Bioactive Secondary Metabolites from the Marine Sponge Genus Agelas

Home , Agelas clathrodes, Agelas schmidti

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Review Bioactive Secondary Metabolites from the Marine Sponge Genus Agelas

Huawei Zhang 1,* ID , Menglian Dong 1, Jianwei Chen 1, Hong Wang 1, Karen Tenney 2 and Phillip Crews 2 ID

1 Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China; [email protected] (M.D.); [email protected] (J.C.); [email protected] (H.W.) 2 Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz 95064, CA, USA; [email protected] (K.T.); [email protected] (P.C.) * Correspondence: [email protected]; Tel.: +86-571-8832-0613

Received: 19 September 2017; Accepted: 3 November 2017; Published: 8 November 2017

Abstract: The marine sponge genus Agelas comprises a rich reservoir of species and natural products with diverse chemical structures and biological properties with potential application in new drug development. This review for the ﬁrst time summarized secondary metabolites from Agelas sponges discovered in the past 47 years together with their bioactive effects.

Keywords: marine sponge; Agelas; secondary metabolite; natural product; bioactivity

1. Introduction The search for natural drug candidates from marine organisms is the eternal impetus to pharmaceutical scientists. For the past six decades, marine sponges have been a proliﬁc and chemically diverse source of natural compounds with potential therapeutic application [1,2]. The marine sponge Agelas (Porifera, Demospongiae, Agelasida, Agelasidae) is widely distributed in the marine eco-system and includes at least 19 species (Figure1): A. axifera, A. cerebrum, A. ceylonica, A. citrina, A. clathrodes, A. conifera, A. dendromorpha, A. dispar, A. gracilis, A. linnaei, A. longissima, A. mauritiana, A. nakamurai, A. nemoechinata, A. oroides, A. sceptrum, A. schmidtii, A. sventres, and A. wiedenmayeri. Since the beginning of the 1970s, many research groups around the world have carried out chemical investigation on Agelas spp., resulting in fruitful achievements. Their studies revealed that Agelas sponges harbor many bioactive secondary metabolites, including alkaloids (especially bromopyrrole derivatives), terpenoids, glycosphingolipids, carotenoids, fatty acids and meroterpenoids [3]. These natural products are an attractive resource for drug candidates due to their rich chemodiversity and interesting biological activities.

Mar. Drugs 2017, 15, 351; doi:10.3390/md15110351 www.mdpi.com/journal/marinedrugs Mar. Drugs 2017, 15, 351 2 of 29 Mar. Drugs 2017, 15, 351 2 of 29

Agelas clathrodes Agelas conifera

Agelas dispar Agelas inequalis

Agelas mauritiana Agelas sceptrum

Agelas wiendermayeri Agelas sp.

Figure 1. Photos of Agelas sponges provided by professor Crews. Figure 1. Photos of Agelas sponges provided by professor Crews. 2. Natural Products from Agelas Genus 2. Natural Products from Agelas Genus The chemical diversity of natural products is determined by the biological diversity of organisms. ToThe date, chemical 291 secondary diversity metabolites of natural ( products1–291) have isdetermined been isolated by and the biologicalcharacterized diversity from the of organisms.marine Tosponge date, 291 Agelas secondary spp. (Table metabolites 1). These chemicals (1–291) have were been introduced isolated and and assorted characterized as follows from according the marine to spongetheir biologicalAgelas spp. sources. (Table 1). These chemicals were introduced and assorted as follows according to their biological sources.

Mar. Drugs 2017, 15, 351 3 of 29 Mar. Drugs 2017, 15, 351 3 of 29 Mar. Drugs 2017, 15, 351 3 of 29 Mar. Drugs 2017, 15, 351 3 of 29 2.1.2.1. Agelas Agelas axifera axifera 2.1. Agelas axifera 2.1. Agelas axifera ThreeThree newnew alkaloids,alkaloids, namednamed axistatinsaxistatins 11 (1(1),), 22 (2(2),), andand 33 (3(3)) (Figure(Figure2 ),2), were were isolated isolated and and Three new alkaloids, named axistatins 1 (1), 2 (2), and 3 (3) (Figure 2), were isolated and characterizedcharacterizedThree new fromfrom alkaloids,Agelas Agelas axiferanamedaxiferacollected collectedaxistatinsin in the1 the (1 Republic ),Republic 2 (2), andof of Palau Palau3 (3) and and(Figure found found 2), to towere exhibit exhibit isolated inhibitory inhibitory and characterized from Agelas axifera collected in the Republic of Palau and found to exhibit inhibitory characterizedeffectseffects on on cancer cancer from cell cell Agelas lines, lines, axifera including including collected P388, P388, BXPC-3, inBXPC-3, the Republic MCF-7,MCF-7, of SF-268,SF-268, Palau NCI-H460, NCI-H460,and foundKM20L2 KM20L2to exhibit andand inhibitory DU-145.DU-145. effects on cancer cell lines, including P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2 and DU-145. effectsTheThe exquisitely exquisitely on cancer sensitive cellsensitive lines, Gram-negative Gram-negativeincluding P388, pathogen pathogen BXPC-3, NeisseriaMCF-7, Neisseria SF-268, gonorrheae gonorrheae NCI-H460,and and the the KM20L2 opportunistic opportunistic and DU-145. fungus fungus The exquisitely sensitive Gram-negative pathogen Neisseria gonorrheae and the opportunistic fungus TheCryptococcusCryptococcus exquisitely neoformansneoformans sensitive wereGram-negative inhibited inhibited by pathogen by 1–13– 3withwith Neisseria MIC MIC values valuesgonorrheae of 1–8, of 1–8,and 2–4, the 2–4, and opportunistic and8 μg/mL, 8 µg/mL, and fungus 1–4, and 2, Cryptococcus neoformans were inhibited by 1–3 with MIC values of 1–8, 2–4, and 8 μg/mL, and 1–4, 2, 1–4,Cryptococcusand 2,8–16 and μ 8–16 g/mL,neoformansµg/mL, respectively. were respectively. inhibited Furthermore, by Furthermore, 1–3 withthese MIC compounds these values compounds of had1–8, antimicrobial2–4, had and antimicrobial 8 μg/mL, effect and on effect 1–4,Gram- on 2, and 8–16 μg/mL, respectively. Furthermore, these compounds had antimicrobial effect on Gram- andGram-positivepositive 8–16 bacteria,μg/mL, bacteria, respectively.including including Staphylococcus Furthermore,Staphylococcus aureus these aureus, Streptococcuscompounds, Streptococcus hadpneumoniae pneumoniaeantimicrobial, Enterococcus, Enterococcus effect onfaecalis Gram- faecalis and positive bacteria, including Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis and positiveandMicrococcusMicrococcus bacteria, luteus luteus including [4]. [4]. Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis and Micrococcus luteus [4]. Micrococcus luteus [4].

1 2 3 1 2 3 1 2 3 Figure 2. Chemical structures of compounds 1–3. Figure 2. Chemical structures of compounds 1–3. Figure 2. Chemical structures of compounds 1–3. 2.2. Agelas cerebrum 2.2. Agelas cerebrum 2.2. Agelas cerebrum Marine sponge Agelas cerebrum was classified as a new species in 2001 [5]. Chemical investigation Marine spongespongeAgelas Agelas cerebrumcerebrumwas was classified classified as as a a new new species species in in 2001 2001 [5 [5].]. Chemical Chemical investigation investigation of of CaribbeanMarine sponge specimen Agelas A. cerebrumcerebrum led was to classified the isolation as a of new three species brom ininated 2001 compounds, [5]. Chemical 5-bromopyrrole- investigation Caribbeanof Caribbean specimen specimenA. A. cerebrum cerebrumled led to to the the isolation isolation of of three three brominated brominated compounds, compounds, 5-bromopyrrole-2- 5-bromopyrrole- of2-carboxylic Caribbean specimenacid (4), 4-bromopyrrole-2-carboxylicA. cerebrum led to the isolation acid of three (5) and brom 3,4-bromopyrroleinated compounds,-2-carboxylic 5-bromopyrrole- acid (6) carboxylic2-carboxylic acid acid ( 4(),4), 4-bromopyrrole-2-carboxylic 4-bromopyrrole-2-carboxylic acidacid ((55)) andand 3,4-bromopyrrole-2-carboxylic3,4-bromopyrrole-2-carboxylic acid ( 6)) 2-carboxylic(Figure 3) [6]. acid Biological (4), 4-bromopyrrole-2-carboxylic tests indicated that these isolatesacid (5 )had and strong 3,4-bromopyrrole cytotoxic activities-2-carboxylic in vitro acid against (6) (Figure3 3)) [[6].6]. Biological tests indicated that these isolates had had strong strong cytotoxic cytotoxic activities activities inin vitro vitro against (Figurehuman 3) tumor [6]. Biological cell lines tests at ≥ 1indicated mg/mL, thatincluding these isolates A549, HT29 had strong and MDA-MB-231. cytotoxic activities in vitro against human tumor cellcell lineslines atat≥ ≥1 mg/mL, including including A549, A549, HT29 and MDA-MB-231. human tumor cell lines at ≥1 mg/mL, including A549, HT29 and MDA-MB-231.

4: R1 = H, R2 =H, R3 = Br 4: R1 = H, R2 =H, R3 = Br 4:5: R R11= = H, H, R R22=H, = Br, R 3R=3 Br= H 5: R1 = H, R2 = Br, R3 = H 5:6: R R11 = = H, Br, R R2 2= = Br, Br, R R3 3= = H H. 6: R1 = Br, R2 = Br, R3 = H. 6: R1 = Br, R2 = Br, R3 = H. Figure 3. Chemical structures of compounds 4–6. Figure 3. Chemical structures of compounds 4–6. Figure 3. Chemical structures of compounds 4–6. 2.3. Agelas ceylonica 2.3. Agelas ceylonica 2.3. Agelas ceylonica Only one case of chemical study on Agelas ceylonica has been reported [7]. The specimen of A. Only one case of chemical study on Agelas ceylonica has been reported [7]. The specimen of A. ceylonicaOnly collectedone one case case fromof of chemical chemical India Mandapam study study on on Agelas Agelascoast ceylonicawas ceylonica found hashas to been produce been reported reported one methyl[7]. [7 ].The Theester specimen specimen hanishin of A. of(7 ) ceylonica collected from India Mandapam coast was found to produce one methyl ester hanishin (7) ceylonicaA.(Figure ceylonica 4),collected collectedwhich fromhas from been India India previously Mandapam Mandapam found coast coast in wasthe was marinefound found to sponge to produce produce Homaxinella one one methyl methyl sp. ester[8]. ester hanishin hanishin ( (77)) (Figure 4), which has been previously found in the marine sponge Homaxinella sp. [8]. (Figure4 4),), whichwhich hashas beenbeen previouslypreviously found found in in the the marine marine sponge sponge HomaxinellaHomaxinella sp.sp. [[8].8].

7 7 7 Figure 4. Chemical structures of compounds 7. Figure 4. Chemical structures of compounds 7. Figure 4. Chemical structures of compounds 7. 2.4. Agelas citrina 2.4. Agelas citrina 2.4. Agelas citrina The Caribbean specimen of Agelas citrina was firstly found to yield three new diterpene alkaloids, The Caribbean specimen of Agelas citrina was firstly found to yield three new diterpene alkaloids, (−)-agelasidineThe Caribbean E ( specimen8), (−)-agelasidine of Agelas citrinaF (9) and was agelasinefirstly found N (to10 yield) [9]. threeLatter new chemical diterpene investigation alkaloids, (−)-agelasidine E (8), (−)-agelasidine F (9) and agelasine N (10) [9]. Latter chemical investigation (− )-agelasidine E (8), (−)-agelasidine F (9) and agelasine N (10) [9]. Latter chemical investigation

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2.4. Agelas citrina

Mar. DrugsThe Caribbean2017, 15, 351 specimen of Agelas citrina was ﬁrstly found to yield three new diterpene alkaloids,4 of 29 (−)-agelasidine E (8), (−)-agelasidine F (9) and agelasine N (10)[9]. Latter chemical investigation showedshowed that this this sponge sponge also also produces produces four four new new pyrrole-imidazole pyrrole-imidazole alkaloids, alkaloids, citrinamines citrinamines A–D A–D (11– (1411),– 14and), andone onebromopyrrole bromopyrrole alkaloid alkaloid N-methylagelongineN-methylagelongine (15) ((Figure15) (Figure 5) [10].5)[ 10Compounds]. Compounds 12–1412 had–14 hadantimicrobial antimicrobial activities activities whereas whereas no noinhibitory inhibitory effe effectct on on cell cell proliferation proliferation of of mouse mouse fibroblasts ﬁbroblasts was foundfound forfor 1111––1414..

