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Topoisomerase enzymes play a vital role in DNA strand management. Topoisomerase IIα in humans is known to promote the untangling of DNA and to be active in cell replication. Selectively inhibiting Topoisomerase in actively replicating cancer cells is a method of potential interest for the chemotherapy of cancer. This approach stems from research on naturally occurring inhibitors of Topoisomerase IIα that can be further altered and synthesized to better bind to the enzyme and hamper its function. This work started with a recently reported naturally occurring chemotherapy lead (1E,4E)-1,7-bis(4-hydroxyphenyl)hepta-1,4-dien-3-one, referred to as DHDK, found in mistletoe. This lead molecule was optimized to have molecular parameters that are more consistent with known median drug values as a correspondent for its physiochemical properties. The alteration of this chemical was evaluated for its docking with Topoisomerase IIα using MOE-2022 computational software (Chemical Computing, Ltd.) and the best added candidate was chosen for synthesis and testing. Here we report on the progress of synthesizing the altered lead molecule. This research was made possible by the funding of the Chemistry Department of Tennessee Technological University, Cookeville, TN.
Haynes et al. (Fri,) studied this question.