Design, Synthesis and Anti-cancer Evaluation of Nitrogen-containing Derivatives of 30-Carboxyl of Gambogic Acid

Author(s):

Hong Li, Huiping Lin, Jiajun Li, Kaixin Chen, Zanhong Chen, Jianye Zhang, Yan Huang, Xin Zhao, Huihui Ti* and Yiwen Tao*   Pages 454 - 463 ( 10 )

Abstract:

<p>Background: Gambogic acid (GA) is a natural product from the resin of the Garcinia species, which showed significant activity in the induction of apoptosis. t can be one promising lead compound for the design and synthesis of new anticancer drugs. <p> 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. <p> Methods: The designed 15 derivatives were synthesized via esterification or amidation of 30-carboxylate. The synthetic compounds were characterized <i>via</i> different spectroscopic techniques, including X-ray single crystal diffraction, MS and NMR. The cytotoxic activity of the designed derivatives was evaluated <i>in vitro</i> against A549, HepG-2, and MCF-7 cell lines using methyl thiazolyl tetrazolium (MTT) test. <p> 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. <p> 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.</p>

Keywords:

Gambogic acid, nitrogen-contained derivatives, anti-cancer, MTT assay, spectroscopic techniques, MCF-7 cell lines.

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