8: R = CH2OH 10 9: R = CHO

11 12

13 14

Figure 5. Chemical structures of compounds 88––1515..

2.5. Agelas clathrodes Marine sponge Agelas clathrodes was the excellent producer of secondary metabolites, including Marine sponge Agelas clathrodes was the excellent producer of secondary metabolites, including glycosphingolipid derivatives (GSLs) and alkaloids. Clarhamnoside (16), containing an unusual L- glycosphingolipid derivatives (GSLs) and alkaloids. Clarhamnoside (16), containing an unusual rhamnose unit in the sugar head, was the first rhamnosylated α-galactosylceramide from A. clathrodes L-rhamnose unit in the sugar head, was the ﬁrst rhamnosylated α-galactosylceramide from A. clathrodes collected along the coast of Grand Bahamas Island (Sweetings Cay) [11]. The Caribbean sponge A. collected along the coast of Grand Bahamas Island (Sweetings Cay) [11]. The Caribbean sponge clathrodes could metabolize clathrosides A–C (17–19) and isoclathrosides A–C (20–22), which, A. clathrodes could metabolize clathrosides A–C (17–19) and isoclathrosides A–C (20–22), which, respectively, belonged to two families of different glycolipids [12]. Compound 23 was also isolated from respectively, belonged to two families of different glycolipids [12]. Compound 23 was also isolated from the Caribbean specimen (Figure 6) [13]. It was noted that all the GSLs from A. clathrodes were actually the Caribbean specimen (Figure6)[ 13]. It was noted that all the GSLs from A. clathrodes were actually elucidated as mixtures of homologs, which play an important role in therapeutic immunomodulation. elucidated as mixtures of homologs, which play an important role in therapeutic immunomodulation. Six alkaloids, (−)-agelasidine A (24), (−)-agelasidine C (25), (−)-agelasidine D (26), clathramide A(27), clathramide B (28) and clathrodin (29), were detected in the Caribbean sponge A. clathrodes (Figure7). Bioassay results suggested that compound 24 possessed inhibitory effect on Staphilococcus aureus but no effect on fungi, while 25 and 26 were shown to have antimicrobial activities against S. aureus, Klebsiella pneumoniae and Proteus vulgaris [14]. In vitro cytotoxic test indicated that

Mar. Drugs 2017, 15, 351 4 of 29

showed that this sponge also produces four new pyrrole-imidazole alkaloids, citrinamines A–D (11– 14), and one bromopyrrole alkaloid N-methylagelongine (15) (Figure 5) [10]. Compounds 12–14 had antimicrobial activities whereas no inhibitory effect on cell proliferation of mouse fibroblasts was found for 11–14.

8: R = CH2OH 10 9: R = CHO

11 12

13 14

15 Mar. Drugs 2017, 15, 351 5 of 29 Figure 5. Chemical structures of compounds 8–15.

2.5. Agelas clathrodes 25 and 26 signiﬁcantly inhibited the growth of CHO-K1 cells with the ED50 values of 5.70 and 2.21 µMarineg/mL, sponge respectively. Agelas Compoundclathrodes was26 thealso excellent possessed producer the inhibition of secondary against metabolites, the growth including of E. coli andglycosphingolipidHafnia alvei [15 ],derivatives while 27 and (GSLs)28 had and a alkaloids. moderate antifungalClarhamnoside activity (16 against), containingAspergillus an unusual niger [16 L].- Mar.Interestingly,rhamnose Drugs 2017 unit, 15 compound in, 351 the sugar29 head,contained was the a nonbrominatedfirst rhamnosylated pyrrole α-galactosylceramide and a guanidine moietyfrom A. [clathrodes17].5 Oneof 29 specimencollected along of A. clathrodesthe coast fromof Grand the SouthBahamas China Island Sea was(Sweetings shown Cay) to produce [11]. The an ionicCaribbean compound sponge (30 A.), whichclathrodes had could weak cytotoxicitymetabolize againstclathrosides cancer A–C cell lines(17– A54919) and and isoclathrosides SGC7901 with ICA–C50 values (20–22 of), 26.5 which, and 22.7respectively,µg/mL, belonged respectively to two [18 families]. Four brominatedof different glycolipids compounds, [12]. dispacamides Compound 23 A–D was ( also31–34 isolated) (Figure from7), werethe Caribbean detected notspecimen only in (FigureA. clathrodes 6) [13]., but It was also noted in A. coniferathat all, theA. disparGSLs andfromA. A. longissima clathrodes, andwere exhibited actually antihistamineelucidated as mixtures activity [of19 homologs,,20]. which play an important role in therapeutic immunomodulation. 17: R = CH2CH2CH3 20: R = CH2CH2CH3 18: R = H(CH3)CH2CH3 21: R = CH(CH3)CH2CH3 19: R = CH2CH(CH3)2 22: R= CH2CH(CH3)2

23 Mar. Drugs 2017, 15, 351 5 of 29 Figure 6. Chemical structures16 of compounds 16–23.

respectively [18]. Four brominated compounds, dispacamides23 A–D (31–34) (Figure 7), were detected not only in A. clathrodes, but also in A. conifera, A. dispar and A. longissima, and exhibited antihistamine activity [19,20]. FigureFigure 6. 6.ChemicalChemical structures structures of ofcompounds compounds 1616–23–23. .

Six alkaloids, (−)-agelasidine A (24), (−)-agelasidine C (25), (−)-agelasidine D (26), clathramide A (27), clathramide B (28) and clathrodin (29), were detected in the Caribbean sponge A. clathrodes (Figure 7). Bioassay results suggested that compound 24 possessed inhibitory effect on Staphilococcus aureus but no effect on fungi, while 25 and 26 were shown to have antimicrobial activities against S. 25: R = H 27: R1 = H, R2 = COOH aureus, Klebsiella24 pneumoniae and Proteus vulgaris [14]. In vitro cytotoxic test indicated that 25 and 26 26: R = OH 28: R1 = COOH, R2 = H significantly inhibited the growth of CHO-K1 cells with the ED50 values of 5.70 and 2.21 μg/mL, respectively. Compound 26 also possessed the inhibition against the growth of E. coli and Hafnia alvei [15], while 27 and 28 had a moderate antifungal activity against Aspergillus niger [16]. Interestingly, compound 29 contained a nonbrominated pyrrole and a guanidine moiety [17]. One specimen of A. clathrodes from the South China Sea was shown to produce an ionic compound (30), which had weak 31: R = Br 33: R = Br cytotoxicity against29 cancer cell lines A54930 and SGC7901 with IC50 values of 26.5 and 22.7 μg/mL, respectively [18]. Four brominated compounds, dispacamides32: RA–D = H ( 31–34) (Figure 7),34: wereR = H detected not only in A. clathrodes, but also in A. conifera, A. dispar and A. longissima, and exhibited antihistamine FigureFigure 7. 7. ChemicalChemical structures structures of of compounds compounds 24–34.. activity [19,20]. 2.6. Agelas conifera Chemical study of two specimens of Agelas conifera from the Florida Keys and Belize led to the isolation of two new dimeric bromopyrrole alkaloids, bromosceptrin (35) and debromosceptrin (36), respectively [21,22]. Seven new bromopyrrole metabolites (37–43) were firstly purified from the 25: R = H 27: R1 = H, R2 = COOH Caribbean sponge24 A. conifera [23], but the detailed structure elucidation of ageliferin (41), bromoageferin (42) and dibromoageliferin26: ( R43 =) OHwere established by Kobayashi28: R1 = COOH, and hisR2 =co-workers H [24]. Bioassay results indicated that compounds 37, 41, 42 and 43 possessed biological activities

31: R = Br 33: R = Br 29 30 32: R = H 34: R = H

Figure 7. Chemical structures of compounds 24–34.

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2.6. Agelas conifera Chemical study of two specimens of Agelas conifera from the Florida Keys and Belize led to the isolation of two new dimeric bromopyrrole alkaloids, bromosceptrin (35) and debromosceptrin (36), respectively [21,22]. Seven new bromopyrrole metabolites (37–43) were firstly purified from the Caribbean sponge A. conifera [23], but the detailed structure elucidation of ageliferin (41), bromoageferin (42) and dibromoageliferin (43) were established by Kobayashi and his co-workers [24]. BioassayMar. Drugs results 2017, indicated15, 351 that compounds 37, 41, 42 and 43 possessed biological activities6 againstof 29 Bacillus subtilis at 10 µg/disk and 41 and 42 could inhibit the growth of E. coli at 10 µg/disk. Using against Bacillus subtilis at 10 μg/disk and 41 and 42 could inhibit the growth of E. coli at 10 μg/disk. new protein-guided methods by its affinity to proteins within tumor cell proteomes, one unique Using new protein-guided methods by its affinity to proteins within tumor cell proteomes, one polyhydroxybutyrated β-GSL coniferoside (44), was detected in A. conifera derived from Puerto Rico unique polyhydroxybutyrated β-GSL coniferoside (44), was detected in A. conifera derived from as wellPuerto as another Rico as well GSL as derivative another GSL (45 )derivative (Figure8 )[(4525) ,(Figure26]. 8) [25,26].

R1 R2 R3 R4 R5 37: Br H H H A 35 36 38: Br Br Br Br A 39: H H H Br B 40: Br H H Br B

41: R1 = H, R2 = H 42: R1 = Br, R2 = H 44 43: R1 = Br, R2 = Br

FigureFigure 8. 8.Chemical Chemical structures structures of compounds 3535–45–45. .

2.7. Agelas dendromorpha 2.7. Agelas dendromorpha Natural product analysis of the marine sponge Agelas dendromorpha revealed three novel agelastatinsNatural product (46–48) analysiswith pyrrole-2-imidazole of the marine structure. sponge AgelasAgelastatin dendromorpha A (46) wasrevealed obtained threefrom the novel agelastatinsAxinellid ( 46specimen–48) with grown pyrrole-2-imidazole in the Coral Sea and structure. had strong Agelastatin cytotoxicity A[27]. (46 Agelastatins) was obtained E (47 from) and the AxinellidF (48) specimen(Figure 9) grownpurified in from the Coralthe New Sea Caledonian and had strong A. dendromorpha cytotoxicity were [27 ].shown Agelastatins to exhibit E weak (47) and F(48cytotoxicity) (Figure9) against puriﬁed the from KB cell the line New at 30 Caledonian μM [28]. A. dendromorpha were shown to exhibit weak cytotoxicity against the KB cell line at 30 µM[28].

47: R1 = H, R2 = CH3, R3 = CH3 46 48: R1 = Br, R2 = H, R3 = H

Figure 9. Chemical structures of compounds 46–48.

Mar. Drugs 2017, 15, 351 6 of 29 against Bacillus subtilis at 10 μg/disk and 41 and 42 could inhibit the growth of E. coli at 10 μg/disk. Using new protein-guided methods by its affinity to proteins within tumor cell proteomes, one unique polyhydroxybutyrated β-GSL coniferoside (44), was detected in A. conifera derived from Puerto Rico as well as another GSL derivative (45) (Figure 8) [25,26].

R1 R2 R3 R4 R5 37: Br H H H A 35 36 38: Br Br Br Br A 39: H H H Br B 40: Br H H Br B

41: R1 = H, R2 = H 42: R1 = Br, R2 = H 44 43: R1 = Br, R2 = Br

Figure 8. Chemical structures of compounds 35–45.

2.7. Agelas dendromorpha Natural product analysis of the marine sponge Agelas dendromorpha revealed three novel agelastatins (46–48) with pyrrole-2-imidazole structure. Agelastatin A (46) was obtained from the Axinellid specimen grown in the Coral Sea and had strong cytotoxicity [27]. Agelastatins E (47) and FMar. (48 Drugs) (Figure2017, 159), 351purified from the New Caledonian A. dendromorpha were shown to exhibit weak7 of 29 cytotoxicity against the KB cell line at 30 μM [28].

