A single compound able to inhibit both TopoⅠandⅡmay present the advantage of improving anti-proliferative activity,with reduced toxic side effects,with respect to the combination of two inhibitors.We designed and sy...A single compound able to inhibit both TopoⅠandⅡmay present the advantage of improving anti-proliferative activity,with reduced toxic side effects,with respect to the combination of two inhibitors.We designed and synthesized 28 compounds of indeno[1,2-b]indole derivatives as a new class of TopoⅠandⅡinhibitor and successfully identified compound 2-3 j,which showed the most potent cell growth inhibition with IC50=0.74μM against HCT-116 cell line.Compound 2-3 j was also evaluated as a potent topoisomeraseⅠandⅡinhibitor and can induce apoptosis in human colon cancer cells.2-3 j showed potency against a small panel of drug sensitive and multidrug resistant(MDR)cell lines,and it reversed the MDR of K562/A02,MCF-7/Adr,and KB/Vcr cells at 0.5μM,with reversal fold values of 3.2,10.1,and 5.8,respectively.2-3 j might inhibit the function of ABCG2 to increase intracellular drug accumulation and enhance the sensitivity of conventional chemotherapeutic agents for MDR cells.2-3 j could be a promising lead for the development of a new class of antitumor drug acting as inhibitors of TopoⅠ&Ⅱand ABCG2.展开更多
基金The National Natural Science Foundation of China(Grant No.81573272,81273370)Changjiang Scholars and Innovative Research Team in University(Grant No.IRT13028)
文摘A single compound able to inhibit both TopoⅠandⅡmay present the advantage of improving anti-proliferative activity,with reduced toxic side effects,with respect to the combination of two inhibitors.We designed and synthesized 28 compounds of indeno[1,2-b]indole derivatives as a new class of TopoⅠandⅡinhibitor and successfully identified compound 2-3 j,which showed the most potent cell growth inhibition with IC50=0.74μM against HCT-116 cell line.Compound 2-3 j was also evaluated as a potent topoisomeraseⅠandⅡinhibitor and can induce apoptosis in human colon cancer cells.2-3 j showed potency against a small panel of drug sensitive and multidrug resistant(MDR)cell lines,and it reversed the MDR of K562/A02,MCF-7/Adr,and KB/Vcr cells at 0.5μM,with reversal fold values of 3.2,10.1,and 5.8,respectively.2-3 j might inhibit the function of ABCG2 to increase intracellular drug accumulation and enhance the sensitivity of conventional chemotherapeutic agents for MDR cells.2-3 j could be a promising lead for the development of a new class of antitumor drug acting as inhibitors of TopoⅠ&Ⅱand ABCG2.
