Bioactive Secondary Metabolites from the Marine Sponge Genus Agelas.

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.

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 (Figure 1): 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.

Figure 1

Photos of Agelas sponges provided by professor Crews.

2. Natural Products from Agelas Genus

The chemical diversity of natural products is determined by the biological diversity of organisms. To date, 291 secondary metabolites (1–291) have been isolated and characterized from the marine sponge Agelas spp. (Table 1). These chemicals were introduced and assorted as follows according to their biological sources.

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]
A. clathrodes	Grand Bahamas Island	clarhamnoside (16)	[11]
	Caribbean	clathrosides A–C (17–19), isoclathrosides A–C (20–22), glycosphingolipid (23), (−)-agelasidine A (24), (−)-agelasidine C (25), (−)-agelasidine D (26), clathramides A (27) and B (28), clathrodin (29), dispacamides A–D (31–34)	[12,13,14,15,16,17,19,20]
	South China Sea	3,3-bis(uracil-l-yl)-propan-1-aminium (30)	[18]
A. conifera	Florida Keys	bromosceptrin (35)	[21]
	Belize	debromosceptrin (36)	[22]
	Caribbean	bromopyrroles (37–43), glycosphingolipid (45)	[23,24,26]
	Puerto Rico	coniferoside (44)	[25]
A. dendromorpha	the Coral Sea	agelastatin A (46)	[27]
	the New Caledonia	agelastatins E (47) and F (48)	[28]
A. dispar	Caribbean	dispyrin (49), dibromoagelaspongin methyl ether (50), longamide B (51), clathramides C (52) and D (53), aminozooanemonin (55), pyridinebetaines A (56) and B (57)	[29,30,32]
	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)	[36,37,38,39]
A. mauritiana	South China Sea	(−)-80-oxo-agelasine B (78), (+)-agelasine B (79), (+)-8’-oxo-agelasine C (80), agelasine V (81), (+)-8’-oxo-agelasine E (82), 8’-oxo-agelasine D (83), ageloxime B (84), (+)-2-oxo-agelasidine C (85), 4-bromo-N-(butoxymethyl)-1H-pyrrole-2-carboxamide (95)	[40,41]
	Enewetak	agelasimine A (86), agelasimine B (87), purino-diterpene (88), 5-debromomidpacamide (96)	[42,43,47]
	Pohnpei	epi-agelasine C (89)	[44]
	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]
A. nakamurai	Okinawa	agelasidines B (113) and C (114), nakamurols A–D (115–118), 2-oxoagelasiines A (119) and F (120), 10-hydro-9-hydroxyagelasine F (121), agelasines E (122) and F (123), slagenins A–C (140–142), mukanadins A–C (143–145)	[55,56,57,58,65,66]
	Indonesia	(−)-agelasine D (124), (−)-ageloxime D (125)	[35]
	South China Sea	isoagelasine C (126), isoagelasidine B (127)	[59]
	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]
A. nemoechinata	South China Sea	nemoechines A–D (146–149), nemoechioxide A (150), nemoechines F (151) and G (152)	[67,68]
	Okinawa	oxysceptrin (153)	[69]
A. oroides	the Great Barrier Reef	agelorin A (154), agelorin B (155), 11-epi-fistularin-3 (156), pyrrole-2-carboxamide (157), N-formyl-pymole-2-carboxamid (158), 2,4,6,6-tetramethyl-3(6H)-pyridone (159)	[70,71,72]
	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]
A. sceptrum	Jamaica	26-nor-25-isopropyl-ergosta-5,7,22 E-trien-3β-ol (190)	[78]
	Belize	sceptrin (191)	[79]
	Bahamas	15′-oxoadenosceptrin (192), decarboxyagelamadin C (193)	[80]
A. schmidtii	Caribbean	monohydroxyl sterols (194–196)	[81]
	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]
Unclassified Agelas sp.	No record	dibromoagelaspongin hydrochloride (203)	[85]
	Okinawa	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) 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)	[86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,105,106,107,108,116]
	Yap Island	agelasines H (253) and I (254)	[102]
	Papua New Guinea	agelasine M (255), 2-oxo-agelasine B (256), gelasines A (257) and B (258), (−)-7-N-methyldibromophakellin (281), (−)-7-N-methylmonobromophakellin (282), agelagalastatin (291)	[103,112,117]
	Palau Island	agelines A (259) and B (260)	[104]
	South China Sea	longamides D–F (270–272), 3-oxethyl-4-[1-(4,5-dibromopyrrole-2-yl)-formamido]-butanoic acid methyl ester (273), 2-oxethyl-3-[1-(4,5-dibromopyrrole-2-yl)-formamido]-methyl propionate (274), 9-oxethyl-mukanadin F (275), hexazosceptrin (276), agelestes A (277) and B (278) and (9S,10R,9’S,10’R)-nakamuric acid (279)	[109,110]
	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]

