Chemical Constituents And Bioactivities Of The Marine Sponge Plakortis Simplex From Xi Sha Islands

The marine sponges have formed a complex and powerful chemical protection system during their long evolution of the survival in order to resist infringement. They create and accumulate a large number of secondary metabolites, featuring special chemical structures and bioactivities, including a large number of new compounds showing antitumor, anti-virus, anti-bacterial, anti-inflammatory and immune regulation activities. Marine natural products have been the focus of chemistry research for along time.The marine spong Plakortis simplex belongs to class Demospongiae, order Hamosclerophorida and family Plakinidae. There are series of phytochemical reports on this sponge from many research groups all over the world. The results show that marine sponges of the genus plakortis are rich in novel compounds with good biological activities. Up to now, a large number of secondary metabolites have been reported from this genus of sponge, including cyclic peroxides, furano , --unsaturated esters, terpenes, glycosphingolipids, and alkaloids. Many of them exhibited significant biological activities including antitumor, antimalarial, immunosuppressive and anti-histamine. In the course of our continuing search for drug leads from marine sponges inhabited in the South China Sea, we studied the chemical constituents and bioactivities of the marine sponge P. simplex from the Xisha islands of the South China Sea.Twenty two compounds (1-22) were isolated and purified from the CH2Cl2 fraction of the methanol extract, guiding by cytotoxic assay, and by using solvent extraction and chromatographic methods including VLC, LPLC, MPLC, HPLC on silica gel, ODS C-18 and Sephadex LH-20. These structures, including 19 polyketides, 2 alkaloids and 1 triterpenoids, were elucidated by 1H-NMR, 13C-NMR, 1H-1H COSY, HMQC (HSQC), HMBC, NOESY (ROESY) and MS as: simplextones A-C (1-3), plakortones (H-T) (4-16), (2Z,6R,8R,9E)[3-Ethyl-5-(2-ethyl-hex-3-enyl)-6-ethyl-5H-furan-2-ylidene]-acetic acid methyl ester (17), methyl (2Z,6R,8S)-4,6-diethyl-3,6-epoxy-8-methyeodeca-2,4- dienoate (18), methyl (2Z,6R,8S)-3,6-epoxy-4,6,8-triethyldodeca-2,4-dienoate (19), (2Z, 6R,8R,9E)[3-ethyl-5-(2-ethyl-hex-3-enyl)-6-methyl-5H-furan-2-ylidene]-acetic acid methyl ester (20), monotriajaponide A (21), 3-indole formaldehyde (22), 3-indole acid (23) and (32R,33R,34S)-32,33,34,35-bacteriohopanetetrol (24). Compounds 1-16 are new polyketides, of which absolute configurations were assigned by using X-ray crystallographic analysis, modified Mosher's method, and quantum mechanical calculation of the electronic circular dichroism (ECD) spectrum. Compounds 1?3 featured an unprecedented polyketide skeleton via the connection of a single carbon carbon bond to form a cyclopentane. A plausible biogenetic pathway for these new compounds is illustrated in this paper. Most of the polyketides obtained from the marine sponge of genus Plakortis appear to involve three or four ethyl branches, as a result of intact butyrate incorporation in their biosynthesis. The butyrate unites together with acetate and propionate units might be required to assemble the polyketide skeleton. The linear polyketide precursor is further undergoes a series of reactions including dehydrogenation, cyclization, reduction and hydroxylation to form a cyclopentane. The cyclopentane intermediate is then released from the acyl carrier protein (ACP) after modified by the formation of an epoxide, and the opening of the epoxide intermediates, leads to the insertion of a hydroxyl group with the concomitant lactonization of theγ-lactone.Some new compounds were evaluated for activity screening of cytotoxicity, protein tyrosine phosphatase 1B and aurora kinase A. Compound 1 exhibited cytotoxicity against cancer cell lines HCT-116, SW480, SGC7901 and HeLa with IC₅0 value of 26.3, 57.4, 64.7, and 60.6 ?M, respectively; compounds 4, 6, 10, 13 and 14 exhibited cytotoxicity against cancer cell line HCT-116 with IC₅0 value of 32.7, 14.8, 31.6, 76.5 and 43.5 ?M, respectively; compound 10 showed potential inhibitory activity against PTP1B with an IC₅0 value of 15.6μM.The studies focused on the chemical constituents of Plakortis simplex and their bioactivities. Bioassay-guided fractionation led to the isolation of 16 new polyketides, together with ?? known compounds. Multiple methods have been used to determine the absolute configurations of the new structures. A plausible biogenetic pathway for these new compounds was proposed. The results of bioactivity test indicate that some compounds exhibited potential cytotoxicity and PTP1B inhibitory activity, which could provide new leads for the development of new anticancer drugs or treatment of diabetes, obesity and other drugs, and also play an important role for the development and medicinal usage of the marine biological resources.