Chemical constituents and biological activities of the genus Subergorgia.

The genus Subergorgia (coelenterata, Gorgonacea, Subergorgiidae) is distributed in the Indo-pacific region. Previous investigations on the various species of the genus have revealed the presence of a number of new compounds including alkaloids, sesquiterpenes, diterpenes, and steroids. Certain biological activities particularly cytotoxic activity have been observed for the isolated constituents and compositions derived from the coral. This review covers the secondary metabolites reported from the genus Subergorgia and their biological properties.

INTRODUCTION

The family Subergorgiidae comprises calcareous sclerites corals; members of the genus Subergorgia possess fan- or brush-like branches. Subergorgia suberosa [Figure 1] is one of the most widely distributed species particularly found in the Indo-pacific tropical regions from the Red Sea to the Central Pacific. It is mostly found attached to reef slopes at depths of 15–20 m, and in terms of size it is usually 50 cm high and wide. A wide range of new secondary metabolites have been isolated from the genus Subergorgia comprising alkaloids, sesquiterpenes, diterpenes, and steroids.[1-10]

Figure 1

Subergorgia suberosa

Taxonomy

Kingdom: Animalia

Phylum: Cnidaria

Class: Anthozoa

Order: Alcyonacea

Family: Subergorgiidae

Genus: Subergorgia

Morphology

S. suberosa possess white tentacles, reddish brown polyps and small spindle-like sclerites. The other species of the genus Subergorgia possess free branches and densely branched fans. The sclerites vary in colour from yellowish red to dark red and even colour less in certain species.[3]

CHEMICAL CONSTITUENTS AND BIOLOGICAL ACTIVITIES

The chemicals constituents isolated from the various species of the genus Subergorgia are detailed below and the new compounds reported are listed in Table 1.

Table 1

New chemical constituents from the genus Subergorgia

Subergorgia hicksoni

Chromatographic separations of S. hicksoni led to the isolation of two new [Figure 2a] sesquiterpenes 8-methoxy-methoxycalamenene (1) and 5-hydroxy-8-methoxycalamenene (2).[5]

Figure 2a

Constituents (1-21)

Subergorgia mollis

Wu et al. reported a new steroid [Figure 2a], 11α, 15α-diacetoxy-17α-pregna-4, 20-dien-3-one (3), along with a known steroid 17α-pregna-4, 20-dien-3-one, from the formosan gorgonian S. mollis.[11]

Subergorgia reticulata

Guo reported five known polyhydroxylated steroids anyaols A-E [Figure 2a], among which some exhibited cytotoxic activity.[12] Investigations of the dichloromethane/ethanol extract of the South China Sea gorgonian coral S. reticulata resulted in the identification of two new compounds reticulatic acid (4) and reticulatin (5) and a known compound 3, 22, 25-trihydroxy-16-24, 20-24-bisepoxy-3β, 16β, 20S, 22R, 24S-cholest-5-ene.[10]

Yang et al. isolated nine known compounds batyl alcohol, cholesterol, cholesta-7, 22-diene-3β, 5α, 6β-triol, ergostra-7, 22-diene-3β, 5α, 6β-triol, 5, 8-epidioxycampesta-6, 22-dien-3-ol, guanine, theine, thymine, and uracil from the South China Sea gorgonian coral S. reticulata.[13]

Isolations of the ethyl acetate extract of the Chinese gorgonian coral S. reticulata afforded a new briarane-type diterpenoid reticulolide (6), together with the known compounds (-)-11α, 20α-epoxy-4-deacetyljunceellolide D, junceellin, junceellolide A, praelolide, umbraculolide A, and umbraculolide C. Among these compounds, praelolide and junceellin exhibited anti-settlement activity against the larva of Bugula neritina at a concentration of 50 μg/mL.[14]

Limna Mol et al. isolated three new sesquiterpenes (+)-(7R, 10S)-2,5-dimethoxy calamenene (7), (+)-(7R, 10S)-2-methoxy-5-acetoxy calamenene (8), and (+)-(7R, 10S)-2-methoxy calamenene (9) from the methanol extract of the Indian gorgonian S. reticulata. The isolated compounds (7-9) showed potent inhibitory effects against cyprids of Balanus amphitrite with EC50 values of 4.4, 7.8, and 0.03 μg/mL, respectively. The compounds also showed appreciable activity against Artemia nauplii with an EC50 value 50 μg/mL.[6]

Bioguided isolations of S. reticulata resulted in the identification of three known compounds (+)-(7R, 10S)-2-methoxy calamenene, (+)-(7R, 10S)-2,5-dimethoxy calamenene, and (+)-(7R, 10S)-2-methoxy,5-acetoxy calamenene. Among these compounds, (+)-(7R, 10S)-2-methoxy,5-acetoxy calamenene showed potent antifouling activity against the cyprids of B. amphitrite with EC50 value of 0.0335 μg/mL and a high therapeutic ratio of 799.[15]

