Cytotoxicities, Telomerase and Topoisomerases I Inhibitory Activities and Interactions of Terpyridine Derivatives with DNAs  

作　　者：WEI Chunying GAO Ning 

机构地区：[1]Key Laboratory of Chemical Biology and Molecular Engineering, Ministry of Education, Institute of Molecular Science, Shanxi University, Taiyuan 030006, P. R. China

出　　处：《Chemical Research in Chinese Universities》2015年第6期970-975,共6页高等学校化学研究（英文版）

基　　金：Supported by the National Natural Science Foundation of China（No.21171108）.

摘　　要：A novel compound 4-methyl-7-{[4-（2,2＇：6＇,2＂-terpyridin-4＇-yl）benzyl]amino}-2H-chromen-2-one（1） was synthesized, and its DNA-binding properties, cytotoxicity, and telomerase and Topo I inhibitory activities were evaluated. For comparison, the anti-proliferative and Topo I inhibitory activities of another two analogues 2 and 3 were also investigated. Compound 1 is able to stabilize the structures of human telomere（h-tert） and promoter（c-myc and c-kit2） G-quadruplexes and h-tert i-motif. The association constants（Kb） are about 106 L/mol for h-tert G-quadruplex and/-motif, while the values are about l0s L/mol for both promoter G-qaudruplexes and calf thymus DNA（ct-DNA）. The binding of compound 1 induces the change of h-tert G-quadruplex from hybrid to antiparallel structure and exhibits 88.7% inhibition of telomerase activity at 8 μmol/L. Both compounds 1 and 3 inhibit signifi- cantly Topo I-mediated relaxation of pBR322 DNA. Compounds 1 and 2 show a high inhibitory efficacy on HepG2 and MCF-7 cancer cell lines with IC50 values of about 10^-6 mol/L. The three compounds also induce a delay of cell cycle progression. The coumarin group is vital for improving the biological activity ofterpyridine derivatives.A novel compound 4-methyl-7-{[4-（2,2＇：6＇,2＂-terpyridin-4＇-yl）benzyl]amino}-2H-chromen-2-one（1） was synthesized, and its DNA-binding properties, cytotoxicity, and telomerase and Topo I inhibitory activities were evaluated. For comparison, the anti-proliferative and Topo I inhibitory activities of another two analogues 2 and 3 were also investigated. Compound 1 is able to stabilize the structures of human telomere（h-tert） and promoter（c-myc and c-kit2） G-quadruplexes and h-tert i-motif. The association constants（Kb） are about 106 L/mol for h-tert G-quadruplex and/-motif, while the values are about l0s L/mol for both promoter G-qaudruplexes and calf thymus DNA（ct-DNA）. The binding of compound 1 induces the change of h-tert G-quadruplex from hybrid to antiparallel structure and exhibits 88.7% inhibition of telomerase activity at 8 μmol/L. Both compounds 1 and 3 inhibit signifi- cantly Topo I-mediated relaxation of pBR322 DNA. Compounds 1 and 2 show a high inhibitory efficacy on HepG2 and MCF-7 cancer cell lines with IC50 values of about 10^-6 mol/L. The three compounds also induce a delay of cell cycle progression. The coumarin group is vital for improving the biological activity ofterpyridine derivatives.

关 键 词：TERPYRIDINE COUMARIN QUADRUPLEX TELOMERASE Topoisomerase I 

分 类 号：Q523[生物学—生物化学] O629.36[理学—有机化学]