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Design and Synthesis of Chlorinated and Fluorinated 7-Azaindenoisoquinolines as Potent Cytotoxic Anticancer Agents That Inhibit Topoisomerase I.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-06-28 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01870
Mohamed S A Elsayed 1 , Yafan Su 1 , Ping Wang 1 , Taresh Sethi 2 , Keli Agama 2 , Azhar Ravji 2 , Christophe E Redon 2 , Evgeny Kiselev 2 , Katharine A Horzmann 3 , Jennifer L Freeman 3 , Yves Pommier 2 , Mark Cushman 1
Affiliation  

The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model. Some of the new Top1 inhibitors also possess moderate inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2), two enzymes that are involved in DNA damage repair resulting from Top1 inhibitors, and they produce significantly more DNA damage in cancer cells than in normal cells. Eighteen of the new compounds had cytotoxicity mean-graph midpoint (MGM) GI50 values in the submicromolar (0.033–0.630 μM) range. Compounds 16b and 17b are the most potent in human cancer cell cultures with MGM GI50 values of 0.063 and 0.033 μM, respectively. Possible binding modes to Top1 and TDP1were investigated by molecular modeling.

中文翻译:


设计和合成氯化和氟化 7-氮杂茚并异喹啉作为抑制拓扑异构酶 I 的有效细胞毒性抗癌剂。



7-氮杂茚并异喹啉是细胞毒性拓扑异构酶 I (Top1) 抑制剂。先前报道的代表带有3-硝基。本报告记录了用 3-氯和 3-氟取代基取代具有潜在遗传毒性的 3-硝基,从而产生在人类癌细胞培养物中具有高 Top1 抑制活性和有效细胞毒性的化合物,并在动物模型中降低致死率。一些新的 Top1 抑制剂还对酪氨酰 DNA 磷酸二酯酶 1 (TDP1) 和酪氨酰 DNA 磷酸二酯酶 2 (TDP2) 具有中等抑制活性,这两种酶参与 Top1 抑制剂引起的 DNA 损伤修复,并且它们产生显着更多的 DNA癌细胞的损伤程度高于正常细胞。其中 18 种新化合物的细胞毒性平均图中点 (MGM) GI 50值在亚微摩尔 (0.033–0.630 μM) 范围内。化合物16b17b在人类癌细胞培养物中最有效,MGM GI 50值分别为 0.063 和 0.033 μM。通过分子建模研究了 Top1 和 TDP1 的可能结合模式。
更新日期:2017-06-28
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