2.1. Agelas axifera

Three new alkaloids, named axistatins 1 (1), 2 (2), and 3 (3) (Figure 2), were isolated and characterized from Agelas axifera collected in the Republic of Palau and found to exhibit inhibitory effects on cancer cell lines, including P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2 and DU-145. The exquisitely sensitive Gram-negative pathogen Neisseria gonorrheae and the opportunistic fungus Cryptococcus neoformans were inhibited by 1–3 with MIC values of 1–8, 2–4, and 8 μg/mL, and 1–4, 2, and 8–16 μg/mL, respectively. Furthermore, these compounds had antimicrobial effect on Gram-positive bacteria, including Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis and Micrococcus luteus [4].

Figure 2

Chemical structures of compounds 1–3.

2.2. Agelas cerebrum

Marine sponge Agelas cerebrum was classified as a new species in 2001 [5]. Chemical investigation of Caribbean specimen A. cerebrum led to the isolation of three brominated compounds, 5-bromopyrrole-2-carboxylic acid (4), 4-bromopyrrole-2-carboxylic acid (5) and 3,4-bromopyrrole-2-carboxylic acid (6) (Figure 3) [6]. Biological tests indicated that these isolates had strong cytotoxic activities in vitro against human tumor cell lines at ≥1 mg/mL, including A549, HT29 and MDA-MB-231.

Figure 3

Chemical structures of compounds 4–6.

2.3. Agelas ceylonica

Only one case of chemical study on Agelas ceylonica has been reported [7]. The specimen of A. ceylonica collected from India Mandapam coast was found to produce one methyl ester hanishin (7) (Figure 4), which has been previously found in the marine sponge Homaxinella sp. [8].

Figure 4

Chemical structures of compounds 7.

2.4. Agelas citrina

The Caribbean specimen of Agelas citrina was firstly found to yield three new diterpene alkaloids, (−)-agelasidine E (8), (−)-agelasidine F (9) and agelasine N (10) [9]. Latter chemical investigation 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.

Figure 5

Chemical structures of compounds 8–15.

2.5. Agelas clathrodes

Marine sponge Agelas clathrodes was the excellent producer of secondary metabolites, including glycosphingolipid derivatives (GSLs) and alkaloids. Clarhamnoside (16), containing an unusual 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. 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 the Caribbean specimen (Figure 6) [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.

Figure 6

Chemical structures of compounds 16–23.

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. aureus, Klebsiella pneumoniae and Proteus vulgaris [14]. In vitro cytotoxic test indicated that 25 and 26 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 cytotoxicity against cancer cell lines A549 and SGC7901 with IC50 values of 26.5 and 22.7 μg/mL, respectively [18]. Four brominated compounds, dispacamides 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].

Figure 7

Chemical structures of compounds 24–34.

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]. Bioassay results indicated that compounds 37, 41, 42 and 43 possessed biological activities 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].

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 F (48) (Figure 9) purified from the New Caledonian A. dendromorpha were shown to exhibit weak cytotoxicity against the KB cell line at 30 μM [28].

Figure 9

Chemical structures of compounds 46–48.

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].

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 11) [34]. Antimalarial tests showed that these metabolites possessed inhibitory effects on Plasmodium falciparum with IC50 values of 0.5–10 μg/mL.

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].

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 pyrrolopiperazine nucleus [37]. Two new GSL analogs (76 and 77) were also found in the Caribbean A. longissima [38,39].

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, 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 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 [42,43,44]. 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 exhibited moderate activities against P. falciparum and low cytotoxicity on MCF-7 cells [45].

Figure 14

Chemical structures of compounds 78–92.

The same species of A. mauritiana grown in different places were found to produce different pyrrole derivatives, such as debromodispacamides B (93) and D (94) from Solomon Island specimen [46], 4-bromo-N-(butoxymethyl)-1H-pyrrole-2-carboxamide (95) from the South China Sea [41], 5-debromomidpacamide (96) from Enewetak Atoll [47], mauritamide A (97) from Fiji [48] and mauritiamine (98) from Hachijo-jima Island [49]. Compound 98 exhibited inhibitory effect on larval metamorphosis of the barnacle Balanus amphitrite with ED50 value of 15 μg/mL and moderate antibacterial activity against Flavobacterium marinotypicum with the inhibition zone of 10 mm at 10 µg/disk. Interestingly, the Pacific sponge A. mauritiana was found to metabolize other pyrroles, including debromokeramadine (99), benzosceptrin A (100), nagelamide S (101) and nagelamide T (102) (Figure 15) [50,51].

