Optimization of the Lactam Side Chain of 7-Azaindenoisoquinoline Topoisomerase I Inhibitors and Mechanism of Action Studies in Cancer Cells

详细信息    查看全文

• 作者：Evgeny Kiselev ; Dhriti Sooryakumar ; Keli Agama ; Mark Cushman ; Yves Pommier
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 27, 2014
• 年：2014
• 卷：57
• 期：4
• 页码：1289-1298
• 全文大小：535K
• 年卷期：v.57,no.4(February 27, 2014)
• ISSN：1520-4804

文摘

Optimization of the lactam 蠅-aminoalkyl substituents in a series of 7-azaindenoisoquinolines resulted in new anticancer agents with improved Top1 inhibitory potencies and cancer cell cytotoxicities. The new compounds 14鈥?7 and 19 exhibited mean graph midpoint cytotoxicity (GI₅₀) values of 21鈥?1 nM in the NCI panel of 60 human cancer cell cultures. Ternary 7-azaindenoisoquinoline鈥揇NA鈥揟op1 cleavage complexes that persist for up to 6 h were detected in HCT116 colon cancer cells. Ternary complexes containing 7-azaindenoisoquinolines were significantly more stable than those in which camptothecin was incorporated. DNA content distribution histograms showed S-phase block 3 h after drug removal. Drug-induced DNA damage in HCT116 cells was revealed by induction of the histone 纬-H2AX marker. The 7-azaindenoisoquinolines were able to partially overcome resistance in several drug-resistant cell lines, and they were not substrates for the ABCB1 drug efflux transporter. Molecular modeling studies indicate that the 7-azaindenoisoquinolines intercalate at the DNA cleavage site in DNA鈥揟op1 covalent complexes with the lactam side chain projecting into the major groove. Overall, the results indicate that the 7-azaindenoisoquinolines are promising anticancer agents that merit further development.