Quantitative Structure-Activity Relationship Studies on Indenoisoquinoline Topoisomerase I Inhibitors as Anticancer Agents in Human Renal Cell Carcinoma Cell Line SN12C

International Journal of Molecular Sciences

Yi Zhi³  Jin Yang¹  Shengchao Tian³  Fang Yuan³  Yang Liu³  Yi Zhang¹  Pinghua Sun²  Bo Song³ 

[1] Department of Cell Biology, Third Military Medical University, Chongqing 400038, China; E-Mails:;Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China; E-Mail:;Urology Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; E-Mails:

关键词: CoMFA;    CoMSIA;    QSAR;    indenoisoquinoline;    Top1 inhibitors;   

DOI  :  10.3390/ijms13056009

来源: mdpi

【 摘 要 】

Topoisomerase I is important for DNA replication and cell division, making it an attractive drug target for anticancer therapy. A series of indenoisoquinolines displaying potent Top1 inhibitory activity in human renal cell carcinoma cell line SN12C were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated, as well as some measures taken, including region focusing, bootstrapping and the “leave-group-out” cross-validation method. The satisfactory CoMFA model predicted a q² value of 0.659 and an r² value of 0.949, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic and H-bond acceptor descriptors, predicted a q² value of 0.523 and an r² value of 0.902. The models were graphically interpreted by contour plots which provided insight into the structural requirements for increasing the activity of a compound, providing a solid basis for future rational design of more active anticancer agents.

【 授权许可】

CC BY   
© 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.