Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 86, Issue -, Pages 175-188Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.08.003
Keywords
Asiatic acid; Synthesis; Anilines; Cytotoxicity; Apoptosis
Categories
Funding
- 973 project [2011CB512005, 2012CB723501]
- National Natural Science Foundation of China [81260472, 21101035]
- Guangxi Natural Science Foundation of China [2011GXNSFD018010, 2010GXNSFF013001]
- Bagui Scholar project
- Foundation of Ministry of Education Innovation Team [IRT1225]
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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, H-1 NMR and C-13 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 mitochondria] 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 proapoptotic 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. (c) 2014 Elsevier Masson SAS. All rights reserved.
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