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-substitutedace

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• 作者：Jiawang Liu ; Guohui Cui ; Ming Zhao ; Chunying Cui ; Jingfang Ju ; Shiqi Peng
• 关键词：MES-SA/Dx5 ; Reversing resistance ; Anti-proliferation ; SAR ; Benzyl 1 ; 2 ; 3 ; 5 ; 11 ; 11a-hexahydro-3 ; 3-dimethyl-1-oxo-6H-imidazo[3&#x2032 ; 4&#x2032 ; 1 ; 2]pyridin[3 ; 4-b]indol-2-substituted-acetates
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2007
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 December 2007
• 卷：15
• 期：24
• 页码：7773-7788
• 文件大小：296 K

摘要

Based on the structural analysis of fumitremorgin C (FTC), imidazoline and β-carboline amino acid benzylester, 14 novel 2-substitutedtetracyclic derivatives of tetrahydrocarboline ng>4ang>–ng>nng> were prepared. We demonstrated that the exposure of MES-SA/Dx5 cells to some of ng>4ang>–ng>nng> 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 μmol/L to 0.33 ± 0.05 μmol/L for 2-(2-butyl)-derivative ng>4cng>, to 1.03 ± 0.22 μmol/L for 2-methyl-derivative ng>4dng>, to 0.46 ± 0.04 μmol/L for 2-benzyl-derivative ng>4fng>, to 0.98 ± 0.25 μmol/L for 2-indole-3-yl-methyl-derivative ng>4hng>, to 0.36 ± 0.03 μmol/L for 2-benzyloxycarbonylmethyl-derivative ng>4ing>, to 0.77 ± 0.08 μmol/L for 2-benzyloxycarbonylethyl-derivative ng>4jng>, and to 0.77 ± 0.08 μmol/L for 2-benzyloxycarbonylamino-n-butyl-derivative ng>4lng>. Proliferation assays of ng>4ang>–ng>nng> indicated ng>4cng>,ng>fng>,ng>ing>,ng>jng> 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 ng>4ang>–ng>nng> were critical for both sensitizing doxorubicin and the cellular anti-proliferative effect.