Cytotoxic constituents of Glycosmis ovoidea collected in Vietnam

Compounds derived from natural sources have been major contributors to the area of cancer chemotherapy for decades. As part of an ongoing effort to discover anticancer drug leads from tropical plants, a large-scale collection of Glycosmis ovoidea Pierre (Rutaceae), was made at Nui Chua National Park, Vietnam. Activity -guided fractionation of the chloroform-soluble fractions led to the isolation of nine coumarins, including the new compound, 1-(7-methoxy-2-oxo-2H-chromen-8-yl)-3-methyl-1-oxobut-2-en-2-yl (S)-2-methylbutanoate (1). An close analogue of 1, namely, kincuongin (2), was deemed as non-cytotoxic (IC50 > 10 mu M) against five different cancer cell lines. However, co-administration of kimcuongin (2) showed an approximately 100 times potentiation of the MCF-7 breast cancer cell cytotoxicity of the previously reported flavonoid, 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (10). To provide a mechanistic basis for the cancer cell line inhibition enhancement observed, an initial in silico study on compound 10 indicated that it interacts with isoforms of the NF -KB complex. In a confirmatory western blot experiment conducted, kimcuongin (2) was found to potentiate the effects of flavone 10 in inhibiting both NF -KB and PARP-1. In vivo investigations using a zebrafish (Danio rerio) model showed that compounds 2, 3, 5, and 6 did not exhibit any discernible toxicity at concentrations up to 50 mu M.

Automated summary

Compound kimcuongin (2) isolated from Vietnamese tropical plants showed high cytotoxicity against breast cancer cells in combination with other compounds and enhanced the inhibitory effects of flavonoid 10 on NF -KB and PARP-1. In the zebrafish model, compounds 2, 3, 5, and 6 did not exhibit discernible toxicity effects.