ketoneµ (204) (Figure 20) [93]. Similarly, re-examination of the Thai Mycale sp., by line withagainst IC 50the= HeLa 0.8 cancerg/mL cell [94 ].line with IC50 = 0.8 µg/mL [94]. Phuwapraisirisan et al., led to the isolation of mycaperoxide H (205) (Figure 20), which was cytotoxic against the HeLa cancer cell line with IC50 = 0.8 µg/mL [94].

Figure 19. Chemical structures 185–193. Figure 19. Chemical structures 185–193. Two aromatic keto-carotenoids,Figure clathriacine 19. Chemical ( 206structures) and trikentriohodine185–193. (207) (Figure 20), were Twoisolated aromatic from the keto-carotenoids,marine sponge identified clathriacine as C. frondifera (206,) which, and trikentriohodineif correct, is now a junior (207) synonym (Figure 20), Two aromatic keto-carotenoids, clathriacine (206) and trikentriohodine (207) (Figure 20), were wereof isolated C. (Thalysias from) vulpine the marine [95,96]. sponge identiﬁed as C. frondifera, which, if correct, is now a junior isolated from the marine sponge identified as C. frondifera, which, if correct, is now a junior synonym synonymof C. ( ofThalysiasC. (Thalysias) vulpine) vulpine[95,96]. [95,96].

Figure 20. Chemical structures of 194–207.

2.13. Steroidal Compounds FigureFigure 20. 20.Chemical Chemical structures of of 194194–207–207. .

2.13. ThreeSteroidal highly Compounds oxygenated steroids, named contignasterol (208) and clathriols A (209) and B (210) (Figure 21), were isolated from the New Zealand marine sponge C. (Clathria) lissosclera. While 208 Three highly oxygenated steroids, named contignasterol (208) and clathriols A (209) and B (210) exhibited a histamine release inhibitory activity with an IC50 = 0.8 ± 0.32 μg/mL, 209 and 210 showed (Figure 21), were isolated from the New Zealand marine sponge C. (Clathria) lissosclera. While 208

exhibited a histamine release inhibitory activity with an IC50 = 0.8 ± 0.32 μg/mL, 209 and 210 showed

Mar. Drugs 2018, 16, 214 19 of 26

2.13. Steroidal Compounds Three highly oxygenated steroids, named contignasterol (208) and clathriols A (209) and B (210) (Figure 21), were isolated from the New Zealand marine sponge C. (Clathria) lissosclera. While 208 exhibited a histamine release inhibitory activity with an IC50 = 0.8 ± 0.32 µg/mL, 209 and 210 showed anti-inﬂammatory activity against the production of superoxide stimulated with N-formyl-methionine-leucine-phenylalanine (fmlp) or phorbol myristate acetate (PMA), with IC50 values of −33/27 and 140/130 µg/mL, respectively. Moreover, 209 also displayed a 72% inhibition of the histamine release in peritoneal mast cells and a 76% inhibition of human peripheral blood neutrophil at a concentration of 30 µM[17,18]. Bioassay-guided fractionation of the CHCl3-MeOH crude extract of the marine sponge Clathria sp., collected from the Red sea, resulted in the isolation of a sulfated sterol, clathsterol (211) (Figure 21), which displayed moderate antiviral activity against HIV-1 at a concentration of 10 µg/mL [16]. Biemansterol (212), along with the previously reported 24β-methylcholesta-5, 7, 22, 25-tetraen-3β-ol (213) (Figure 21), were isolated from the Okinawan marine sponge Biemna sp. [97]. Compound 212, which possesses a rare 22, 25-diene side chain displayed in vitro cytotoxicity against murine lymphoma L1210 and human epidermoid KB cell lines, with IC50 values of 3 and 1.3 µM, respectively [97]. Foristerol (214) (Figure 21), a steroid featuring an unusual seven-membered lactone ring, was reported from the Chinese marine sponge, B. fortis [98], while 5α, 8α-epidioxy-24(S)-ethylcholest-6-en-3β-ol (215) (Figure 21) was isolated from the Madagascar marine sponge B. triraphis [99]. Huang and Guo [100] described the isolation of nine steroids, including melithasterol B (216), (24R)-ergosta-7,22-dien-3, 5, 6-triol (217), (24R)-ergosta-4, 6, 8(14), 22-tetraen-3-one (218), (24R)-ergosta-4, 7, 22-trien-3-one (219), (24R)-ergosta-6, 22-dien-5, 8-epidioxy-3-ol (220), 6-hydroxycholest-4-en-3-one (221), cholest-4-en-3, 6-dione (222), cholest-4-en-3-one (223) and cholest-5, 22-dien-3-one (224) (Figure 21), from the Chinese marine sponge B. fortis. Compound 222 displayed mild inhibition of T- and B-lymphocytes proliferation and potent hPTP1B inhibitory activity, with IC50 = 1.6 µM[100]. Youssef et al. [101] reported the isolation of ehrenasterol (225) and (22E)-ergosta-5, 8, 22-trien-7-one-3β-ol (226), along with the previously reported (24R)-ergosta-6, 22-dien-5, 8-epidioxy-3-ol (220) and 216 (Figure 21), from the Red Sea marine sponge B. ehrenbergi. Compound 225 exhibited antibacterial activity with an inhibition zone of 20 mm at 100 µg/disc against E. coli. Moreover, both 225 and 226 showed weak cytotoxicity against a human colon adenocarcinoma (HCT-116) cancer cell line, with IC50 of 45 and 40 µg/mL, respectively [101]. The steroidal oligoglycosides, mycalosides A–I (227–235) (Figure 22), were isolated from the Caribbean sponge M. laxissima. These compounds represent the ﬁrst examples of steroidal oligoglycosides reported from marine sponges. The fraction containing 227–235, along with the pure mycaloside A(227) and mycaloside G (233), showed growth inhibition of fertilized eggs of the marine urchin (Strongylocentrotus nudus), with EC50 of 7.4 and 3.2 µg/mL, respectively [102,103].

