Several N-aryl maleopimaric acid diimides (3a-3d, 4a-4g) were synthesized and
evaluated their topoisomerase I inhibitory activities along with cytotoxicities against NCI,
MGC-803, Bel-7404 and Hct-116 cell lines. The pharmacological dates revealed that most of
structure analogs exhibited moderate to high levels of anticancer activities against the tested
cancer cell lines. Compound 4g with phenylalanine substituent exhibited significant cytotoxicity
against MGC-803 and Hct-116 cells (IC50 was 9.85±1.24 and 8.47±0.95 µM, respectively). All
the synthesized compounds exhibited no cytotoxicity against HUVEC cells. In addition, maleopimaric diimides showed stronger
cytotoxicity and topoisomerase I inhibitory activity compared to that of maleopimaric acid. Structure–activity relationship study showed
that carboxyl and diimide moieties were important to display Topo I inhibitory activities. Further experiments proved that 4g could
induce apoptosis of MGC-803 cells. In addition, the further mechanisms of compound 4g-induced apoptosis in MGC-803 cells
demonstrated that compound 4g induced the activations of caspase-4, caspase-8 and caspase-3 for causing cell apoptosis, and altered antiand
pro-apoptotic proteins. Moreover, cell cycle analysis indicated that the derivative 4g mainly arrested MGC-803 cells in S stage.
Keywords: Maleopimaric acid, Topoisomerase I, Anticancer, Cytotoxicity, Apoptosis.
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