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.
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.
Liu
Jiawang
J
College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
Cui
Guohui
G
Zhao
Ming
M
Cui
Chunying
C
Ju
Jingfang
J
Peng
Shiqi
S
D000085:Acetates / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D000085:Acetates; D000970:Antineoplastic Agents; D007093:Imidazoles; D011725:Pyridines; D004317:Doxorubicin