Development of topoisomerase I inhibitors as anticancer agents
Currently, the only topoisomerase I (top1) inhibitors approved by the U.S. Food and Drug Administration for the treatment of cancer are topotecan and irinotecan, synthetic derivatives of the natural product camptothecin. Although these drugs serve to validate top1 as a therapeutic target, the pharmacokinetic properties of the camptothecin derivatives are less than ideal and necessitate the development of novel, non-camptothecin top1 inhibitors. The indenoisoquinolines are a novel class of top1 inhibitors that display potent anticancer activity. The mechanism of action of these molecules involves the stabilization of a ternary complex consisting of a drug molecule, DNA, and top1. This classifies the indenoisoquinolines as top1 poisons with a mechanism of action similar to the camptothecins. Unlike the camptothecins, however, the indenoisoquinolines have improved pharmacokinetic properties such as increased hydrolytic stability and more persistent ternary cleavage complexes upon drug removal, making them ideal candidates for drug development. The described research focuses on the design, synthesis, and structure-activity relationships (SAR) of novel indenoisoquinolines as both top1 inhibitors and anticancer agents. The discovery of highly active nitrated indenoisoquinolines is described along with their rational design and optimization providing novel lead compounds more potent than camptothecin. Details concerning the replacement of the methylenedioxy ring with methoxy groups; the optimization of nitrated, methoxy-substituted indenoisoquinolines; and the optimization of the indenoisoquinoline 9-position are described. Furthermore, a novel hypothetical model utilizing charge complementarity and pi-stacking interactions to aid the rational design of top1 inhibitors is reported in conjunction with standard structure-based drug design. A novel synthesis of unsubstituted and substituted indenoisoquinolines is described along with the use of the key intermediates from this work in the design and synthesis of bisindenoisoquinolines. The optimization of lactam side chain length for potent biological activity was performed and a discourse on the SAR of indenoisoquinolines in a hollow fiber assay is provided.
Cushman, Purdue University.
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