Studies on chemical structure modification and biology of a natural product, Gambogic acid (I): Synthesis and biological evaluation of oxidized analogues of gambogic acid

Gambogic acid (GA), a natural product, exhibits high potency in inhibiting cancer cell growth through the effective induction of apoptosis. In order to investigate the structure–activity relationships of GA derivatives, 11 oxidized derivatives of GA were synthesized. Some of them showed strong inhibitory effects on HT-29, Bel-7402, BGC-823, A549, and SKOV 3 cell lines. Moreover, in this paper the cellular growth inhibitor 39-hydroxy-6-methoxy-gambogic acid methyl ester (10) was identified as a HepG2 cell apoptosis inhibitor through Annexin-V/PI double staining assay and the expression of the related apoptotic proteins (Bax and Bcl-2). Compound 10 may serve as a potential lead compound for the development of new anticancer drugs. Further SAR studies of GA derivatives indicated that modification of carbon–carbon double bond at C-32/33 or C-37/38 and of the methyl groups at C-39/C-35 can improve antitumor activity.

Graphical abstractEleven gambogic acid analogues were synthesized. We also performed SAR studies of gambogic acid. A promising derivative 10, as a potent apoptosis inducer in HepG2 cells was characterized.Figure optionsDownload full-size imageDownload as PowerPoint slide