Subergorgia suberosa

Isolations of the gorgonian coral S. Suberosa led to the isolation subergorgic acid (10) [Figure 2a and 2b], which showed cardiotoxic properties and significant activity against “Soman” toxicity in mice.[16-17] Bokesch et al. reported a new cytotoxic sesquiterpene, suberosenone (11), along with known piscicidal sesquiterpenes, buddledins C-D, suberosenone indicated significant cytotoxic activity against tumor cell lines.[18]

Figure 2b

Constituents (22-38)

A new steroid 3,9-dioxo-9,11-secocholesta-5,7-dien-11-al (12) was reported from S. suberosa together with the known compounds avenasterol, campesterol, cholesterol, fucosterol, 3β-hydroxypregn-5-en-20-one, 24-propylidenecholest-5-en-3β-ol, subergorgic acid, lathosterol, and zymosterol.[1]

Chemical investigation of the methanol extract of the gorgonian coral S. suberosa obtained from the Indian ocean resulted in isolation of four new compounds, methyl 2β-hydroxysubergorgate (13), methyl 2β-acetoxysubergorgate (14), 2β-hydroxysubergorgic acid (15), and methyl subergorgate (16), along with the known compound subergorgic acid.[7]

Chromatographic separations of the S. suberosa afforded three new secosterols, 3β, 6α, 11-trihydroxy-9, 11-seco-5α-cholest-7-ene-9-one (17), 24S- methyl-3β, 6α, 11-trihydroxy-9, 11-seco-5α-cholest-7, 22E-diene-9-one (18), and 24R-methyl-3β,6α,11-trihydroxy-9, 11-seco-5α-cholest-7, 22E-diene-9-one (19).[19] A compound Subergorgia suberosato sesquiterpene was isolated from S. suberosa which is suggested to act as a new antidote for soman. A procedure was developed for isolating isosubergorgic acid from S. suberosa; isosubergorgic acid is claimed to possess acetylcholine esterase inhibitory activity, thus it is suggested to treat Alzheimer's disease.[20-21]

Chromatographic separations of the Taiwanese gorgonian coral S. suberosa resulted in the identification of four new β-caryophyllene-derived sesquiterpenes alcohols, suberosols A-D (20-23), together with two known β-caryophyllene-derived sesquiterpenes ketones, buddledins C-D. Certain isolated constituents exhibited cytotoxic activity.[22]

Chromatographic separations of the ethyl acetate extract of the Taiwanese Gorgonian coral S. suberosa led to the isolation of two new subergane-based sesquiterpenes, subergorgiol (24) and 2β-acetoxysubergorgic acid (25), together with four known compounds subergorgic acid methyl ester, subergorgic acid 2β-acetoxy methyl ester, 2β-hydroxysubergorgic acid, and subergorgic acid. Among the compounds, subergorgic acid methyl ester showed moderate cytotoxic activity against the growth of HeLa cancer cells.[23] Subrahmanyam et al. reported 3,3-dimethoxy-5α-pregnan-20-one gorgonian S. suberosa.[24]

Chromatographic separations of the ethanol/dichloromethane extracts of the South China Sea gorgonian S. suberosa yielded a new sesquiterpene alkaloid, 6-(9’-purine-6’,8’-diolyl)-2β-suberosanone (26), along with three known compounds, suberosenol A, subergorgic acid, and subergorgiol. Among the compounds, (26) indicated moderate cytotoxic activity against the human breast carcinoma MDA-MB-231 cell line with an IC50 value of 8.87 μg/mL.[25]

Examinations of the gorgonian sea coral S. suberosa collected from the Mandapam coast, resulted in the identification of four compounds, batyl alcohol, subergorgic acid N-hexadecanoyl-2-amino-1,3-dihydroxyoctadec-4-ene, and thymine.[26] A formulation was developed for the isolation of a sesquiterpene ketone, which is claimed to inhibit the growth of tumor cells and treat breast cancer, leukemia, oral cancer, liver cancer, and lung cancer.[27]

Isolations of the ethanol/dichloromethane extract of the South China Sea gorgonian S. suberosa afforded three new polyhydroxylated sterols, 3β,6α,11,20β,24-pentahydroxy-9,11-seco-5α-24-ethylcholest-7,28-diene-9-one (27), 3-(1’,2’-ethandiol)-24-methylcholest-8(9),22E-diene-3β,5α,6α,7α,11α-pentaol (28), and 24-methylcholest-7,22 E-diene-3β,5α,6β,25-tetraol (29) along with six known steroids 24α-methylcholest-7,22E-diene-3β,5α,6β,9α-tetraol, 24α-methylcholest-7,22-dien-3β,5α,6β-triol, 3β,6α,11-trihydroxy-9,11-seco-5α-cholest-7-ene-9-one, 3β,6α,5,11-tetrahydroxy-9,11-seco-5α-cholest-7-ene-9-one, 3-O-β-D-glucopyranosyl-β-sitosterol, and 25-O-acetyl-3-O-[β-D-arabinopyranosyl-oxy]-cholest-5-ene-3β,19,25-triol.[9]