47: R1 = H, R2 = CH3, R3 = CH3 46 48: R1 = Br, R2 = H, R3 = H

Mar. Drugs 2017, 15, 351 FigureFigure 9. 9. ChemicalChemical structures structures of of compounds compounds 4646––4848. . 7 of 29

2.8.2.8. Agelas Agelas dispar dispar It is notable that Caribbean Agelas dispar harbors a distinct biogeographical bromination trend. It is notable that Caribbean Agelas dispar harbors a distinct biogeographical bromination trend. Five compounds containing bromine, dispyrin (49), dibromoagelaspongin methyl ether (50), Five compounds containing bromine, dispyrin (49), dibromoagelaspongin methyl ether (50), longamide longamide B (51), clathramides C (52) and D (53), have been found in the Caribbean sponge A. dispar B(51), clathramides C (52) and D (53), have been found in the Caribbean sponge A. dispar [29,30]. [29,30]. Only compound 51 had moderate anti-bacterial activities against B. subtilis and S. aureus with Only compound 51 had moderate anti-bacterial activities against B. subtilis and S. aureus with MIC MIC values of about 50 μg/mL. The GSL derivative (54) and betaine alkaloids (55–57) were detected values of about 50 µg/mL. The GSL derivative (54) and betaine alkaloids (55–57) were detected in the in the Caribbean A. dispar [31,32]. Antibacterial tests indicated that compounds 55 and 56 had the CaribbeaninhibitoryA. activities dispar [31 against,32]. Antibacterial B. subtilis and tests S. aureus indicated with that MIC compounds values ranging55 and from56 had2.5 to the 8.0 inhibitory μg/mL activities[32]. The against first quaternaryB. subtilis andderivativeS. aureus of withadenine MIC in values nature, ranging agelasine from (58 2.5) (Figure to 8.0 µ10),g/mL was [ 32also]. Thefound first quaternaryin A. dispar derivative [33]. of adenine in nature, agelasine (58) (Figure 10), was also found in A. dispar [33].

52: R1 = H, R2=COOH 49 50 51 53: R1 = COOH, R2 = H

54 55 56

57 58

FigureFigure 10.10. ChemicalChemical structures of compounds compounds 4949––5858. .

2.9. Agelas gracilis 2.9. Agelas gracilis Bioassay-guided fractionation of the crude extract of the deep-sea sponge Agelas gracilis collected Bioassay-guided fractionation of the crude extract of the deep-sea sponge Agelas gracilis collected in southern Japan afforded three novel antiprotozoan compounds, gracilioethers A–C (59–61) (Figure in southern Japan afforded three novel antiprotozoan compounds, gracilioethers A–C (59–61) 11) [34]. Antimalarial tests showed that these metabolites possessed inhibitory effects on Plasmodium (Figure 11)[34]. Antimalarial tests showed that these metabolites possessed inhibitory effects on falciparum with IC50 values of 0.5–10 μg/mL. Plasmodium falciparum with IC50 values of 0.5–10 µg/mL.

2.10. Agelas linnaei Eleven novel brominated pyrrole derivatives (62–72) (Figure 12) were puriﬁed from the Indonesian sponge Agelas linnaei and compounds 66–69 had prominent activities against the murine L1578Y mouse lymphoma cell line59 with IC50 values of 9.55, 9.25,60 16.76 and 13.06 µM, respectively 61 [35]. Figure 11. Chemical structures of compounds 59–61.

2.10. Agelas linnaei Eleven novel brominated pyrrole derivatives (62–72) (Figure 12) were purified from the Indonesian sponge Agelas linnaei and compounds 66–69 had prominent activities against the murine L1578Y mouse lymphoma cell line with IC50 values of 9.55, 9.25, 16.76 and 13.06 μM, respectively [35].

Mar. Drugs 2017, 15, 351 7 of 29

2.8. Agelas dispar It is notable that Caribbean Agelas dispar harbors a distinct biogeographical bromination trend. Five compounds containing bromine, dispyrin (49), dibromoagelaspongin methyl ether (50), longamide B (51), clathramides C (52) and D (53), have been found in the Caribbean sponge A. dispar [29,30]. Only compound 51 had moderate anti-bacterial activities against B. subtilis and S. aureus with MIC values of about 50 μg/mL. The GSL derivative (54) and betaine alkaloids (55–57) were detected in the Caribbean A. dispar [31,32]. Antibacterial tests indicated that compounds 55 and 56 had the inhibitory activities against B. subtilis and S. aureus with MIC values ranging from 2.5 to 8.0 μg/mL [32]. The first quaternary derivative of adenine in nature, agelasine (58) (Figure 10), was also found in A. dispar [33].

52: R1 = H, R2=COOH 49 50 51 53: R1 = COOH, R2 = H

54 55 56

57 58

Figure 10. Chemical structures of compounds 49–58.

2.9. Agelas gracilis Bioassay-guided fractionation of the crude extract of the deep-sea sponge Agelas gracilis collected in southern Japan afforded three novel antiprotozoan compounds, gracilioethers A–C (59–61) (Figure Mar. Drugs11) [34].2017 Antimalarial, 15, 351 tests showed that these metabolites possessed inhibitory effects on Plasmodium8 of 29 falciparum with IC50 values of 0.5–10 μg/mL.

59 60 61

Figure 11. Chemical structures of compounds 59–61. Mar. Drugs 2017, 15, 351 Figure 11. Chemical structures of compounds 59–61. 8 of 29 2.10. Agelas linnaei NH2 Eleven novelHN brominatedN pyrrole derivatives (62–72) (Figure 12) were purified from the HO Br Indonesian spongeNN Agelas linnaei and compounds 66–69 had prominent activities against the murine L1578Y mouse lymphoma cell line with IC50 values of 9.55, 9.25, 16.76 and 13.06 μM, respectively [35]. Br O 62 63 64

65 72

66: R1 = H, R2 = Br 67: R1 = H, R2 = I 70: R = H 68: R1 = Br, R2 = Br 71: R = CH2CH3 69: R1 = Br, R2 = I

FigureFigure 12. 12.Chemical Chemical structures structures ofof compoundscompounds 6262––7272. .

2.11. Agelas longissima 2.11. Agelas longissima Five alkaloids (73–77) (Figure 13) have been isolated from Agelas longissima specimens, all of Fivewhich alkaloids were collected (73–77 from) (Figure the Caribbean 13) have Sea. been Agelongine isolated ( from73) containedAgelas longissima a pyridiniumspecimens, ring instead all of whichof werethe commonly collected found from theimidazole Caribbean nucleus Sea. in Agelongine Agelas alkaloids (73) and contained was shown a pyridinium to be specific ring to insteadinhibit of the commonlythe agonist found 5-hydroxytryptamine imidazole nucleus (5-HT) in Agelas [36].alkaloids Compound and was 75 shownwas unique to be speciﬁc for its to unusual inhibit the agonistpyrrolopiperazine 5-hydroxytryptamine nucleus (5-HT)[37]. Two [36 new]. Compound GSL analogs75 (was76 and unique 77) were for itsalso unusual found in pyrrolopiperazine the Caribbean nucleusA. longissima [37]. Two [38,39]. new GSL analogs (76 and 77) were also found in the Caribbean A. longissima [38,39].

2.12. Agelas mauritiana Agelas mauritiana is one of the most fruitful producers of secondary metabolites among all Agelas species. Thirty-five compounds (78–112) have been isolated and identified from A. mauritiana, 73 74 including terpenoids, pyrrole derivatives, GSLs, carotenoids and other alkaloids. Specimens of A. mauritiana collected from the South China Sea were found to metabolize eight terpenoids (78–85)[40,41]. Compound 79 possessed inhibitory effects on S. aureus with MIC90 value of 1–8 µg/mL µ and activities against PC9, A549, HepG2, MCF-7, and U937 cell lines with IC50 values of 4.49–14.41 M. Compound 84 possessed activities against C. neoformans, S. aureus, methicillin-resistant S. aureus and 75 76 Leishmania donovani with IC50/MIC values of 4.96/10.00, 7.21/10.00, 9.20/20.00 and 28.55/33.19 µg/mL, respectively. Agelasimines A (86) and B (87) and an unusual purino-diterpene (88) were purified from Eniwetak A. mauritiana and 86 and 87 had inhibitory effect on L1210 leukemia with ED50 values of 2.1 and 3.9 nM, respectively. From Pohnpei-derived A. mauritiana, epi-agelasine C (89) was isolated and shown to have no activity against S. aureus, Vibrio costicola, E. coli and B. subtilis [42–44]. Chemical analysis of one specimen of A. auritiana collected from the Solomon Islands afforded agelasines J(90), K (91) and L (92) (Figure 14), which exhibited77 moderate activities against P. falciparum and low cytotoxicity on MCF-7 cells [45]. Figure 13. Chemical structures of compounds 73–77.

2.12. Agelas mauritiana Agelas mauritiana is one of the most fruitful producers of secondary metabolites among all Agelas species. Thirty-five compounds (78–112) have been isolated and identified from A. mauritiana,

Mar. Drugs 2017, 15, 351 8 of 29

NH2

HN N HO Br NN

Br O 62 63 64

65 72

66: R1 = H, R2 = Br 67: R1 = H, R2 = I 70: R = H 68: R1 = Br, R2 = Br 71: R = CH2CH3 69: R1 = Br, R2 = I

Figure 12. Chemical structures of compounds 62–72.

2.11. Agelas longissima Five alkaloids (73–77) (Figure 13) have been isolated from Agelas longissima specimens, all of which were collected from the Caribbean Sea. Agelongine (73) contained a pyridinium ring instead of the commonly found imidazole nucleus in Agelas alkaloids and was shown to be specific to inhibit the agonist 5-hydroxytryptamine (5-HT) [36]. Compound 75 was unique for its unusual Mar. Drugspyrrolopiperazine2017, 15, 351 nucleus [37]. Two new GSL analogs (76 and 77) were also found in the Caribbean 9 of 29 A. longissima [38,39].

73 74

Mar. Drugs 2017, 15, 351 9 of 29

including terpenoids, pyrrole derivatives, GSLs, carotenoids and other alkaloids. Specimens of A. mauritiana collected from the South China Sea were found to metabolize eight terpenoids (78–85)

[40,41]. Compound 79 possessed inhibitory effects on S. aureus with MIC90 value of 1–8 μg/mL and 75 76 activities against PC9, A549, HepG2, MCF-7, and U937 cell lines with IC50 values of 4.49–14.41 μM. Compound 84 possessed activities against C. neoformans, S. aureus, methicillin-resistant S. aureus and Leishmania donovani with IC50/MIC values of 4.96/10.00, 7.21/10.00, 9.20/20.00 and 28.55/33.19 μg/mL, respectively. Agelasimines A (86) and B (87) and an unusual purino-diterpene (88) were purified from Eniwetak A. mauritiana and 86 and 87 had inhibitory effect on L1210 leukemia with ED50 values of 2.1 and 3.9 nM, respectively. From Pohnpei-derived A. mauritiana, epi-agelasine C (89) was isolated and shown to have no activity against S. aureus, Vibrio costicola, E. coli and B. subtilis [42–44]. Chemical 77 analysis of one specimen of A. auritiana collected from the Solomon Islands afforded agelasines J (90), K (91) and L (92) (Figure 14),Figure which 13. Chemical exhibited structures moderate of compounds activities 73against–77. P. falciparum and low Figure 13. Chemical structures of compounds 73–77. cytotoxicity on MCF-7 cells [45]. 2.12. Agelas mauritiana Agelas mauritiana is one of the most fruitful producers of secondary metabolites among all Agelas species. Thirty-five compounds (78–112) have been isolated and identified from A. mauritiana,

78 79 80

81 82

83 84 85

86 87

88 89

Figure 14. Cont.

Mar. Drugs 2017, 15, 351 10 of 29

90 91 92

Figure 14. Chemical structures of compounds 78–92. Figure 14. Chemical structures of compounds 78–92.