Figure 15

Chemical structures of compounds 93–102.

Agelasphins (103–110) from the Okinawan A. mauritiana were the first example of galactosylceramides containing an α-galactosyl linkage [52,53]. These compounds exhibited high activity with the relative tumor proliferation rate (T/C) ranging from 160% to 190% and 200–400% relative 3H-TdR incorporation at B16 melanoma cells at 20 µg/mL. Two natural carotenoids, isotedanin (111) and isoclathriaxanthin (112) (Figure 16), were also detected in the specimen of A. mauritiana from Kagoshima [54].

Figure 16

Chemical structures of compounds 103–112.

2.13. Agelas nakamurai

Thirty-three chemicals have been characterized from Agelas nakamurai, including 16 terpenoids and 17 pyrrole alkaloids. The Okinawan A. nakamurai seems to occupy the majority of terpenoid compounds, including agelasidines B (113) and C (114) [55], nakamurols A–D (115–118) [56], 2-oxoagelasiines A (119) and F (120), 10-hydro-9-hydroxyagelasine F (121) [57], agelasines E (122) and F (123) [58]. Compounds 113 and 114 were found to have inhibitory effects on the growth of S. aureus at 3.3 µg/mL and on contractile responses of smooth muscles. Compounds 119 and 120 showed markedly reduced activity against Mycobacterium smegmatis. The Indonesian A. nakamurai was found to yield two novel diterpenes, (−)-agelasine D (124) and (−)-ageloxime D (125). Antibacterial assay revealed 124 could inhibit the growth of Staphylococcus epidermidis with a MIC value < 0.0877 µM [35]. Isoagelasine C (126) and isoagelasidine B (127) were isolated from specimen of the South China Sea and possessed weak cytotoxicities against HL-60, K562 and HCT-116 cell lines with IC50 values ranging from 18.4 to 39.2 µM [59]. A new diterpene (128) (Figure 17) with a 9-methyladenum moiety produced by the Papua New Guinean A. nakamurai Hoshino was shown to be inactive against HIV-1 integrase, E. coli and Pseudomonas aeruginosa at 12.5 µg/mL [60].

Figure 17

Chemical structures of compounds 113–128.

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 inhibition against Candida albicans with a MIC value of 60 µg/mL [61]. Bromopyrrole alkaloid was one of the most common secondary metabolites from marine sponges [62]. Two bromopyrrole alkaloids (134 and 135) were firstly isolated from the Papua New Guinean A. nakamurai in 1998 [60]. Ageladine A (136) containing 2-aminoimidazolopyridine was shown to have inhibitory effects on 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 µg/mL, respectively [63]. Chemical investigation of the Indonesia A. nakamurai afforded longamide C (137) [35]. Nakamuric acid (138) and its methyl ester (139) were characterized from the Indopacific specimen and shown to be active against B. subtilis [64]. The Okinawan A. nakamurai was found to produce six brominated pyrrole derivatives, slagenins A–C (140–142) and mukanadins A–C (143–145) (Figure 18), of which 141 and 142 showed inhibitory effect on murine leukemia L1210 cells in vitro with IC50 values of 7.5 and 7.0 µg/mL, respectively [65,66].

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 aff. nemoechinata collected from the South China Sea. Compounds 146–148 had enantiomeric configurations and 146 had an unusual cyclopentene-fused imidazole ring system. Bioassay results suggested that only 149 had cytotoxicity against HL-60 cell lines with an IC50 value of 9.9 µM [67]. Two new nemoechine members, nemoechines F (151) and G (152) possessing N-methyladenine, were purified from the South China Sea-derived A. nemoechinata. Compound 152 had weak toxicity against Jurkat cell line with an IC50 value of 17.1 µM [68]. Oxysceptrin (153) (Figure 19) derived from the Okinawan A. nemoechinata was a potent actomyosin ATPase activator [69].

Figure 19

Chemical structures of compounds 146–153.

2.15. Agelas oroides

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

Figure 20

Chemical structures of compounds 154–189.

