Received for publication September 11, 2007.
Revised November 19, 2007.
Accepted for publication November 28, 2007.

A Three-dimensional Quantitative Structure-activity Analysis of a New Class of Bisphenol Topoisomerase II Inhibitors

Abstract

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

Key words: Structure-activity relationships and modeling, Mechanisms of cell killing/apoptosis, Topoisomerases