The same90 species of A. mauritiana 91grown in different places were found 92 to produce different The samepyrrole species derivatives, of A. such mauritiana as debromodispacamidesgrown in different B (93) and places D (94 were) from found Solomon to Island produce specimen different pyrrole derivatives,[46], 4-bromo- suchN-(butoxymethyl)-1H-pyrr asFigure debromodispacamides 14. Chemicalole-2-carboxamide structures of Bcompounds (93 (95)) andfrom 78–92 Dthe. ( 94South) from China Solomon Sea [41], Island5- debromomidpacamide (96) from Enewetak Atoll [47], mauritamide A (97) from Fiji [48] and mauritiamine specimen [46], 4-bromo-N-(butoxymethyl)-1H-pyrrole-2-carboxamide (95) from the South China (The98) from same Hachijo-jima species of A.Island mauritiana [49]. Compound grown in 98 different exhibited placesinhibitory were effect found on larval to produce metamorphosis different of Sea [41], 5-debromomidpacamide (96) from Enewetak Atoll [47], mauritamide A (97) from Fiji [48] pyrrolethe derivatives,barnacle Balanus such amphitrite as debromodispacamides with ED50 value of 15B ( 93μg/mL) and and D ( 94moderate) from Solomonantibacterial Island activity specimen against and mauritiamine[46], Flavobacterium4-bromo-N (98-(butoxymethyl)-1H-pyrr marinotypicum) from Hachijo-jima with the inhibitionole-2-carboxamide Island [zone49]. of Compound 10 ( 95mm) fromat 10 98μtheg/disk.exhibited South Interestingly, China inhibitory Sea the [41], Pacific effect 5- on larvaldebromomidpacamide metamorphosissponge A. mauritiana of the(96 )was barnaclefrom found Enewetak Balanusto metabolize Atoll amphitrite [47], other mauritamide withpyrroles, ED A 50 including(97value) from ofFijidebromokeramadine 15[48]µ andg/mL mauritiamine and moderate (99), antibacterial(98) frombenzosceptrin activityHachijo-jima againstA (100 Island), nagelamideFlavobacterium [49]. Compound S (101) marinotypicum 98and exhibited nagelamide inhibitory Twith (102 )effect the(Figure inhibitionon 15)larval [50,51]. metamorphosis zone of 10 of mm at 10 µg/disk.the barnacle Interestingly, Balanus amphitrite the Paciﬁc with ED sponge50 valueA. of mauritiana15 μg/mL andwas moderate found antibacterial to metabolize activity other against pyrroles, includingFlavobacterium debromokeramadine marinotypicum with (99), the benzosceptrin inhibition zone A of (100 10 ),mm nagelamide at 10 μg/disk. S (101 Interestingly,) and nagelamide the Pacific T (102) sponge A. mauritiana was found to metabolize other pyrroles, including debromokeramadine (99), (Figure 15)[50,51]. benzosceptrin A (100), nagelamide S (101) and nagelamide T (102) (Figure 15) [50,51].

93:R = H 95 94:R = OH

93:R = H 95 94:R = OH 96 97

96 97 98 99

98 99

100 101

102

Figure 15. Chemical structures of compounds 93–102.

102

Figure 15. Chemical structures of compounds 93–102. Figure 15. Chemical structures of compounds 93–102.

Mar. Drugs 2017, 15, 351 11 of 29 Mar. Drugs 2017, 15, 351 11 of 29 Mar. Drugs 2017, 15, 351 11 of 29 Agelasphins (103–110) from the Okinawan A. mauritiana were the ﬁrst example of AgelasphinsAgelasphins ((103103––110110) ) fromfrom thethe OkinawanOkinawan A. A.mauritiana mauritiana were were the thefirst firstexample example of of galactosylceramides containing an α-galactosyl linkage [52,53]. These compounds exhibited high galactosylceramidesgalactosylceramides containingcontaining an an α -galactosylα-galactosyl linkage linkage [52,53]. [52,53]. Th eseTh esecompounds compounds exhibited exhibited high high activity with the relative tumor proliferation rate (T/C) ranging from 160% to 190% and 200–400% activityactivity with the relativerelative tumor tumor proliferation proliferation rate rate (T/C) (T/C) ranging ranging from from 160% 160% to 190% to 190% and 200–400%and 200–400% relative 3H-TdR incorporation at

103: R = CH3 103: R = CH3 107: n = 21, R = 104: R = CH2CH3 107: n = 21, R = 110: n = 20, Y = 10 and/or Z = 11; 104: R = CH2CH3 108: n = 22, R = 110: n = 20, Y = 10 and/or Z = 11; 105: R = CH(CH3)2 108: n = 22, R = n = 21, Y = 9 and/or Z = 10 105: R = CH(CH3)2 109: n = 13, R = n = 21, Y = 9 and/or Z = 10 106: R = CH(CH3)C2H5 109: n = 13, R = 106: R = CH(CH3)C2H5

111 112 111 112 Figure 16. Chemical structures of compounds 103–112. Figure 16. Chemical structures of compounds 103–112. Figure 16. Chemical structures of compounds 103–112. 2.13. Agelas nakamurai 2.13. Agelas nakamurai 2.13. AgelasThirty-three nakamurai chemicals have been characterized from Agelas nakamurai, including 16 terpenoids Thirty-three chemicals have been characterized from Agelas nakamurai, including 16 terpenoids and Thirty-three17 pyrrole alkaloids. chemicals The have Okinawan been characterized A. nakamurai fromseems Agelas to occupy nakamurai the majority, including of terpenoid 16 terpenoids and 17 pyrrole alkaloids. The Okinawan A. nakamurai seems to occupy the majority of terpenoid andcompounds, 17 pyrrole including alkaloids. agelasidines The Okinawan B (113 )A. and nakamurai C (114) [55],seems nakamurols to occupy A–D the majority(115–118) of[56], terpenoid 2- compounds, including agelasidines B (113) and C (114)[55], nakamurols A–D (115–118)[56], compounds,oxoagelasiines including A (119) and agelasidines F (120), 10-hydro-9-hydroxyagelasine B (113) and C (114) [55], F nakamurols(121) [57], agelasines A–D (115 E (–122118) )and [56], 2- 2-oxoagelasiines A (119) and F (120), 10-hydro-9-hydroxyagelasine F (121)[57], agelasines E (122) oxoagelasiinesF (123) [58]. Compounds A (119) and 113 Fand (120 114), 10-hydro-9-hydroxyagelasinewere found to have inhibitory effects F (121 on) [57], the growth agelasines of S. Eaureus (122 ) and andat F3.3 (123 μg/mL)[58 ].and Compounds on contractile113 responsesand 114 were of smooth found muscles. to have inhibitoryCompounds effects 119 and on the120 growth showed of S. F (123) [58]. Compounds 113 and 114 were found to have inhibitory effects on the growth of S. aureus aureusmarkedlyat 3.3 reducedµg/mL andactivity on contractileagainst Mycobacterium responses of smegmatis smooth. muscles.The Indonesian Compounds A. nakamurai119 and was120 foundshowed at 3.3 μg/mL and on contractile responses of smooth muscles. Compounds 119 and 120 showed markedlyto yield reducedtwo novel activity diterpenes, against (−)-agelasineMycobacterium D (124 smegmatis) and (−)-ageloxime. The Indonesian D (125).A. Antibacterial nakamurai was assay found markedly reduced activity against Mycobacterium smegmatis. The Indonesian A. nakamurai was found torevealed yield two 124 novel could diterpenes, inhibit the growth (−)-agelasine of Staphylococcus D (124) and epidermidis (−)-ageloxime with a MIC D (value125). < Antibacterial 0.0877 μM [35]. assay to yield two novel diterpenes, (−)-agelasine D (124) and (−)-ageloxime D (125). Antibacterial assay revealedIsoagelasine124 could C (126 inhibit) and isoagelasidine the growth of BStaphylococcus (127) were isolated epidermidis from specimenwith a MIC of the value South < 0.0877 Chinaµ SeaM[ 35]. revealed 124 could inhibit the growth of Staphylococcus epidermidis with a MIC value < 0.0877 μM [35]. Isoagelasineand possessed C (126 weak) and cytotoxicities isoagelasidine against B (127 HL-60,) were K562 isolated and fromHCT-116 specimen cell lines of thewith South IC50 Chinavalues Sea Isoagelasineranging from C 18.4 (126 to) 39.2and μisoagelasidineM [59]. A new diterpeneB (127) were (128 isolated) (Figure from17) with specimen a 9-methyladenum of the South moiety China Sea and possessed weak cytotoxicities against HL-60, K562 and HCT-116 cell lines with IC50 values ranging andproduced possessed by the weak Papua cytotoxicities New Guinean against A. nakamurai HL-60, Hoshino K562 andwas shownHCT-116 to be cell inactive lines againstwith IC HIV-50 values from 18.4 to 39.2 µM[59]. A new diterpene (128) (Figure 17) with a 9-methyladenum moiety produced ranging1 integrase, from E. 18.4coli andto 39.2 Pseudomonas μM [59]. aeruginosaA new diterpene at 12.5 μ (g/mL128) (Figure[60]. 17) with a 9-methyladenum moiety by the Papua New Guinean A. nakamurai Hoshino was shown to be inactive against HIV-1 integrase, produced by the Papua New Guinean A. nakamurai Hoshino was shown to be inactive against HIV- E. coli Pseudomonas aeruginosa µ 1 integrase,and E. coli and Pseudomonasat 12.5 aeruginosag/mL at [ 6012.5]. μg/mL [60].

113 114

OH 113 114

OH 115 116 117

115 116 117

Figure 17. Cont.

Mar. Drugs 2017, 15, 351 12 of 29 Mar. Drugs 2017, 15, 351 12 of 29

N N

N N X H2N

O 118 119 120

121 122 123

124 125 126

127 128

FigureFigure 17. 17. ChemicalChemical structures structures of of compounds compounds 113113––128128. .

Five non-brominated pyrrole derivatives, nakamurines A–E (129–133), were purified from the Five non-brominated pyrrole derivatives, nakamurines A–E (129–133), were purified from the South China Sea A. nakamurai [59,61]. Bioassay results showed that compound 130 had weak South China Sea A. nakamurai [59,61]. Bioassay results showed that compound 130 had weak inhibition inhibition against Candida albicans with a MIC value of 60 μg/mL [61]. Bromopyrrole alkaloid was against Candida albicans with a MIC value of 60 µg/mL [61]. Bromopyrrole alkaloid was one of one of the most common secondary metabolites from marine sponges [62]. Two bromopyrrole the most common secondary metabolites from marine sponges [62]. Two bromopyrrole alkaloids alkaloids (134 and 135) were firstly isolated from the Papua New Guinean A. nakamurai in 1998 [60]. (134 and 135) were firstly isolated from the Papua New Guinean A. nakamurai in 1998 [60]. Ageladine Ageladine A (136) containing 2-aminoimidazolopyridine was shown to have inhibitory effects on A(136) containing 2-aminoimidazolopyridine was shown to have inhibitory effects on Matrix Matrix metalloproteinases-1, -2, -8, -9, -12 and -13 with IC50 values of 1.2, 2.0, 0.39, 0.79, 0.33, and 0.47 metalloproteinases-1, -2, -8, -9, -12 and -13 with IC values of 1.2, 2.0, 0.39, 0.79, 0.33, and 0.47 µg/mL, μg/mL, respectively [63]. Chemical investigation of50 the Indonesia A. nakamurai afforded longamide respectively [63]. Chemical investigation of the Indonesia A. nakamurai afforded longamide C (137)[35]. C (137) [35]. Nakamuric acid (138) and its methyl ester (139) were characterized from the Indopacific Nakamuric acid (138) and its methyl ester (139) were characterized from the Indopacific specimen specimen and shown to be active against B. subtilis [64]. The Okinawan A. nakamurai was found to and shown to be active against B. subtilis [64]. The Okinawan A. nakamurai was found to produce six produce six brominated pyrrole derivatives, slagenins A–C (140–142) and mukanadins A–C (143–145) brominated pyrrole derivatives, slagenins A–C (140–142) and mukanadins A–C (143–145) (Figure 18), (Figure 18), of which 141 and 142 showed inhibitory effect on murine leukemia L1210 cells in vitro of which 141 and 142 showed inhibitory effect on murine leukemia L1210 cells in vitro with IC50 values with IC50 values of 7.5 and 7.0 μg/mL, respectively [65,66]. of 7.5 and 7.0 µg/mL, respectively [65,66].

Mar. Drugs 2017, 15, 351 13 of 29 Mar. Drugs 2017, 15, 351 13 of 29

Mar. Drugs 2017, 15, 351 13 of 29

129 130 131 (+)-132

(−)-132 (+)-133 (−)-133 134

138: R = H 135 136 137 139: R = CH3 138: R = H 135 136 137 139: R = CH3

140: R = H 142 143 141: R = CH3

144 145

Figure 18. Chemical structures of compounds 129–145. 144Figure 18. Chemical structures of compounds 129145–145.

