Wang Weisi, Sun Xiao, Sun Deheng, Li Shizhu, Yu Yang, Yang Tingyuan, Yao Junmin, Chen Zhuo, Duan Liping
National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, WHO Collaborating Centre for Malaria, Schistosomiasis, and Filariasis, Key laboratory of Parasitology and Vector Biology of the Chinese Ministry of Health, Shanghai, 200025, China.
ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
ChemMedChem. 2016 Dec 16;11(24):2675-2681. doi: 10.1002/cmdc.201600391. Epub 2016 Nov 23.
Novel carbazole aminoalcohols were designed and synthesized as anticancer agents. Among them, alkylamine-chain-substituted compounds showed the most promising antiproliferative activity, with IC values in the single-digit micromolar range against two human tumor cell lines. Topoisomerase I (topo I) is likely to be one of the targets of these compounds. Results of comet assays and molecular docking indicate that the representative compounds may act as topo I poisons, causing single-strand DNA damage by stabilizing the topo I-DNA cleavage complex. In particular, the most potent compound, 1-(butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol (6), was shown to be able to induce G -phase cell-cycle arrest and apoptosis in HeLa cells.
设计并合成了新型咔唑氨基醇作为抗癌剂。其中，烷基胺链取代的化合物表现出最有前景的抗增殖活性，对两种人类肿瘤细胞系的IC值在个位数微摩尔范围内。拓扑异构酶 I（topo I）可能是这些化合物的靶点之一。彗星试验和分子对接结果表明，代表性化合物可能作为topo I毒药，通过稳定topo I-DNA裂解复合物导致单链DNA损伤。特别是，最有效的化合物1-(丁基氨基)-3-(3,6-二氯-9H-咔唑-9-基)丙-2-醇（6）被证明能够诱导HeLa细胞的G期细胞周期停滞和凋亡。
