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Bioorg Med Chem. 2007 Dec 15;15(24):7773-88. Epub 2007 Sep 1.

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.

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College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.


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 IC(50) value to doxorubicin from 1.55+/-0.26 micromol/L to 0.33+/-0.05 micromol/L for 2-(2-butyl)-derivative 4c, to 1.03+/-0.22 micromol/L for 2-methyl-derivative 4d, to 0.46+/-0.04 micromol/L for 2-benzyl-derivative 4f, to 0.98+/-0.25 micromol/L for 2-indole-3-yl-methyl-derivative 4h, to 0.36+/-0.03 micromol/L for 2-benzyloxycarbonylmethyl-derivative 4i, to 0.77+/-0.08 micromol/L for 2-benzyloxycarbonylethyl-derivative 4j, and to 0.77+/-0.08 micromol/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.

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