2.14. Agelas nemoechinata Figure 18. Chemical structures of compounds 129–145. 2.14. Agelas nemoechinata Nemoechines A–D (146–149) and nemoechioxide A (150) were obtained from the sponge Agelas 2.14. Agelas nemoechinata aff.Nemoechines nemoechinata A–D collected (146– 149from) and the nemoechioxide South China Sea. A (150 Compounds) were obtained 146–148 from had the enantiomeric sponge Agelas aff. nemoechinataconfigurationsNemoechinescollected and from146A–D had ( the146 an South–149 unusual) and China nemoechioxide cyclopentene-fused Sea. Compounds A (150 im)146 wereidazole–148 obtained hadring enantiomericsystem. from the Bioassay sponge conﬁgurations results Agelas andsuggested146aff. hadnemoechinata an that unusual only collected 149 cyclopentene-fused had cytotoxicityfrom the South against imidazole China HL-60 Sea. cell ring Compounds lines system. with Bioassayan 146 IC–50148 value resultshad of enantiomeric9.9 suggested μM [67]. that configurations and 146 had an unusual cyclopentene-fused imidazole ring system. Bioassay results onlyTwo149 newhad nemoechine cytotoxicity members, against nemoechines HL-60 cell F lines(151) and with G an(152 IC) possessing50 value ofN-methyladenine, 9.9 µM[67]. were Two new suggested that only 149 had cytotoxicity against HL-60 cell lines with an IC50 value of 9.9 μM [67]. nemoechinepurified from members, the South nemoechines China Sea-derived F (151 )A. and nemoechinata G (152) possessing. CompoundN 152-methyladenine, had weak toxicity were against puriﬁed Two new nemoechine members, nemoechines F (151) and G (152) possessing N-methyladenine, were fromJurkat the South cell line China with Sea-derivedan IC50 valueA. of nemoechinata17.1 μM [68].. Oxysceptrin Compound (152153)had (Figure weak 19) toxicity derivedagainst from the Jurkat Okinawanpurified from A. nemoechinata the South China was Sea-deriveda potent actomyosin A. nemoechinata ATPase. Compound activator [69]. 152 had weak toxicity against cell line with an IC value of 17.1 µM[68]. Oxysceptrin (153) (Figure 19) derived from the Okinawan Jurkat cell line 50with an IC50 value of 17.1 μM [68]. Oxysceptrin (153) (Figure 19) derived from the A. nemoechinataOkinawan A.was nemoechinata a potent actomyosinwas a potent ATPaseactomyosin activator ATPase [69 activator]. [69].

(+)-146 (+)-147 (+)-148 149 (−)-146 (−)-147 (−)-148 (+)-146 (+)-147 (+)-148 149 (−)-146 (−)-147 (−)-148

150 151 152 153 Figure 19. Chemical structures of compounds 146–153. 150 151 152 153

FigureFigure 19. 19.Chemical Chemicalstructures structures of compounds compounds 146146–153–153. .

Mar. Drugs 2017, 15, 351 14 of 29 Mar. Drugs 2017, 15, 351 14 of 29

2.15.2.15. Agelas Agelas oroides oroides Thirty-sixThirty-six secondary secondary metabolites metabolites (154 (154–189–189) (Figure) (Figure 20 )20) have have been been isolated isolated from from the marinethe marine sponge Agelassponge oroides Agelas, including oroides, pyrroleincluding derivatives, pyrrole derivatives, sterols and sterols fatty acids.and fatty Chemical acids. Chemical investigation investigation of A. oroides fromof A. the oroides Great from Barrier the Reef Great afforded Barrier threeReef afforded fistularin-3 thr derivatives,ee fistularin-3 agelorin derivatives, A (154 agelorin), agelorin A (154 B (),155 ) andagelorin 11-epi -fistularin-3B (155) and (11-156epi).-fistularin-3 These metabolites (156). These exhibited metabolites antimicrobial exhibited activities antimicrobial against activitiesB. subtilis andagainstM. luteus B. subtilisand 156 andhad M. moderateluteus and cytotoxicity156 had moderate against cytotoxicity breast cancer agai cellsnst breast [70]. cancer Later on,cells two [70]. new naturallyLater on, occurring two new pyrrolenaturally derivatives occurring (pyrrole157 and derivatives158) and 2,4,6,6-tetramethyl-3(6 (157 and 158) and 2,4,6,6-tetramethyl-H)-pyridone (159) 3(6H)-pyridone (159) were obtained from the same specimen [71,72]. Mediterranean A. oroides was were obtained from the same specimen [71,72]. Mediterranean A. oroides was shown to produce shown to produce four novel compounds, cyclooroidin (160), taurodispacamide A (161), four novel compounds, cyclooroidin (160), taurodispacamide A (161), monobromoagelaspongin (162) monobromoagelaspongin (162) and (−)-equinobetaine B (163), of which 161 displayed strong and (−)-equinobetaine B (163), of which 161 displayed strong antihistaminic activity [73,74]. Five antihistaminic activity [73,74]. Five bromopyrrole alkaloids (164–168) and fifteen sterols (169–183) bromopyrrole alkaloids (164–168) and fifteen sterols (169–183) were detected in the sponge A. oroides were detected in the sponge A. oroides collected in the Bay of Naples [75,76]. Interestingly, one collectedimidazole in thecompound Bay of Naples (184), [taurine75,76]. Interestingly,(185) and some one fatty imidazole acids (186 compound–189) were (184 also), taurine found (185in the) and someNorthern fatty acids Aegean (186 Sea-derived–189) were specimen also found [77]. in the Northern Aegean Sea-derived specimen [77].

154 155

156 157 158 159

164: R = OCH3 160 161 162 163 165: R = NH2 166: R = OH

167 168

183 184

186: n = 11 187: n = 12 185 188: n = 13 189: n = 14

Figure 20. Chemical structures of compounds 154–189. Figure 20. Chemical structures of compounds 154–189.

Mar. Drugs 2017, 15, 351 15 of 29 Mar. Drugs 2017, 15, 351 15 of 29 Mar. Drugs 2017, 15, 351 15 of 29 2.16.2.16. Agelas Agelas sceptrum sceptrum 2.16. Agelas sceptrum OneOne novel novel C C2929 sterolsterol containing containing the the typical typical nucleus nucleus of of ergoster ergosterol,ol, 26-nor-25-isopropyl-ergosta- 26-nor-25-isopropyl-ergosta- 5,7,225,7,22OneEE-trien-3-trien-3 novelβ -ol-olC29 ( (190sterol190),), was was containing purified puriﬁed thefrom from typical the the Jamaican Jamaican nucleus A.A. of sceptrum sceptrumergoster [78].[ol,78 ].26-nor-25-isopropyl-ergosta- Sceptrin Sceptrin ( (191191)) was was obtained obtained from5,7,22from A.EA.-trien-3 sceptrum sceptrumβ-ol collected collected(190), was at Glover at purified Glover Reef fromReef and the found and Jamaican found to have toA. a havesceptrumbroad a spectrum broad [78]. Sceptrin spectrum of antimicrobial (191 of) antimicrobialwas activitiesobtained againstfromactivities A. sceptrumS. against aureus collectedS., B. aureus subtilis, atB. Glover subtilis, C. albicans Reef, C. albicans and, Pseudomonas found, Pseudomonas to have aeruginosa a aeruginosabroad ,spectrum Alternaria, Alternaria of antimicrobialsp.sp. and and CladosporiumCladosporium activities cucumerinumagainstcucumerinum S. aureus [79].[79]. ,Chemical ChemicalB. subtilis study study, C. ofalbicans of the the sponge sponge, Pseudomonas from from Bahamas Bahamas aeruginosa afforded afforded, Alternaria two two hybrid hybrid sp. pyrrole-imidazoleand pyrrole-imidazole Cladosporium 0 alkaloids:cucumerinumalkaloids: 15 15′-oxoadenosceptrin [79].-oxoadenosceptrin Chemical study (192 ( 192of) theand) and sponge decarboxyagelamadin decarboxyagelamadin from Bahamas afforded C C(193 (193) (Figuretwo) (Figure hybrid 21) 21 [80]. pyrrole-imidazole)[80 ]. alkaloids: 15′-oxoadenosceptrin (192) and decarboxyagelamadin C (193) (Figure 21) [80].

190 191 190 191

192 193 192 193 FigureFigure 21. 21. ChemicalChemical structures structures of of compounds compounds 190190––193193.. Figure 21. Chemical structures of compounds 190–193.

2.17.2.17. Agelas Agelas schmidtii schmidtii 2.17. Agelas schmidtii Three monohydroxyl sterols (194194–196196) were isolated from the Caribbean AgelasAgelas schmidtii schmidtii [81]. ThreeThree monohydroxyl monohydroxyl sterols sterols ( (194––196)) were were isolated isolated from from the the Caribbean Caribbean Agelas schmidtii [81].[81]. Additionally, four carotenoids namedα α-carotene197 (197), isorenieratene198 (198), trikentriorhodin199 (199) Additionally, fourfour carotenoidscarotenoids named named -caroteneα-carotene ( (197), isorenieratene), isorenieratene ( (198), trikentriorhodin), trikentriorhodin ( ()199 and) and zeaxanthin200 (200) (Figure 22) were also derived from this sponge collected from West Indies [82]. andzeaxanthin zeaxanthin ( )(200 (Figure) (Figure 22) were22) were also also derived derived from from this spongethis sponge collected collected from from West West Indies Indies [82]. [82].

194 196 197 194 7 195: Δ 196 197 195: Δ7

198 199 198 199

200 200 Figure 22 Chemical structures of compounds 194–200. Figure 22 22. ChemicalChemical structures structures of of compounds compounds 194194––200200..

Mar. Drugs 2017, 15, 351 16 of 29 Mar. Drugs 2017, 15, 351 16 of 29 Mar. Drugs 2017, 15, 351 16 of 29 2.18. Agelas sventres 2.18. Agelas sventres Only one new bromopyrrole alkaloid, sventrin ( 201) (Figure 23),23), has been puriﬁedpurified from the Mar. Drugs 2017, 15, 351 16 of 29 CaribbeanOnly one sponge new Agelas bromopyrrole sventres. Biological alkaloid, sventrinassay assay showed (201) (Figurethat this 23), chemical has been has purified feedingfeeding deterrentdeterrentfrom the Caribbean sponge Agelas sventres. Biological assay showed that this chemical has feeding deterrent activity2.18. againstAgelas sventres omnivorous reef ﬁshfish [[83].83]. activity against omnivorous reef fish [83]. Only one new bromopyrrole alkaloid, sventrin (201) (Figure 23), has been purified from the Caribbean sponge Agelas sventres. Biological assay showed that this chemical has feeding deterrent activity against omnivorous reef fish [83].

201 201 Figure 23. Chemical structure of compounds 201. Figure 23. Chemical structure of compounds 201. 201 2.19. Agelas wiedenmayeri 2.19. Agelas wiedenmayeri Figure 23. Chemical structure of compounds 201. Chemical investigation of Agelas wiedenmayeri from Florida Keys afforded one new pyrrole Chemical investigation of Agelas wiedenmayeri from Florida Keys afforded one new pyrrole derivative,2.19.Chemical Agelas 4-bromopyrrole-2-carboxyhomoarginine wiedenmayeriinvestigation of Agelas wiedenmayeri (from202) (Figure Florida 24), Keys which afforded might onebe alternatively new pyrrole a derivative, 4-bromopyrrole-2-carboxyhomoarginine (202) (Figure 24), which might be alternatively derivative,biosynthetic 4-bromopyrrole-2-carboxyhomoarginine precursor of hymenidin/oroidin-related ( alkaloids202) (Figure [84]. 24), which might be alternatively a biosynthetica biosyntheticChemical precursor precursor investigation of of hymenidi hymenidin/oroidin-related of Agelasn/oroidin-related wiedenmayeri fromalkaloids alkaloids Florida [84]. [Keys84 ]. afforded one new pyrrole derivative, 4-bromopyrrole-2-carboxyhomoarginine (202) (Figure 24), which might be alternatively a biosynthetic precursor of hymenidin/oroidin-related alkaloids [84].

