Zakharenko Alexandra, Luzina Olga, Koval Olga, Nilov Dmitry, Gushchina Irina, Dyrkheeva Nadezhda, Švedas Vytas, Salakhutdinov Nariman, Lavrik Olga
Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences , Novosibirsk, 630090, Russian Federation.
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences , Novosibirsk, 630090, Russian Federation.
J Nat Prod. 2016 Nov 23;79(11):2961-2967. doi: 10.1021/acs.jnatprod.6b00979. Epub 2016 Nov 14.
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a repair enzyme for stalled DNA-topoisomerase 1 (Top1) cleavage complexes and other 3'-end DNA lesions. TDP1 is a perspective target for anticancer therapy based on Top1-poison-mediated DNA damage. Several novel usnic acid derivatives with an enamine moiety have been synthesized and tested as inhibitors of TDP1. The enamines of usnic acid showed IC values in the range of 0.16 to 2.0 μM. These compounds revealed moderate cytotoxicity against human tumor MCF-7 cells. These new compounds enhanced the cytotoxicity of the established Top1 poison camptothecin by an order of magnitude.
酪氨酰-DNA磷酸二酯酶1（TDP1）是一种针对停滞的DNA拓扑异构酶1（Top1）切割复合物及其他3'-末端DNA损伤的修复酶。基于Top1中毒介导的DNA损伤，TDP1是抗癌治疗的一个潜在靶点。几种带有烯胺部分的新型扁枝衣酸衍生物已被合成并作为TDP1抑制剂进行测试。扁枝衣酸的烯胺显示出0.16至2.0 μM范围内的IC值。这些化合物对人肿瘤MCF-7细胞显示出中等细胞毒性。这些新化合物将已确立的Top1毒药喜树碱的细胞毒性提高了一个数量级。
