title: Synthesis and Pharmacological Evaluation of Maleopimaric N-arylimides: Identification of Novel Proapoptotic Agents.
abstract: 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.
authors.forename: Guiyang
authors.initials: G
authors.lastname: Yao
authors.forename: Manyi
authors.initials: M
authors.lastname: Ye
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, P.R. China. zxliao@seu.edu.cn.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Liao
authors.affiliation: Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, P.R. China. whengshan@163.com.
authors.forename: Hengshan
authors.initials: H
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007094:Imides / Q000138:chemical synthesis* / Q000494:pharmacology; D014315:Triterpenes / Q000737:chemistry*
chemical_list: D007094:Imides; D014315:Triterpenes; C027815:maleopimaric acid