A QSAR study of substituted benzo[a]phenazines as potential anticancer agents

A quantitative structure-activity relationship (QSAR) of a series of substituted benzo[a]phenazines, in regard to their anticancer activity, has been studied using the density functional theory (DFT) method, molecular mechanics method (MM+) and statistical method. Via a stepwise regression analysis, some main independent factors affecting the activity of the compounds were selected out, and then the QSAR equation was established. In this equation, the total net charge (QR) of the substituent (R) (excluding H atoms), the net charge (QC4) of the C atom at site 4 on A-ring, as well as the ratio (r=VR/SR) of the volume to the area of the substituent R are the main independent factors contributing to the anticancer activity of the compounds. The fitting correlation coefficient (R2) and the cross-validated coefficient (q2) values for the model established by this study are 0.815 and 0.745, respectively. The results suggest that among the three selected parameters in the QSAR equation, two are R's properties (QR and r) itself and one is the property (QC4) of C4 atom directly linked to R, and thus R should be a part of active zone. This simple equation can be used to estimate the anticancer activity for new compounds of this series of compounds by calculating these three independent parameters prior to synthesis. Based on this model, four new compounds with rather high anticancer activity have been theoretically designed and they are waiting for experimental verification.