Abstract 3510: The molecular docking-based design and biological evaluation of a novel series of bisintercalating DNA-binding bisanthrapyrazole compounds containing amine linkers

Abstract

Abstract Anticancer drugs that bind to DNA and inhibit DNA-processing enzymes represent an important class of anticancer drugs. In order to find stronger DNA binding and more potent cytotoxic compounds, a series of bisanthrapyrazole derivatives containing amine linkers were designed and evaluated by molecular docking techniques. Because the anthrapyrazoles are unable to be reductively activated like doxorubicin and other anthracyclines, they should lack the cardiotoxicity exhibited by this class of antitumor agent. The concentration dependent increase in DNA melting temperature was used to determine the strength of DNA binding and the bisintercalation potential of the newly synthesized analogs. These compounds were also assessed for their ability to inhibit: 1) the growth of the human erythroleukemic K562 cell line; 2) the decatenation activity of DNA topoisomerase IIα; 3) the relaxation activity of DNA topoisomerase I. Finally, the compounds were evaluated as topoisomerase IIα poisons by measuring the topoisomerase IIα-mediated double strand cleavage of DNA. All of the bisanthrapyrazoles inhibited K562 cell growth in the low to submicromolar concentration range and also strongly inhibited the decatenation activity of topoisomerase IIα. However, none of the bisanthrapyrazole compounds act as topoisomerase IIα poisons. In conclusion, a novel group of bisanthrapyrazole compounds were designed, synthesized, and biologically evaluated as potential anticancer agents. Support: CIHR, a Canada Research Chair in Drug Development to B.B.H., a National Institutes of Health grant CA090787 to J.C.Y. and the Dishman Foundation at Southwestern University. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3510.