Discovery of a Highly Potent and Novel Gambogic Acid Derivative as an Anticancer Drug Candidate.

BACKGROUND AND PURPOSE: Gambogic acid (GA), a promising anti-cancer agent isolated from the resin of Garcinia species in Southeast Asia, exhibits high potency in inhibiting a wide variety of cancer cells growth. Moreover, the fact that it is amenable to chemical modification makes GA an attractive molecule for the development of anticancer agents. METHODS: Gambogic acid-3-(4-pyrimidinyloxy) propyl ester (compound 4) was derived from the reaction between 4-hydroxypropoxy pyrimidine and GA. Its structure was elucidated by comprehensive analysis of ESIMS, HRESIMS, 1 D NMR data. Antitumor activities of compound 4 and GA in vitro against HepG-2, A549 and MCF-7 cells were investigated by MTT assay. FITC/PI dye were used to test apoptosis. The binding affinity difference of compound 4 and GA binding to IKKbeta was studied by using Discovery Studio 2016. RESULTS: Compound 4 was successfully synthesized and showed strong inhibitory effects on HepG-2, A549 and MCF-7 cells lines with IC50 value of 1.49 +/- 0.11, 1.37 +/- 0.06 and 0.64 +/- 0.16muM, respectively. Molecular docking study demonstrated that four more hydrogen bonds were established between IKKbeta and compound 4, compared with GA. CONCLUSION: Our results suggested that compound 4 showed significant effects in inducing apoptosis. Further molecular docking study indicated that the introduction of pyrimidine could improve GA's binding affinity to IKKbeta. Compound 4 may serve as a potential lead compound for the development of new anticancer drugs.