Abstract

After the identification of a new lead bisphenol compound that had good topoisomerase IIα (EC 5.99.1.3) inhibitory activity, a series of bisphenol analogs were synthesized and tested to identify the structural features that were responsible for their activity. The bisphenols represent a new structural class of topoisomerase II inhibitor that potently inhibited the growth of Chinese hamster ovary and K562 leukemia cells in the low micromolar range. The fact that cell growth inhibition was significantly correlated with topoisomerase IIα inhibition suggests that the catalytic inhibition of topoisomerase IIα probably contributed to their growth inhibitory activity. Only one of the bisphenols (O3OH) tested significantly induced topoisomerase IIα-mediated cleavage of DNA. Most of the bisphenols displayed only low-fold cross-resistance to a K562 subline containing reduced levels of topoisomerase IIα Thus, it is likely that most of the bisphenols inhibited cell growth, not by acting as topoisomerase II poisons, but rather by acting as catalytic inhibitors of topoisomerase IIα. Three-dimensional quantitative structure-activity analysis (3D-QSAR) was carried out on the bisphenols using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to determine the structural features responsible for their activity. The CoMSIA analysis of the topoisomerase IIα inhibitory activity yielded a statistically significant model upon partial least-squares analyses. The 3D-QSAR CoMSIA analysis showed that polar meta hydrogen bond acceptor substituents on the phenyl rings favored inhibition of topoisomerase IIα. For the hydrogen bond donor field, para- and meta-substituted hydroxyl groups favored inhibition. Hydrophobic substituents on the bridge atoms disfavored inhibition.