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.

译文

:7-氮杂茚并异喹啉是细胞毒性拓扑异构酶I(Top1)抑制剂。以前报道的代表带有一个3-硝基基团。本报告记录了潜在的具有遗传毒性的3-硝基被3-氯和3-氟取代基取代,从而导致在人类癌细胞培养中具有高Top1抑制活性和强细胞毒性的化合物,并降低了动物模型的致死率。一些新的Top1抑制剂还具有对酪氨酰DNA磷酸二酯酶1(TDP1)和酪氨酰DNA磷酸二酯酶2(TDP2)的中等抑制活性,这两种酶都参与了由Top1抑制剂引起的DNA损伤修复,并且它们产生的DNA明显更多。在癌细胞中的损伤要比正常细胞中的损伤大。 18种新化合物的细胞毒性平均图中点(MGM)GI50值在亚微摩尔(0.033-0.630μM)范围内。化合物16b和17b在人类癌细胞培养物中最有效,其MGM GI50值分别为0.063和0.033μM。通过分子建模研究了与Top1和TDP1可能的结合模式。

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