2.16. Agelas sceptrum

One novel C29 sterol containing the typical nucleus of ergosterol, 26-nor-25-isopropyl-ergosta-5,7,22E-trien-3β-ol (190), was purified from the Jamaican A. sceptrum [78]. Sceptrin (191) was obtained from A. sceptrum collected at Glover Reef and found to have a broad spectrum of antimicrobial activities against S. aureus, B. subtilis, C. albicans, Pseudomonas aeruginosa, Alternaria sp. and Cladosporium cucumerinum [79]. Chemical study of the sponge from Bahamas afforded two hybrid pyrrole-imidazole alkaloids: 15′-oxoadenosceptrin (192) and decarboxyagelamadin C (193) (Figure 21) [80].

Figure 21

Chemical structures of compounds 190–193.

2.17. Agelas schmidtii

Three monohydroxyl sterols (194–196) were isolated from the Caribbean Agelas schmidtii [81]. Additionally, four carotenoids named α-carotene (197), isorenieratene (198), trikentriorhodin (199) and zeaxanthin (200) (Figure 22) were also derived from this sponge collected from West Indies [82].

Figure 22

Chemical structures of compounds 194–200.

2.18. Agelas sventres

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].

Figure 23

Chemical structure of compounds 201.

2.19. Agelas wiedenmayeri

Chemical investigation of Agelas wiedenmayeri from Florida Keys 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].

Figure 24

Chemical structure of compounds 202.

2.20. Other Agelas spp.

Eighty-nine secondary metabolites (203–291) were isolated and chemically identified from unclassified Agelas species and assorted into two classes, ionic and non-ionic compounds as below.

2.20.1. Ionic Compounds

As described above, ionic compounds are the major secondary metabolites of Agelas sponge, which can be grouped in bromine-containing and non-bromine-containing compounds. It is eminent that all ionic brominated metabolites were produced by the Okinawan Agelas spp. besides dibromoagelaspongin hydrochloride (203) [85]. Agelamadins A (204) and B (205), possessing an agelastatin-like tetracyclic moiety and an oroidin-like linear moiety, were shown to have antimicrobial activity against B. subtilis, M. luteus and C. neoformans [86]. The same specimen was also found to metabolize agelamadins C–F (206–209) and tauroacidin E (210) (Figure 25), of which 209 was the first occurrence bromopyrrole alkaloid for containing aminoimidazole and pyridinium moieties simultaneously [87,88].

Figure 25

Chemical structures of compounds 203–210.

Twenty-one nagelamides (211–231) (Figure 26) have been characterized from the Okinawan Agelas spp. Nagelamides A–H (211–218) and O (219) were shown to possess antimicrobial activities against M. luteus, B. subtilis and E. coli. Compounds 211, 217 and 218 were shown to inhibit the growth of protein phosphatase type 2A with IC50 values of 48, 13 and 46 µM, respectively [89,90]. Nagelamides K (220) and L (221) had inhibitory effect on M. luteus with a MIC value of 16.7 µg/mL [91]. Bioactivity test uncovered that nagelamides M (222) and N (223) exhibited inhibition against A. niger with the same MIC value of 33.3 µg/mL [92]. Nagelamides Q (224) and R (225), of which compound 225 possessed an oxazoline ring for the first time, showed antimicrobial activity against B. subtilis, Trichophyton mentagrophytes, C. neoformans, C. albicans and A. niger [93]. Nagelamides U (226) and V (227) were the first occurence for a bromopyrrole alkaloid containing a γ-lactam ring with an N-ethanesulfonic acid and guanidino moieties, while nagelamide W (228) was the first monomeric bromopyrrole alkaloid with two aminoimidazole moieties in the molecule. Compounds 226 and 228 could inhibit against C. albicans with the same IC50 value of 4 µg/mL [94]. Nagelamides X (229) and Y (230) were unique for their novel tricyclic skeleton consisting of spiro-bonded tetrahydrobenzaminoimidazole and aminoimidazolidine moieties. In addition, nagelamide Z (231) was the first example for dimeric bromopyrrole alkaloid involving the C-8 position in dimerization and displayed strong antimicrobial activity against C. albicans with an IC50 value of 0.25 µg/mL [95].

Figure 26

Chemical structures of compounds 211–231.

