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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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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 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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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