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.