ANTICANCER AND ANTIANGIOGENIC AGENTS FROM ENDOPHYTIC FUNGI ISOLATED FROM THAI MANGROVE PLANTS

Abstract

Chromatographic fractionation of EtOAc crude extracts of an endophytic fungus, Rhytidhysteron rufulum isolated from Bruguiera gymnorrhiza cultured on Sabouraud dextrose broth led to the isolation of five new chromone derivatives, rhytidchromones A-E (1-5), one new isocoumarin derivative (6) and one known α-D-galacto pyranoside methyl (7). All compounds were evaluated for cytotoxic effect against four human tumor cell lines: hepato carcinoma (Hep-G2), gastric carcinoma (KATO-3), human breast cancer (MCF-7) and cervical carcinoma (CaSki). Rhytidchromones A (1), B (2), D (4) and E (5) showed cytotoxicity against Hep-G2, KATO-3, MCF-7 and CaSki with IC50 ranging of 16.0-29.3 µM, while compounds 3, 6 and 7 did not show any significant activity against all tested cell lines. Additionally, purification of EtOAc crude extract of basidiomycetous fungus from Xylocarpus granatum Koenig cultured on corn steep broth by chromatographic technique led to the isolation of one new chamigrane endoperoxide, merulin D (11), and four known derivatives, merulins A-C (8-10) and steperoxide A (12). All isolated compounds were evaluated for their anti-angiogenic activity. Only compound 10 displayed promising activity in both ex vivo and in vivo models. It was found that the activity of 10 was mainly resulted from the suppression of endothelial cell (HUVEC) proliferation and its effect is mediated by reduction in the phosphorylation of Erk1/2. Moreover, a marine-derived fungus Astrophaeriella nypae BCC 3553, isolated from Nypa fruticans was cultivated in LCN medium. Purification of its EtOAc crude extracts led to the isolation of three new secondary metabolites, astronypyrone (13), astronyquinone (14) and astronyurea (15), along with four known compounds, xestodecalactones A and B (16-17), coryotalactone B (18), and dimethoxy-O-methylpulvinone (19). Compounds 14, 16 and 19 were evaluated for their antimalarial activity and toxicity on normal cell lines. Only 19 exhibited antimalarial activity against Plasmodium falciparum K1 strain with an IC50 value of 16.9 µM, without toxicity to normal cells.