Synthesis and biological evaluation of novel aniline-derived asiatic acid derivatives as potential anticancer agents

• New asiatic acid derivatives were synthesized by addition of substituents at C-28 position.
• Many compounds showed better antitumor activities against tumor cells than 5-FU.
• Hydroxy group points to a potential for a significant improvement of anti-proliferative activities.
• Provide further insights into the mechanism of action.
• The compound of 5b induced apoptosis via a Mitochondria-Mediated Pathway.

Asiatic acid (AA) derivatives 4 and 5 modified at the C-11 and C-28 positions were designed and synthesized, their structures were confirmed using HRMS, 1H NMR and 13C NMR. In vitro antitumor activities of all compounds against MGC-803, NCI-H460, HepG2, Hela and 7404 cancer cell lines were evaluated and compared with commercial anticancer drug 5-fluorouracil (5-FU), employing standard MTT assay. The new compounds 5a–5t showed stronger anti-proliferative activity than AA, especially compound 5b was found to be the best inhibition activity on HepG2 cell line. In addition, the mechanism of compound 5b was preliminarily investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining, flow cytometric, qRT-PCR (quantitative real-time PCR) and Western blot. Compound 5b induced the productions of ROS, and altered anti- and pro-apoptotic proteins, leading to mitochondrial dysfunction and activations of caspase-9 and caspase-3 for causing cell apoptosis. Moreover, the cell cycle analysis showed that compound 5b mainly arrested HepG2 cells in G1 stage.

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