3D-QSAR studies of cytotoxic heterocyclic quinones using calculated reduction potential

Most quinones with 2–4 fused aromatic rings exhibit cytostatic activity via DNA intercalation that causes enzyme blockade and reading errors during the replication process. The redox activity of quinones plays a role in the DNA cleavage mediated by oxygen or sulfur radicals. To develop novel anticancer agents based on nitrogen‐containing heterocyclic quinones, pharmacophore models of representative molecules with high activity were generated using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). A series of compounds were aligned to the selected pharmacophore model and the 3D‐quantitative structure activity relationships (QSAR) were analyzed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), resulting in q2 values of 0.734 and r2 of 0.951, and q2 of 0.803 and r2 of 0.917, respectively, in each study. In addition, the potentials for the one‐electron reduction of quinones were calculated from LUMO energies using the semi‐empirical Austin Model 1 (AM1) method. These also showed a good correlation (r2 of 0.816) with the cytotoxic activities of the quinones. Drug Dev Res 2009. © 2009 Wiley‐Liss, Inc.