Anti-Cancer Agents in Medicinal ChemistryAnti-Cancer Agents in Medicinal ChemistryAnti-Cancer Agents in Medicinal Chemistry1871-52061875-5992Bentham Science64424210.2174/0118715206279725231208065031OncologyResearch ArticleDesign, Synthesis and Anti-cancer Evaluation of Nitrogen-containing Derivatives of 30-Carboxyl of Gambogic AcidLiHonginfo@benthamscience.netLinHuipinginfo@benthamscience.netLiJiajuninfo@benthamscience.netChenKaixininfo@benthamscience.netChenZanhonginfo@benthamscience.netZhangJianyeinfo@benthamscience.netHuangYaninfo@benthamscience.netZhaoXininfo@benthamscience.netTiHuihuiinfo@benthamscience.netTaoYiweninfo@benthamscience.netKey Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangdong Academy of Sciences (China National Analytical Center, Guangzhou),School of Chinese Medicinal Resource,, Guangdong Pharmaceutical University1503202424645446307012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1871-5206/article/view/644242

Background:Gambogic acid (GA) is a natural product from the resin of the Garcinia species, which showed significant activity in the induction of apoptosis. It can be one promising lead compound for the design and synthesis of new anticancer drugs.

Objective:The objective of the current study is to design novel nitrogen-contained GA derivatives with better anti-cancer activities and study the effect of the introduction of different nitrogen-contained groups on the activity of GA.

Methods:The designed 15 derivatives were synthesized via esterification or amidation of 30-carboxylate. The synthetic compounds were characterized via different spectroscopic techniques, including X-ray single crystal diffraction, MS and NMR. The cytotoxic activity of the designed derivatives was evaluated in vitro against A549, HepG-2, and MCF-7 cell lines using methyl thiazolyl tetrazolium (MTT) test.

Results:15 nitrogen-contained GA derivatives were successfully synthesized and established. Based on the IC50 values, compounds 9, 10, 11 and 13 showed stronger inhibitory effects on A549, HepG-2, MCF-7 cell lines than GA, while 9 is the most active compound with IC50 value of 0.64-1.49 µM. Most derivatives of GA with esterification of C-30 including cyano-benzene ring were generally weaker than those of pyrimidinyl-substituted derivatives. In addition, length of alkyl linkers between C-30 of GA and nitrogen-contained group produced different effects on A549, HepG-2 and MCF-7 cell lines.

Conclusion:The structure-activity relationship results show that aromatic substituent and linker length play important roles to improve the anticancer activities, while compound 9 with pyrimidine substituent and C-C-C linkers is the most active derivative against tested cell lines, and is a promising anti-cancer agent for further development.

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