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.


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.

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.

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.

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].

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].

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].

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].

Agelas clathrodes
Marine sponge Agelas clathrodes was the excellent producer of secondary metabolites, including glycosphingolipid derivatives (GSLs) and alkaloids. Clarhamnoside (16), containing an unusual Lrhamnose 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)(18)(19) and isoclathrosides A-C (20)(21)(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.

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)(18)(19) and isoclathrosides A-C (20)(21)(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.

Agelas clathrodes
Marine sponge Agelas clathrodes was the excellent producer of secondary metabolites, including glycosphingolipid derivatives (GSLs) and alkaloids. Clarhamnoside (16), containing an unusual Lrhamnose 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)(18)(19) and isoclathrosides A-C (20)(21)(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.  (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].  (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].

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].

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,

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].

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].

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].

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].

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].

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.

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.