202 202 Figure 24. Chemical structure202 of compounds 202. Figure 24. ChemicalChemical structure of compounds 202. 2.20. Other Agelas spp. Figure 24. Chemical structure of compounds 202. 2.20. Other Agelas spp.spp. 2.20.Eighty-nine Other Agelas secondary spp. metabolites (203–291) were isolated and chemically identified from Eighty-nine secondary metabolites (203–291) were isolated and chemically identified from unclassifiedEighty-nineEighty-nine Agelas secondary speciessecondary and metabolites metabolites assorted into (203 two––291291 classes,)) were were ionicisolated isolated and and non-ionic and chemically chemically compounds identified identiﬁed as from below. from unclassified Agelas species and assorted into two classes, ionic and non-ionic compounds as below. unclassiﬁedunclassifiedAgelas Agelasspecies species and and assorted assortedinto into twotwo classes, ionic ionic and and non-ionic non-ionic compounds compounds as below. as below. 2.20.1. Ionic Compounds 2.20.1.2.20.1. Ionic Ionic Compounds Compounds As described above, ionic compounds are the major secondary metabolites of Agelas sponge, whichAs can describeddescribedAs be described grouped above,above, above, in ionicbromine-containing ionic ionic compounds compounds compounds are are theand the major no majormajorn-bromine-containing secondary secondary secondary metabolites metabolites metabolites comp of ofAgelasounds. Agelasof Agelassponge, Itsponge, is eminentsponge, which whichcanthat bewhichall can grouped ionic canbe groupedbe brominated ingrouped bromine-containing in inbromine-containing bromine-containing metabolites and were non-bromine-containing and produced nonon-bromine-containingn-bromine-containing by the compounds.Okinawan comp compounds. Agelasounds. It is It eminent isspp. Iteminent is eminentbesides that all thationicdibromoagelaspongin that brominatedall allionic ionic brominated metabolitesbrominated hydrochloride weremetabolites metabolites produced (203 werewere) by[85]. the produced Agelamadins Okinawan byby Agelasthe theA Okinawan (spp.204Okinawan) besidesand AgelasB dibromoagelasponginAgelas(205 spp.), possessingspp. besides besides an dibromoagelaspongin hydrochloride (203) [85]. Agelamadins A (204) and B (205), possessing an dibromoagelasponginhydrochlorideagelastatin-like ( 203tetracyclic)[85 hydrochloride]. Agelamadins moiety and(203 A ()204an [85]. )oroi and Agelamadinsdin-like B (205), possessinglinear A (204moiety,) anand agelastatin-like wereB (205 shown), possessing tetracyclicto have an agelastatin-like tetracyclic moiety and an oroidin-like linear moiety, were shown to have agelastatin-likemoiety and an oroidin-like tetracyclic linearmoiety moiety, and werean shownoroidin-like to have linear antimicrobial moiety, activitywere againstshown B.to subtilis have, antimicrobialantimicrobial activity activity against against B. B. subtilis subtilis,, M. M. luteus andand C. C. neoformans neoformans [86]. [86]. The The same same specimen specimen was alsowas also antimicrobialM.found luteus to metabolizeand activityC. neoformans agelamadins against[86 B.]. subtilis The C–F same (,206 M.– luteus specimen209) and and tauroacidin wasC. neoformans also found E ( 210[86]. to) metabolize(FigureThe same 25), specimen agelamadinsof which was 209 also C–Fwas foundfound to metabolize to metabolize agelamadins agelamadins C–F C–F ( 206(206––209209) and tauroacidin tauroacidin E E(210 (210) (Figure) (Figure 25), 25), of which of which 209 was 209 was (the206 first–the209 first )occurrence and occurrence tauroacidin bromopyrrole bromopyrrole E (210) (Figure alkaloid alkaloid 25), offor which contcontainingaining209 was aminoimidazole aminoimidazole the first occurrence and and pyridinium bromopyrrole pyridinium moieties moieties alkaloid the first occurrence bromopyrrole alkaloid for containing aminoimidazole and pyridinium moieties forsimultaneously containingsimultaneously aminoimidazole [87,88]. [87,88]. and pyridinium moieties simultaneously [87,88]. simultaneously [87,88]. BrBr Br NHNH Br Br NH OO Br H HN O N H HN N H NH2 HN N N NH2 NH3 O HN H NH O HN N NH2 3 O H HOOC N NH3 O HN O HOOC 2CFH3COO O 2CF COO HOOC 3 204: R=OCH3 2CF3COO 203 206 207 204:205: R=OCH R=OH3 203 204: R=OCH3 206 207 203 205: R=OH 206 207 205: R=OH Figure 25. Cont.

Mar. Drugs 2017, 15, 351 17 of 29

208 209 210

Figure 25. Chemical structures of compounds 203–210. Figure 25. Chemical structures of compounds 203–210.

Twenty-one208 nagelamides (211–231) (Figure209 26) have been characterized from210 the Okinawan Twenty-one nagelamides (211–231) (Figure 26) have been characterized from the Okinawan Agelas spp. Nagelamides A–HFigure (211 25.– 218Chemical) and structuresO (219) were of compounds shown to 203 possess–210. antimicrobial activities Agelasagainstspp. M. Nagelamides luteus, B. subtilis A–H and (211 E. coli–218. Compounds) and O (219 211) were, 217 and shown 218 were to possess shown to antimicrobial inhibit the growth activities againstof proteinM.Twenty-one luteus phosphatase, B. subtilis nagelamides andtypeE. 2A coli(211 .with– Compounds231 )IC (Figure50 values 21126) of,have217 48, and been13 218 andcharacterized were46 μ shownM, respectivelyfrom to inhibitthe Okinawan [89,90]. the growth of proteinNagelamidesAgelas phosphatase spp. NagelamidesK (220 type) and 2AL A–H (221 with )( 211had IC–50 218inhibitoryvalues) and O of effect(219 48,) 13 wereon and M. shown 46luteusµM, towithrespectively possess a MIC antimicrobial value [89 ,of90 16.7]. Nagelamidesactivities μg/mL K(220[91].against) and Bioactivity L M. (221 luteus) test had, B. uncovered inhibitorysubtilis and that effectE. coli nagelamides. onCompoundsM. luteus M 211(with222, )217 and a MICand N 218(223 value were) exhibited of shown 16.7 µinhibition tog/mL inhibit [91 the against]. growth Bioactivity A. test uncoverednigerof proteinwith the that phosphatase same nagelamides MIC valuetype M 2A (of222 33.3with) and μ g/mLIC N50 ( 223values [92].) exhibited Nagelamidesof 48, inhibition13 and Q 46(224 againstμ)M, and respectively A.R ( niger225), withof [89,90].which the same compound 225 possessed an oxazoline ring for the first time, showed antimicrobial activity against MIC valueNagelamides of 33.3 µKg/mL (220) and [92 ].L Nagelamides(221) had inhibitory Q (224 effect) and on R M. (225 luteus), of with which a MIC compound value of 16.7225 μpossessedg/mL B. [91].subtilis Bioactivity, Trichophyton test uncovered mentagrophytes that nagelamides, C. neoformans M, C.(222 albicans) and Nand (223 A.) nigerexhibited [93]. Nagelamidesinhibition against U (226 A.) an oxazoline ring for the first time, showed antimicrobial activity against B. subtilis, Trichophyton andniger V ( 227with) were the samethe first MIC occurence value of for 33.3 a bromopyrroleμg/mL [92]. Nagelamides alkaloid containing Q (224 )a andγ-lactam R (225 ring), of with which an mentagrophytesN-ethanesulfoniccompound, C.225 neoformans possessedacid and guanidino,anC. oxazoline albicans moieties, ringand forA. while the niger first nagelamide[93 time,]. Nagelamides showed W (228 antimicrobial) was U (the226 first) activity and monomeric V against (227) were the firstbromopyrroleB. occurencesubtilis, Trichophyton alkaloid for a bromopyrrole with mentagrophytes two aminoimidazole alkaloid, C. neoformans containing moieties, C. albicans in a theγ-lactam and molecule. A. niger ring Compounds [93]. with Nagelamides an N -ethanesulfonic226 and U (228226 ) acidcould andand guanidinoinhibitV (227) against were moieties, the C. firstalbicans occurence while with the nagelamide for same a bromopyrrole IC50 value W (228 of alkaloid )4 wasμg/mL thecontaining [94]. first Nagelamides monomeric a γ-lactam X ring (229 bromopyrrole with) and an Y alkaloid(230N-ethanesulfonic) withwere two unique aminoimidazole acid andfor guanidinotheir moieties novel moieties, intricyclic the while molecule. nagelamideskeleton Compounds Wconsisting (228) was226 theandof first228spiro-bonded monomericcould inhibit againsttetrahydrobenzaminoimidazolebromopyrroleC. albicans with alkaloid the with same two ICand aminoimidazole50 valueaminoimidazo of 4 µg/mL moietieslidine [moieties.94 in]. the Nagelamides molecule. In addition, Compounds X nagelamide (229) and 226 Y andZ ( 230(231 228)) were uniquewascould for the their inhibitfirst example novel against tricyclic forC. albicansdimeric skeleton with bromopyrrole the consisting same IC alkaloid50 ofvalue spiro-bonded ofinvolving 4 μg/mL the [94]. tetrahydrobenzaminoimidazole C-8 Nagelamides position in Xdimerization (229) and Y and aminoimidazolidineand(230 displayed) were strongunique antimicrobial moieties. for their In activity addition, novel against nagelamidetricyclic C. albicans skeleton Z with (231 an) wasconsisting IC50the value first ofof example0.25 spiro-bonded μg/mL for [95]. dimeric tetrahydrobenzaminoimidazole and aminoimidazolidine moieties. In addition, nagelamide Z (231) bromopyrrole alkaloid involving the C-8 position in dimerization and displayed strong antimicrobial was the first example for dimeric bromopyrroleBr alkaloid involving the C-8 position in dimerization activity against C. albicans with an IC50 valueNH of 0.25 µg/mL [95]. and displayed strong antimicrobial activity againstO C. albicansH with an IC50 value of 0.25 μg/mL [95]. Br N HN NH2 H OBr N H Br N NH N NH 2X H O H Br HN N Br HN NH2 NH 2 H O N Br N H 215: R1 = R2 =H N 9(10),9′(10′) NH 2X 211: R = H 213H: Δ HN Br 216: R1 = Br, R2 = H 212: R = OH 214: 9,9',10,10'-tetrahydroNH2 217: R1 = R2 = Br 215: R1 = R2 =H 211: R = H 213: Δ9(10),9′(10′) 216: R1 = Br, R2 = H 212: R = OH 214: 9,9',10,10'-tetrahydro 217: R1 = R2 = Br

218 219 220

221 222 223

Figure 26. Cont.

