Synthesis, biological evaluation and modeling studies of terphenyl topoisomerase IIα inhibitors as anticancer agents

We report the synthesis and evaluation of a series of novel terphenyls. Compound 17 had the most potent anticancer activity, indicating that the phenolic hydroxyl was a key group. A DNA relaxation test showed that compound 17 had a strong inhibitory effect on TOP2α, but not on TOP1, which was consistent with the docking analysis results. We performed a 3D-QSAR study using CoMFA and CoMSIA to determine, for the first time, the chemical-biological relationship in the inhibition of TOP by terphenyls. The CoMFA and CoMSIA model had good modeling statistics: leave-one-out q2 of 0.605 and 0.622, r2 of 0.998 and 0.994, and r2pred (test set) of 0.742 and 0.660. These results suggest that the ortho-phenolic hydroxyl on ring A is important for producing terphenyls with more efficacious activity. [Display omitted] •Synthesis and evaluation of a series of novel terphenyls inhibited TOP.•The results of 3D-QSAR analysis were consistent with docking analysis.•The contour maps provide useful insight into designing novel TOP inhibitory.