论文部分内容阅读
拓扑异构酶Ⅰ和拓扑异构酶Ⅱ双重抑制剂因为具有双靶点,在提高抗增值活性的同时可以降低毒副作用.作者设计并合成了28个茚[1,2-b]并吲哚衍生物类新型拓扑异构酶Ⅰ和Ⅱ抑制剂,并发现化合物2-3j具有最强抗细胞增殖活性,在HCT-116细胞实验中IC50值为0.74 μM,且可以诱导人直肠癌细胞凋亡.2-3j不仅对药物敏感细胞系有活性,对于多重抗药(MDR)细胞系K562/A02,MCF-7/Adr和KB/Vcr细胞均有逆转抗药性作用,逆转抗药性倍数变化分别为3.2,10.1和5.8.2-3j的作用机理可能是通过抑制ABCG2活性,提高药物细胞内浓度,从而增强MDR细胞对传统化疗药物的敏感度.2-3j可以作为潜在的新型拓扑异构酶Ⅰ&Ⅱ和ABCG2抑制剂先导化合物进行进一步开发和研究.“,”A single compound able to inhibit both Topo Ⅰ and Ⅱ may 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 Topo Ⅰ and Ⅱ inhibitor and successfully identified compound 2-3j,which showed the most potent cell growth inhibition with IC50=0.74 μM against HCT-116 cell line.Compound 2-3j was also evaluated as a potent topoisomerase Ⅰ and Ⅱ inhibitor and can induce apoptosis in human colon cancer cells.2-3j 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 0.5 μM,with reversal fold values of 3.2,10.1,and 5.8,respectively.2-3j might inhibit the function of ABCG2 to increase intracellular drug accumulation and enhance the sensitivity of conventional chemotherapeutic agents for MDR cells.2-3j could be a promising lead for the development of a new class of antitumor drug acting as inhibitors of Topo Ⅰ & Ⅱ and ABCG2.