Mar. Drugs 2017, 15, 351 18 of 29 Mar. Drugs 2017, 15, 351 18 of 29 Mar. Drugs 2017, 15, 351 18 of 29

226: β-H 224 225 227:226: α-H β -H 224 225 227: α-H

229: R = OH 228 231 230: R = H 229: R = OH 228 Figure 26. Chemical structures of compounds 211–231. 231 Figure 26. Chemical230 structures: R = H of compounds 211–231. Eight new bromopyrroleFigure alkaloids, 26. Chemical 2-bromokeramadine structures of compounds (232), 2-bromo-9,10-dihydrokeramadine 211–231. Eight(233), tauroacidins new bromopyrrole C (234) and alkaloids, D (235), mukanadin 2-bromokeramadine G (236), 2-debromonagelamides (232), 2-bromo-9,10-dihydrokeramadine U (237) and G (238), (233),2-debromonagelamide tauroacidinsEight new bromopyrrole C (234 P )(239 and), alkaloids, keramadine D (235), 2-bromokeramadine mukanadin (240) and agelasine G (236 G (),232 (241 2-debromonagelamides),) 2-bromo-9,10-dihydrokeramadine(Figure 27) were detected U in ( 237the ) and (233), tauroacidins C (234) and D (235), mukanadin G (236), 2-debromonagelamides U (237) and G (238), G(238Okinawan), 2-debromonagelamide Agelas spp. [96–99] Antimicrobial P (239), keramadine tests suggested (240 )that and compound agelasine 236 G exhibited (241) (Figure inhibitory 27) were 2-debromonagelamide P (239), keramadine (240) and50 agelasine G (241) (Figure 27) were detected in the detectedeffects in on the C. Okinawanalbicans andAgelas C. neoformansspp. [96 with–99] IC Antimicrobial values of 16 tests and suggested8 μg/mL, respectively that compound [96]. 236 OkinawanCompounds Agelas 237 spp.and 239[96–99] could Antimicrobial inhibit the growth tests suggestedof T. mentagrophytes that compound with IC 23650 values exhibited of 16 inhibitoryand 32 exhibited inhibitory effects on C. albicans and C. neoformans with IC50 values of 16 and 8 µg/mL, effectsμg/mL, on respectively. C. albicans Cytotoxicityand C. neoformans assay revealed with thatIC50 241values showed of 16toxicity and against8 μg/mL, murine respectively lymphoma [96]. respectively [96]. Compounds 237 and 239 could inhibit the growth of T. mentagrophytes with IC50 CompoundsL1210 cells in237 vitro and with 239 an could IC50 inhibitvalue of the 3.1 growthμg/mL [97,99].of T. mentagrophytes with IC50 values of 16 and 32 µ valuesμg/mL, of 16 respectively. and 32 g/mL, Cytotoxicity respectively. assay revealed Cytotoxicity that assay241 showed revealed toxicity that against241 showed murine toxicity lymphoma against murine lymphoma L1210 cells in vitro with an IC value of 3.1 µg/mL [97,99]. L1210 cells in vitro with an IC50 value of 3.1 μg/mL50 [97,99].

232 233 234

235 236 237

Br X H N NH2 235 236 N 237 N NH H O Br X H N NH2 238 239 240N N NH H O

238 239 240

Figure 27. Cont.

Mar. Drugs 2017, 15, 351 19 of 29 Mar. Drugs 2017, 15, 351 19 of 29

Mar. Drugs 2017, 15, 351 19 of 29

241

Figure 27. Chemical structures of compounds 232–241. Figure 27. Chemical structures241 of compounds 232–241.

Nineteen non-bromine-containingFigure 27. Chemical ionic structurescompounds of compounds have been 232 isolated–241. from unclassified Agelas spp.,Nineteen including non-bromine-containing eleven agalasines (242–252 ionic) from compounds Okinawa [100,101], have been two isolatedagelasines from (253 unclassiﬁedand 254) Agelasfromspp., YapNineteen includingIsland non-bromine-containing [102], eleven four agalasineshigher unsaturated (242 ionic–252 compou 9-) fromN-methyladeniniumnds Okinawa have been [100 isolated,101 bicyclic], two from diterpenoids agelasines unclassified ( (253255 Agelas–and258254) ) fromfromspp., Yap Papua including Island New [102 elev Guinea],en four agalasines [103] higher and unsaturated two(242 –quarternary252) from 9-N Okinawa-methyladeninium 9-methyladenine [100,101], salts two bicyclic of agelasines diterpenes diterpenoids ( 253agelines and (255 254(259–)258 ) fromandfrom Papua 260 Yap) from Island New Argulpelu Guinea[102], four [Reef103 higher] [104]. and unsaturated twoCompounds quarternary 9-N 242-methyladeninium–245 9-methyladenine displayed strong bicyclic salts inhibitory diterpenoids of diterpenes effects (255 on agelines–258 Na,) (259K-ATPasefromand Papua260 )and from New antimicrobial Argulpelu Guinea [103] Reef activities and [ 104two]. quarternary[100]. Compounds Agelasine 9-methyladenine242 M–245 (255displayed) exhibited salts of strong diterpenespotent inhibitory activity agelines against effects (259 on and 260) from Argulpelu Reef [104]. Compounds 242–245 displayed strong inhibitory effects on Na, Na,Trypanosoma K-ATPase andbrucei antimicrobial [103], while agelines activities A [(100259].) and Agelasine B (260) M(Figure (255) 28) exhibited showed potent mild ichthyotoxins activity against K-ATPase and antimicrobial activities [100]. Agelasine M (255) exhibited potent activity against Trypanosomaand antimicrobial brucei [103 activities], while [104]. agelines A (259) and B (260) (Figure 28) showed mild ichthyotoxins and Trypanosoma brucei [103], while agelines A (259) and B (260) (Figure 28) showed mild ichthyotoxins antimicrobial activities [104]. and antimicrobial activities [104].

242 243 244

245 246 247

245 N N 246 247 N N N N NH2 N N

O NH2 H X N O O H X Br N O 248 249 250 Br 248 249 250

251 252 253 254 251 252 253 254

Figure 28. Cont.

Mar. Drugs 2017, 15, 351 20 of 29 Mar. Drugs 2017, 15, 351 20 of 29

Mar. Drugs 2017, 15, 351 20 of 29

255 256 257 258

259 260

FigureFigure 28. 28.Chemical Chemical structures of of compounds compounds 242242–260–260. .

2.20.2. Non-Ionic Compounds259 260 2.20.2. Non-Ionic Compounds Since 1983, 29 non-ionicFigure brominated 28. Chemical metabolites structures (261 of– compounds289) have been 242–260 found. in some unclassified AgelasSince spp. 1983, collected 29 non-ionic from the brominated Okinawan metabolites Sea, the South (261 China–289) Sea, have the been Caribbean found inSea, some Papua unclassified New AgelasGuinea2.20.2.spp. and Non-Ionic collected the Indian Compounds from Ocean. the Agesamides Okinawan A Sea, (261 the) and South B (262 China) [105], Sea, benzosceptrin the Caribbean C (263 Sea,) [106], Papua Newnagelamide GuineaSince J and (1983,264) the [107],29 non-ionic Indian nagelamide Ocean. brominated P (265 Agesamides ),metabolites mukanadin A(261 E ((261–266289)),) andmukanadinhave Bbeen (262 found F)[ (267105 in) ], [92],some benzosceptrin nagelamide unclassified C (263I )[(268Agelas106) and], spp. nagelamide 2,2’-didebromonagelamide collected from J (264 the)[ Okinawan107], B nagelamide (269 Sea,) [108] the South were P (265 Chinaobtained),mukanadin Sea, from the Caribbeanthe EOkinawan (266 Sea,), mukanadin Papuaspecimen. New F (267Compound)[Guinea92], nagelamide and 264 thehad Indian a cyclopentane I (268 Ocean.) and Agesamides 2,2’-didebromonagelamidering fused Ato (an261 amin) ando Bimidazole (262) B[105], (269 ring benzosceptrin)[ and108 ]exhibited were C obtained inhibitory(263) [106], from theeffect Okinawannagelamide on S. specimen.aureus J (264 )and [107], C. Compound nagelamide neoformans P264 with(265had), MICmukanadin a cyclopentanevalues E of(266 8.35), mukanadin ring and fused 16.7 Fμ to (g/mL,267 an) [92], amino respectively. nagelamide imidazole ringCompounds andI (268 exhibited) and 268 2,2’-didebromonagelamide and inhibitory 269 were effect inactive on S.against B aureus(269 )murine [108]and wereC. lymphoma neoformans obtained L1210 fromwith andthe MIC Okinawanhuman values epidermoid specimen. of 8.35 and 16.7carcinomaµg/mL,Compound respectively.KB cells264 hadin vitro. a Compoundscyclopentane Chemical study ring268 fusedand of an269 tounidentified anwere amin inactiveo imidazole Agelas against spp. ring from murineand the exhibited South lymphoma China inhibitory Sea L1210 andafforded humaneffect tenon epidermoid newS. aureus non-ionic carcinomaand bromopyrro C. neoformans KB cellsle derivatives, within vitroMIC. longamides Chemicalvalues of 8.35 study D–F and(270 of – an16.7272 unidentified ),μ 3-oxethyl-4-[1-(4,5-g/mL, respectively.Agelas spp. dibromopyrrole-2-yl)-formamido]-butanoic acid methyl ester (273), 2-oxethyl-3-[1-(4,5- from theCompounds South China 268 and Sea 269 afforded were inactive ten new against non-ionic murine bromopyrrole lymphoma L1210 derivatives, and human longamides epidermoid D–F dibromopyrrole-2-yl)-formacarcinoma KB cells in vitro.mido]-methyl Chemical study propionate of an unidentified (274), 9-oxethyl-mukanadin Agelas spp. from the SouthF (275 China) [109], Sea (270–272), 3-oxethyl-4-[1-(4,5-dibromopyrrole-2-yl)-formamido]-butanoic acid methyl ester (273), hexazosceptrinafforded ten (new276), non-ionic agelestes bromopyrro A (277) andle B derivatives, (278) and (9 longamidesS, 10R, 9’S, 10’D–FR)-nakamuric (270–272), 3-oxethyl-4-[1-(4,5- acid (279) [110]. 2-oxethyl-3-[1-(4,5-dibromopyrrole-2-yl)-formamido]-methyl propionate (274), 9-oxethyl-mukanadin Inspiringly,dibromopyrrole-2-yl)-formamido]-b bioassay results revealed thatutanoic (+)- 270acid, (− )-271methyl and (+)-ester272 had(273 significant), 2-oxethyl-3-[1-(4,5- antimicrobial F(275activity)[dibromopyrrole-2-yl)-forma109 ],against hexazosceptrin C. albicans (276mido]-methyl ),with agelestes MIC Apropionatevalues (277) andof (274 B80, (278), 9-oxethyl-mukanadin20) and and (9 S,140 10R ,μ 9’M,S, 10’Frespectively. R(275)-nakamuric) [109], acidMonobromoisophakellin (hexazosceptrin279)[110]. Inspiringly, (276), agelestes (280) bioassaywas A (277isolated) and results Bfrom (278 revealed)the and Caribbean (9S, 10 thatR, 9’ Agelas (+)-S, 10’270R sp.)-nakamuric,( −and)-271 shown andacid to ( (+)-279 possess)272 [110].had significantantifeedantInspiringly, antimicrobial activity bioassay against results activity Thalassoma revealed against bifasciatum thatC. (+)- albicans270 [111]., (−)-271with Chemical and MIC (+)- investigation272 values had significant of 80,of Agelas 20 antimicrobial and sponges 140 µ M, respectively.fromactivity Wewak Monobromoisophakellinagainst and Indonesian C. albicans sea respectively with (280 MIC) was led values to isolated the isolationof from 80, theof20 two Caribbeanand phakellin 140 Agelas alkaloidsμM, sp.respectively. (281 and,282 shown) toand possessMonobromoisophakellin 5-bromophakelline antifeedant activity (283 ()280 [112,113]. against) was isolated InThalassoma addition, from the2,3-dibromopyrrole bifasciatum Caribbean[ 111Agelas]. (sp. Chemical284 )and and shown 2,3-dibromo-5- investigation to possess of Agelasmethoxymethylpyrroleantifeedantsponges from activity Wewak against(285) and belonging Thalassoma Indonesian to bifasciatumnon-ionic sea respectively bromopyrrole[111]. Chemical led alkaloid to investigation the isolation were purified of ofAgelas two from sponges phakellin the alkaloidsmarinefrom (sponge 281Wewak,282 Agelas )and and Indonesian sp. 5-bromophakelline [114]. Apart sea respectively from alkaloids, (283 led)[ to112 fourthe,113 isolation new]. Inbrominated addition,of two phakellin phospholipid 2,3-dibromopyrrole alkaloids fatty (281 acids,282 (284 ) ) and(286 2,3-dibromo-5-methoxymethylpyrroleand–289 5-bromophakelline) (Figure 29) were also(283 )detected [112,113]. in (theIn285 addition, Caribbean) belonging 2,3-dibromopyrrole Agelas to non-ionic spp. [115]. bromopyrrole (284) and 2,3-dibromo-5- alkaloid were methoxymethylpyrrole (285) belonging to non-ionic bromopyrrole alkaloid were purified from the purified from the marine sponge Agelas sp. [114]. Apart from alkaloids, four new brominated marine sponge Agelas sp. [114]. Apart from alkaloids, four new brominated phospholipid fatty acids phospholipid fatty acids (286–289) (Figure 29) were also detected in the Caribbean Agelas spp. [115]. (286–289) (Figure 29) were also detected in the Caribbean Agelas spp. [115].

261 262 263 264

Figure 29. Cont.