A steroid was isolate a steroid 3β,6α,11,20β,24-pentahydroxy-9,11-seco-5α-24-ethylcholest-7,28-diene-9-one from S. suberosa. The constituent is claimed to inhibit the growth of cancer cells of gastric cancer, leukemia, and liver cancer.[28] A purine alkaloid, 3,9-(2-imino-1-methyl-4-imidazolidinone-5-yl)-isopropenely-purine-6,8-dione, was isolated from S. suberosa. The isolated alkaloid is claimed to inhibit the growth of cancer cells of breast adenocarcinoma, liver cancer, gastric cancer, and leukemia.[29]

Isolations of the ethanol/dichloromethane extracts of the South China Sea gorgonian S. suberosa led to the isolation of four new purine alkaloids, 6-(1’-purine-6’,8’-dionyl)suberosanone (30), 3,9-(2-imino-1-methyl-4-imidazolidinone-5-yl)isopropenylpurine-6,8-dione (31), 1-(3’-carbonylbutyl)purine-6,8-dione (32), and 9-(3’-carbonylbutyl)purine-6,8-dione (33), along with three known compounds, guanosine, thymidine, and adenosine. The compounds (30-33) indicated weak cytotoxic activity against human cancer cell lines MDA-MB-231 and A435.[30]

Bioguided isolations of S. suberosa led to the isolation of six known compounds, subergorgic acid, pregn-4-ene-3, 20-dione (progesterone), 5β-pregn-3, 20-dione, 3β-pregn-5-ene-20-one-3-ol, 3β,5β-pregn-20-one-3-ol, and stigma-7,22-dien-3β,5α,6β-triol. The isolated constituents were antilarval against B. amphitrite and B. neritina larvae and antibacterial against 15 marine bacterial strains. Among the constituents, pregn-4-ene-3, 20-dione showed the most potent activity.[31]

Chromatographic separations of the dichloromethane/methanol extract of the South China Sea gorgonian coral S. suberosa led to the isolation of two new steroids, 3β-O-palmitoyl-pregn-5-en-20-one-3-ol (1) and 3β-O- palmitoyl-5α-pregn-20-one-3-ol (2), along with six known steroids, 5α-pregn-1-ene-3,20-dione, 3β, 5α-pregn-20-on-3-ol, 3β-pregn-5-en-20-on-3-ol, 3β, 5β-pregn-20-on-3-ol, 5β-pregn-3, 20-dione, and pregn-4-en-3, 20-dione. Furthermore, this is the first report of these compounds from this coral.[32]

Qi et al. reported three new purine derivatives, 4-carboxy-5, 6-dihydro-4H, 8H-pyrimido[1, 2, 3-cd]purine-8, 10(9H)-dione (34), 7, 9-dihydro-1-(3-oxobutyl)-1H-purine-6, 8-dione (35), and 7-hydro-9-(3-oxobutyl)-1H-purine-6, 8-dione (36), from the ethanol/dichloromethane extracts of the South China Sea gorgonian S. suberosa.[8] Two new steroids, (22E)-14α-hydroxy-cholesta-1, 4, 22-trien-3-one (37) and 3-(1’, 2’-ethandiol)-cholest-3β, 5α, 6α, 11α-tetraol (38), were reported from S. suberosa. The isolated compounds showed cytotoxic activity against human cancer cell lines A549, HONE1, and HeLa. The compounds also indicated antilarval activity against B. amphitrite and B. neritina larvae.[33]

Examinations of the ethyl acetate extract of gorgonian S. suberosa afforded nine known compounds, cholesta-5-ene-3β,7α-diol, cholestane-1β,3β,5α,6β-tetrol, cholesterol, (E)-N-2-(1,3-dihydroxy octadecan-4-en)-hexadecamide, batyl alcohol, thymidine, thymine, uracil, and heptadecane. However, this was the first report of these compounds from S. suberosa.[34] Reddy et al. isolatd the known compounds subergorgic acid and subergorgic acid methyl ester from S. suberosa.[35]

Subergorgia sp.

Bioguided isolations of Subergorgia sp. led to the isolation of astaxanthin; the isolated constituent showed significant cytotoxic activity against human leukemia cell line K562 and inhibited both TNF-α-induced NF-κB-DNA binding and TNF-α-induced IκBα degradation, and nuclear translocation of p50/p65.[36]

CONCLUSION

A significant number of phytopharmacological investigations on the genus Subergorgia show that it is a valuable source of new compounds. However, a limited number of investigations have been attempted on certain species such as S. hicksoni and S. mollis, hence it would be valuable to conduct bioguided phytochemical studies on these species for isolating new secondary metabolites that could possess cytotoxic or other important biological properties.