2.14. Miscellaneous Compounds The unprecedented cytotoxic PKS/NPRS metabolites, mycapolyols A–F (236–241) (Figure 23), were isolated from a Japanese M. izuensis. These compounds displayed cytotoxic activity against the HeLa cells, with IC50 values of 0.06, 0.05, 0.16, 0.40, 0.38 and 0.90 µg/mL, respectively [104]. On the other hand, the ﬁrst naturally occurring 5-thiosugar, 5-thio-D-mannose (242) (Figure 23), was reported from the marine sponge C. (Dendrocia) pyramida [105] while diethylene glycol dibenzoate (243) was reported from C. reinwardtti, collected at the Mandapam coast in the Gulf of Mannar, Tamilnadu, India [106]. 1,5-Diazacyclohenicosane (244) (Figure 23), an aliphatic cyclic diamine was isolated from the Kenyan Mycale sp. [107]. Compound 244 exhibited signiﬁcant cytotoxicity against A549 human lung carcinoma, HT29 human tissue carcinoma, and MDA-MB-231 human breast adenocarcinoma, with GI50 values of 5.41, 5.07 and 5.74 µM, respectively. Mar. Drugs 2018, 16, 214 20 of 26 Mar. Drugs 2018, 16, x 17 of 26 Mar. Drugs 2018, 16, x 17 of 26

Figure 21. Chemical structures of 208–226. Figure 21. Chemical structures of 208–226. Figure 21. Chemical structures of 208–226.

Figure 22. Chemical structures 227–235. Figure 22. Chemical structures 227–235..

Mar. Drugs 2018, 16, 214 21 of 26 Mar. Drugs 2018, 16, x 18 of 26

Figure 23. Chemical structures 236–244. Figure 23. Chemical structures 236–244.

3. Conclusions and Prospects This review presents extensive documented data, focusing on chemical diversity and biological activities of the secondary metabolites, isolated from the three marine sponge genera: Mycale (Arenochalina), Biemna and Clathria, demonstrating these marine species as prolific sources of structurally diverse bioactive compounds. Despite their production of tricyclic guanidine-containing alkaloids, these sponges are classified under two different orders: Mycale (Arenochalina)/Clathria (under the order Poecilosclerida) and Biemna (under the order Biemnida), as recent molecular data revealed that Biemna is not related to the Poecilosclerida, and hence a new order Biemnida was given for the genus Biemna. This finding could highlight the important question of using secondary metabolites as taxonomic markers. Another important chemical feature is the uniqueness of the production of pyridoacridine alkaloids by Biemna sponges, which implies the relatedness of Biemna genus to the order Poecilosclerida. The two hundred and forty-four metabolites reported in this review are put together into fourteen major chemical classes, according to their structural characteristics and biosynthetic origin. The vast array of bioactivities exhibited by some of these metabolites make these marine sponge genera some of the most attractive biological targets, worthy of further exploration.

Author Contributions: A.E.-D. designed and elaborated the manuscript. M.T. helped in manuscript preparation. A.G.A., J.N.A.H. provided comments and additional data. A.E.-M. and A.K. critically revised and improved the manuscript. All the authors approved the final version of the manuscript. Acknowledgments: This work was supported by the mission sector of the Ministry of High Education of the Arab Republic of Egypt (Egyptian cultural bureau in Paris and Athens); Amr El-Demerdash’s, and Mohamed Tammam’s joint supervision were fully funded and supported. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations The following abbreviations are used in this manuscript:

EC50 Half maximal Effective Concentration GI50 Half maximal Growth Inhibition HIV-1 Human Immunodeﬁciency Virus 1 IC50 Half maximal Inhibitory Concentration MIC Minimum Inhibitory Concentration MAD Minimum active Dose MID Minimal Infective Dose Lethal Dose 50 (median concentration of a toxicant that will kill 50% of the test animals within a LD 50 designated period Mar. Drugs 2018, 16, 214 22 of 26

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