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A Three-Dimensional Quantitative Structure-Activity Relationship Study of the Inhibition of the ATPase Activity and the Strand Passing Catalytic Activity of Topoisomerase II by Substituted Purine Analogs

TopoTarget A/S, Copenhagen, Denmark (L.H.J., M.G.); Department of Pathology, Diagnostic Centre RH5431, Copenhagen University Hospital, Copenhagen, Denmark (L.H.J., M.S.); Developmental Therapeutics Program, National Cancer Institute at Frederick, Frederick, Maryland (R.S.); and Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada (H.L., B.B.H.).

Based on the topoisomerase II catalytic inhibitory activity of a previous hit compound, NSC35866, we screened 40 substituted purines or purine-like compounds from the National Cancer Institute repository for their ability to inhibit the ATPase activity of human topoisomerase II. Several compounds, including NSC348400, NSC348401 and NSC348402, were inhibitory at submicromolar concentrations. Three-dimensional quantitative structure-activity relationship models using comparative molecular field and comparative molecular similarity indices analyses were constructed using 24 of these compounds. The ability of 10 selected compounds to inhibit the complete DNA strand passage reaction of topoisomerase II correlated well with their potency as ATPase inhibitors. None of the 40 compounds significantly increased levels of the topoisomerase II-DNA covalent complex, suggesting that they functioned as catalytic topoisomerase II inhibitors and not as topoisomerase II poisons. Although some of these compounds could antagonize the effect of etoposide on the level of topoisomerase II-DNA covalent complex formation in vitro, in contrast to NSC35866, they were not capable of antagonizing etoposide-induced cytotoxicity and DNA strand breaks in cells. Two independently selected human SCLC cell lines with reduced topoisomerase II expression displayed cross-resistance to NSC348400, NBSC348401, and NSC348402, whereas an MDR1 line was fully sensitive. These results suggest that topoisomerase II is a functional cellular target for most of these substituted purine compounds and that these compounds do not display MDR1 liability.

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

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