QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: mol.107.041624v1 73/3/686    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Liang, H. Articles by Hasinoff, B. B. Search for Related Content PubMed PubMed Citation Articles by Liang, H. Articles by Hasinoff, B. B.

A Three-Dimensional Quantitative Structure-Activity Analysis of a New Class of Bisphenol Topoisomerase II Inhibitors

Faculty of Pharmacy, University of Manitoba, Winnipeg, Mannitoba, Canada (H.L., X.W., B.B.H.); and Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (J.C.Y.)

After 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 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 II inhibition suggests that the catalytic inhibition of topoisomerase II probably 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 by acting as catalytic inhibitors of topoisomerase II. 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 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.

Address correspondence to: Dr. Brian Hasinoff, Faculty of Pharmacy, University of Manitoba, Winnipeg, MB R3T 2N2, Canada. E-mail: b_hasinoff{at}umanitoba.ca