Dual-acting agents that possess reversing resistance and anticancer activities: Design, synthesis, MES-SA/Dx5 cell assay, and SAR of benzyl 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo[3 ',4 ': 1,2] pyridin[3,4-b]indol-2-substitutedacetates

作者：Liu Jiawang; Cui Guohui; Zhao Ming; Cui Chunying; Ju Jingfang^*; Peng Shiqi

来源：Bioorganic & Medicinal Chemistry, 2007, 15(24): 7773-7788.

DOI：10.1016/j.bmc.2007.08.061

• MES-SA/ Dx5
• reversing resistance
• anti-proliferation
• SAR
• benzyl 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo[3 ',4 ': 1,2] pyridin[3,4-b]indol-2-substituted-acetates

Based on the structural analysis of fumitremorgin C (FTC), imidazoline and beta-carboline amino acid benzylester, 14 novel 2-substitutedtetracyclic derivatives of tetrahydrocarboline 4a-n were prepared. We demonstrated that the exposure of MES-SA/Dx5 cells to some of 4a-n resulted in significant reduction of resistance of the cells against doxorubicin. This reduced resistance was accompanied by lowering of IC50 value to doxorubicin from 1.55 +/- 0.26 mu mol/L to 0.33 +/- 0.05 mu mol/L for 2-(2-butyl)-derivative 4c, to 1.03 +/- 0.22 mu mol/L for 2-methyl-derivative 4d, to 0.46 +/- 0.04 mu mol/L for 2-benzyl-derivative 4f, to 0.98 +/- 0.25 mu mol/L for 2-indole-3-yl-methyl-derivative 4h, to 0.36 +/- 0.03 mu mol/L for 2-benzyloxycarbonylmethyl- derivative 4i, to 0.77 +/- 0.08 mu mol/L for 2-benzyloxycarbonylethyl-derivative 4j, and to 0.77 +/- 0.08 mu mol/L for 2-benzyloxycarbonylamino-n-butyl-derivative 4l. Proliferation assays of 4a-n indicated 4c, f, i, j were able to inhibit the proliferation of doxorubicin resistant MES-SA/Dx5 cells. The SAR analysis revealed that the benzylester form and the tetracyclic structure of 4a-n were critical for both sensitizing doxorubicin and the cellular anti-proliferative effect.

• 出版日期2007-12-15
• 单位首都医科大学