Eight new bromopyrrole alkaloids, 2-bromokeramadine (232), 2-bromo-9,10-dihydrokeramadine (233), tauroacidins C (234) and D (235), mukanadin G (236), 2-debromonagelamides U (237) and G (238), 2-debromonagelamide P (239), keramadine (240) and agelasine G (241) (Figure 27) were detected in the Okinawan Agelas spp. [96,97,98,99] Antimicrobial tests suggested that compound 236 exhibited inhibitory effects on C. albicans and C. neoformans with IC50 values of 16 and 8 µg/mL, respectively [96]. Compounds 237 and 239 could inhibit the growth of T. mentagrophytes with IC50 values of 16 and 32 µg/mL, respectively. Cytotoxicity assay revealed that 241 showed toxicity against murine lymphoma L1210 cells in vitro with an IC50 value of 3.1 µg/mL [97,99].

Figure 27

Chemical structures of compounds 232–241.

Nineteen non-bromine-containing ionic compounds have been isolated from unclassified Agelas spp., including eleven agalasines (242–252) from Okinawa [100,101], two agelasines (253 and 254) from Yap Island [102], four higher unsaturated 9-N-methyladeninium bicyclic diterpenoids (255–258) from Papua New Guinea [103] and two quarternary 9-methyladenine salts of diterpenes agelines (259 and 260) from Argulpelu Reef [104]. Compounds 242–245 displayed strong inhibitory effects on Na, K-ATPase and antimicrobial activities [100]. Agelasine M (255) exhibited potent activity against Trypanosoma brucei [103], while agelines A (259) and B (260) (Figure 28) showed mild ichthyotoxins and antimicrobial activities [104].

Figure 28

Chemical structures of compounds 242–260.

2.20.2. Non-Ionic Compounds

Since 1983, 29 non-ionic brominated metabolites (261–289) have been found in some unclassified Agelas spp. collected from the Okinawan Sea, the South China Sea, the Caribbean Sea, Papua New Guinea and the Indian Ocean. Agesamides A (261) and B (262) [105], benzosceptrin C (263) [106], nagelamide J (264) [107], nagelamide P (265), mukanadin E (266), mukanadin F (267) [92], nagelamide I (268) and 2,2’-didebromonagelamide B (269) [108] were obtained from the Okinawan specimen. Compound 264 had a cyclopentane ring fused to an amino imidazole ring and exhibited inhibitory effect on S. aureus and C. neoformans with MIC values of 8.35 and 16.7 µg/mL, respectively. Compounds 268 and 269 were inactive against murine lymphoma L1210 and human epidermoid carcinoma KB cells in vitro. Chemical study of an unidentified Agelas spp. from the South China Sea afforded ten new non-ionic bromopyrrole derivatives, longamides D–F (270–272), 3-oxethyl-4-[1-(4,5-dibromopyrrole-2-yl)-formamido]-butanoic acid methyl ester (273), 2-oxethyl-3-[1-(4,5-dibromopyrrole-2-yl)-formamido]-methyl propionate (274), 9-oxethyl-mukanadin F (275) [109], hexazosceptrin (276), agelestes A (277) and B (278) and (9S, 10R, 9’S, 10’R)-nakamuric acid (279) [110]. Inspiringly, bioassay results revealed that (+)-270, (−)-271 and (+)-272 had significant antimicrobial activity against C. albicans with MIC values of 80, 20 and 140 µM, respectively. Monobromoisophakellin (280) was isolated from the Caribbean Agelas sp. and shown to possess antifeedant activity against Thalassoma bifasciatum [111]. Chemical investigation of Agelas sponges from Wewak and Indonesian sea respectively led to the isolation of two phakellin alkaloids (281,282) and 5-bromophakelline (283) [112,113]. In addition, 2,3-dibromopyrrole (284) and 2,3-dibromo-5-methoxymethylpyrrole (285) belonging to non-ionic bromopyrrole alkaloid were purified from the marine sponge Agelas sp. [114]. Apart from alkaloids, four new brominated phospholipid fatty acids (286–289) (Figure 29) were also detected in the Caribbean Agelas spp. [115].

Figure 29

Chemical structures of compounds 261–289.

Only two non-ionic metabolites without bromine, agelasidine A (290) and agelagalastatin (291) (Figure 30), have been detected in two unclassified specimens of Agelas sp. Compound 290 was the first marine natural substance possessing sulfone and guanidine units purified from the Okinawan sample and showed antispasmodic activity [116]. It was notable that compound 24 from the Caribbean A. clathrodes is the optimal isomer of 290. Compound 291 was a new GSL derived from Agelas sp. collected in Papua New Guinea and found to exhibit significant in vitro activity against human cancer cell lines with lung NCI-H460 GI50 0.77 µg/mL to ovary OVCAR-3 GI50 2.8 µg/mL [117].

Figure 30

Chemical structures of compounds 290 and 291.

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.