Mar. Drugs 2017, 15, 351 21 of 29 Mar. Drugs 2017, 15, 351 21 of 29 Mar. Drugs 2017, 15, 351 21 of 29 Br O N H NH Br 2 Br N O N N H H H NH Br O 2 Br N N NNH H H H Br O N NH2 N NNH H H O N NH N N 2 H 265 266 267 O 265 266 267

268 269 (+)-270 (−)-270 268 269 (+)-270 (−)-270

(+)-271 (−)-271 (+)-272 (−)-272 (±)-273

277: R = H (±)-274 275 276 278: R = CH3 277: R = H (±)-274 275 276 278: R = CH3

281: R = Br 279 280 283 282: R = H 281: R = Br 279 280 283 282: R = H

286: n = 13 288: n = 12 284 285 287: n = 14 289: n = 13 286: n = 13 288: n = 12 284 Figure 29. Chemical285 structures of compounds 261–289. Figure 29. Chemical structures of compounds287: n = 14 261–289. 289: n = 13 Only two non-ionic metabolitesFigure 29. Chemical without structures bromine, of agelasidine compounds A261 (290–289) .and agelagalastatin (291) (FigureOnly two 30), non-ionichave been metabolitesdetected in two without unclassified bromine, specimens agelasidine of Agelas A (sp.290 Compound) and agelagalastatin 290 was the (291) Only two non-ionic metabolites without bromine, agelasidine A (290) and agelagalastatin (291) (Figurefirst 30marine), have natural been substance detected inpossessing two unclassified sulfone and specimens guanidine of unitsAgelas purifiedsp. Compound from the Okinawan290 was the (Figure 30), have been detected in two unclassified specimens of Agelas sp. Compound 290 was the firstsample marine and natural showed substance antispasmodic possessing activity sulfone [116]. and It guanidinewas notable units thatpurified compound from 24the from Okinawan the first marine natural substance possessing sulfone and guanidine units purified from the Okinawan sampleCaribbean and showed A. clathrodes antispasmodic is the optimal activity isomer [116 of]. It290 was. Compound notable that 291 compoundwas a new 24GSLfrom derived the Caribbean from sample and showed antispasmodic activity [116]. It was notable that compound 24 from the Agelas sp. collected in Papua New Guinea and found to exhibit significant in vitro activity against A. clathrodesCaribbeanis A. the clathrodes optimal is isomerthe optimal of 290 isomer. Compound of 290. Compound291 was a291 new was GSL a new derived GSL derived from Agelas from sp. human cancer cell lines with lung NCI-H460 GI50 0.77 μg/mL to ovary OVCAR-3 GI50 2.8 μg/mL [117]. collectedAgelas in sp. Papua collected New in Guinea Papua andNew found Guinea to and exhibit found significant to exhibitin significant vitro activity in vitro against activity human against cancer cell lineshuman with cancer lung cell NCI-H460 lines with GIlung50 NCI-H4600.77 µg/mL GI50 to 0.77 ovary μg/mL OVCAR-3 to ovary GIOVCAR-350 2.8 µg/mL GI50 2.8 [ 117μg/mL]. [117].

290 291: n = 21 or 20, m = 10 or 11

Figure290 30. Chemical structures of compounds291: n = 21290 or and 20, 291 m. = 10 or 11

Figure 30. Chemical structures of compounds 290 and 291. Figure 30. Chemical structures of compounds 290 and 291.

Mar. Drugs 2017, 15, 351 22 of 29

Table 1. Agelas-derived secondary metabolites.

Organism Locality Secondary Metabolite References Agelas axifera the Republic of Palau axistatins 1 (1), 2 (2), 3 (3) [4] A. cerebrum Caribbean 5-bromopyrrole-2-carboxylic acid (4), 4-bromopyrrole-2-carboxylic acid (5), 3,4-bromopyrrole-2-carboxylic acid (6)[6] A. ceylonica the Mandapam coast hanishin (7) [7] A. citrina Caribbean (−)-agelasidine E (8), (−)-agelasidine F (9), agelasine N (10), citrinamines A–D (11–14), N-methylagelongine (15)[9,10] Grand Bahamas Island clarhamnoside (16) [11] A. clathrodes clathrosides A–C (17–19), isoclathrosides A–C (20–22), glycosphingolipid (23), (−)-agelasidine A (24), (−)-agelasidine C (25), Caribbean [12–17,19,20] (−)-agelasidine D (26), clathramides A (27) and B (28), clathrodin (29), dispacamides A–D (31–34) South China Sea 3,3-bis(uracil-l-yl)-propan-1-aminium (30) [18] Florida Keys bromosceptrin (35) [21] Belize debromosceptrin (36) [22] A. conifera Caribbean bromopyrroles (37–43), glycosphingolipid (45) [23,24,26] Puerto Rico coniferoside (44) [25] the Coral Sea agelastatin A (46) [27] A. dendromorpha the New Caledonia agelastatins E (47) and F (48) [28] dispyrin (49), dibromoagelaspongin methyl ether (50), longamide B (51), clathramides C (52) and D (53), Caribbean [29,30,32] aminozooanemonin (55), pyridinebetaines A (56) and B (57) A. dispar San Salvador Island triglycosylceramide (54) [31] agelasine (58) [33] A. gracilis South Japan gracilioethers A–C (59–61) [34] A. linnaei Indonesia brominated pyrrole derivatives (62–72) [35] A. longissima Caribbean agelongine (73), 3,7-dimethylisoguanine (74), longamide (75), glycosphingolipids (76 and 77)[36–39] (−)-80-oxo-agelasine B (78), (+)-agelasine B (79), (+)-8’-oxo-agelasine C (80), agelasine V (81), (+)-8’-oxo-agelasine E (82), South China Sea 8’-oxo-agelasine D (83), ageloxime B (84), (+)-2-oxo-agelasidine C (85), 4-bromo-N-(butoxymethyl)-1H-pyrrole- [40,41] 2-carboxamide (95) Enewetak agelasimine A (86), agelasimine B (87), purino-diterpene (88), 5-debromomidpacamide (96)[42,43,47] Pohnpei epi-agelasine C (89) [44] A. mauritiana Solomon Islands agelasines J (90), K (91) and L (92), debromodispacamides B (93) and D (94)[45,46] Fiji mauritamide A (97) [48] Hachijo-jima Island mauritiamine (98) [49] the Paciﬁc sea ebromokeramadine (99), benzosceptrin A (100), nagelamides S (101) and T (102)[50,51] Okinawa agelasphins (103–110) [52,53] Kagoshima isotedanin (111), isoclathriaxanthin (112) [54] Mar. Drugs 2017, 15, 351 23 of 29

Table 1. Cont.

Organism Locality Secondary Metabolite References agelasidines B (113) and C (114), nakamurols A–D (115–118), 2-oxoagelasiines A (119) and F (120), Okinawa [55–58,65,66] 10-hydro-9-hydroxyagelasine F (121), agelasines E (122) and F (123), slagenins A–C (140–142), mukanadins A–C (143–145) Indonesia (−)-agelasine D (124), (−)-ageloxime D (125) [35] South China Sea isoagelasine C (126), isoagelasidine B (127) [59] A. nakamurai Papua New Guinea diterpene (128), bromopyrrole alkaloids (134 and 135) [60] South China Sea nakamurines A–E (129–133) [59,61] Japan ageladine A (136) [63] Indonesia longamide C (137) [35] Indopacific nakamuric acid (138) and its methyl ester (139) [64] South China Sea nemoechines A–D (146–149), nemoechioxide A (150), nemoechines F (151) and G (152)[67,68] A. nemoechinata Okinawa oxysceptrin (153) [69] agelorin A (154), agelorin B (155), 11-epi-fistularin-3 (156), pyrrole-2-carboxamide (157), N-formyl-pymole-2-carboxamid (158), the Great Barrier Reef [70–72] 2,4,6,6-tetramethyl-3(6H)-pyridone (159) A. oroides Mediterranea Sea cyclooroidin (160) and taurodispacamide A (161), monobromoagelaspongin (162), (−)-equinobetaine B (163)[73,74] Naples bromopyrroles (164–168), sterols (169–183) [75,76] the Northern Aegean Sea 3-amino-1-(2-aminoimidazoyl)-prop-1-ene (184), taurine (185), fatty acid mixtures (186–189)[77] Jamaica 26-nor-25-isopropyl-ergosta-5,7,22 E-trien-3β-ol (190) [78] A. sceptrum Belize sceptrin (191) [79] Bahamas 150-oxoadenosceptrin (192), decarboxyagelamadin C (193) [80] Caribbean monohydroxyl sterols (194–196) [81] A. schmidtii West Indies α-carotene (197), isorenieratene (198), trikentriorhodin (199) and zeaxanthin (200)[82] A. sventres Caribbean sventrin (201) [83] A. wiedenmayeri Florida Keys 4-bromopyrrole-2-carboxyhomoarginine (202) [84] No record dibromoagelaspongin hydrochloride (203) [85] agelamadins A (204) and B (205), agelamadins C–F (206–209), tauroacidin E (210), nagelamides A–H (211–218), nagelamides K–O (219–223), nagelamides Q (224) and R (225), nagelamides U–Z (226–231), 2-bromokeramadine (232), 2-bromo-9,10-dihydrokeramadine (233), tauroacidins C (234) and D (235), mukanadin G (236), 2-debromonagelamides U (237) Okinawa [86–101,105–108,116] and G (238), 2-debromonagelamide P (239), keramadine (240), agelasine G (241), agelasines A–D (242–245), agelasines O–U (246–252), agesamides A (261) and B (262), benzosceptrin C (263), nagelamides J (264) and P (265), mukanadins E (266) and F (267), nagelamide I (268), 2,2’-didebromonagelamide B (269), agelasidine A (290) Unclassified Yap Island agelasines H (253) and I (254) [102] Agelas sp. agelasine M (255), 2-oxo-agelasine B (256), gelasines A (257) and B (258), (−)-7-N-methyldibromophakellin (281), Papua New Guinea [103,112,117] (−)-7-N-methylmonobromophakellin (282), agelagalastatin (291) Palau Island agelines A (259) and B (260) [104] longamides D–F (270–272), 3-oxethyl-4-[1-(4,5-dibromopyrrole-2-yl)-formamido]-butanoic acid methyl ester (273), South China Sea 2-oxethyl-3-[1-(4,5-dibromopyrrole-2-yl)-formamido]-methyl propionate (274), 9-oxethyl-mukanadin F (275), [109,110] hexazosceptrin (276), agelestes A (277) and B (278) and (9S,10R,9’S,10’R)-nakamuric acid (279) Caribbean Sea monobromoisophakellin (280), brominated phospholipid fatty acids (286–289)[111,115] Indonesia 5-bromophakelline (283) [113] No record 2,3-dibromopyrrole (284) and 2,3-dibromo-5-methoxymethylpyrrole (285)[114] Mar. Drugs 2017, 15, 351 24 of 29

3. Conclusions Many efforts have been devoted to implement chemical investigation of Agelas sponges during the past 47 years, from 1971 to 2017. Meanwhile, great achievements have been made on chemical diversity of their secondary metabolites. Agelas sponges are widely distributed in the ocean, especially in the Okinawa Sea, the Caribbean Sea and the South China Sea. Deep ocean technologies for specimen collecting should be used to search more unknown species of Agelas sponges, such as manned and remotely operated underwater vehicles. Advanced separation methodologies should be deployed to explore more bioactive secondary metabolites of these sponges, such as UPLC-MS, metabolomics approach [74]. Furthermore, special attention should be paid to symbiotic microorganisms of Agelas sponges owing to the fact that a great number of therapeutic agents of marine sponges are biosynthesized by their symbiotic microbes [118]. By a combination of gene engineering, pathway reconstructing, enzyme engineering and metabolic networks, these microbes can be modiﬁed to produce more novel chemicals containing enhanced structural features or a large quantity of known valuable compounds for pharmaceutical production.

Acknowledgments: Financial support from the National Natural Science Foundation of China (Nos. 41776139 and 81773628), the Zhejiang Provincial Natural Science Foundation of China (LY16H300007 and LY16H300008) and the US National Cancer Institute grants (R01 CA 047135) are gratefully acknowledged. Author Contributions: H.Z. conceived and wrote the paper; M.D. and J.C. searched and collected all references; and H.W., K.T. and P.C. made suggestive revision and provided eight photos of Agelas sponges. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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