Abstract
Based on the topoisomerase IIα 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 IIα. 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 IIα correlated well with their potency as ATPase inhibitors. None of the 40 compounds significantly increased levels of the topoisomerase IIα-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 IIα-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 IIα expression displayed cross-resistance to NSC348400, NBSC348401, and NSC348402, whereas an MDR1 line was fully sensitive. These results suggest that topoisomerase IIα is a functional cellular target for most of these substituted purine compounds and that these compounds do not display MDR1 liability.
Footnotes
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↵1 The structures and names of all the National Cancer Institute NSC numbered compounds used in this study may be found at the following website: http://129.43.27.140/ncidb2/.
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This work was supported by the Canadian Institutes of Health Research, the Canada Research Chairs program, the Province of Manitoba, through the Manitoba Research and Innovation Fund and a Canada Research Chair in Drug Development (for B.H.) and by TopoTarget A/S.
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ABBREVIATIONS: HPLC, high-pressure liquid chromatography; kDNA, kinetoplast DNA; 3D, three-dimensional; QSAR, quantitative structure-activity relationship; CoMFA, comparative molecular field analysis; CoMSIA, comparative molecular similarity index analysis; ICRF-187, dexrazoxane; ICRF-193, 4-((2R,3S)-3-(3,5-dioxopiperazin-1-yl)butan-2-yl)piperazine-2,6-dione; ICRF-154, 4-(2-(3,5-dioxopiperazin-1-yl)ethyl)piperazine-2,6-dione; F 11782, tafluposide.
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↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received May 18, 2006.
- Accepted July 31, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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