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Int. J. Mol. Sci. 2012, 13(5), 6009-6025; doi:10.3390/ijms13056009
Article

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

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1 Urology Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China 2 Department of Cell Biology, Third Military Medical University, Chongqing 400038, China 3 Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China Current address: Department of Urology, the 452nd Hospital of People’s Liberation Army, Chengdu 610021, China.
* Authors to whom correspondence should be addressed.
Received: 9 March 2012 / Revised: 4 May 2012 / Accepted: 11 May 2012 / Published: 18 May 2012

Abstract

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.
Keywords: CoMFA; CoMSIA; QSAR; indenoisoquinoline; Top1 inhibitors CoMFA; CoMSIA; QSAR; indenoisoquinoline; Top1 inhibitors
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Zhi, Y.; Yang, J.; Tian, S.; Yuan, F.; Liu, Y.; Zhang, Y.; Sun, P.; Song, B.; Chen, Z. Quantitative Structure-Activity Relationship Studies on Indenoisoquinoline Topoisomerase I Inhibitors as Anticancer Agents in Human Renal Cell Carcinoma Cell Line SN12C. Int. J. Mol. Sci. 2012, 13, 6009-6025.

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