Synthesis and Study of Natural and Non-natural Antiproliferative Agents

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 DESCRIPTION (provided by applicant): Our laboratory is focused on the development of practical synthetic routes to structurally complex natural products that have been shown to inhibit the growth of human cancer cells. Through the use of highly efficient, modular strategies, we are able to prepare large numbers of related structures (analogs) for evaluation as new chemotherapeutic agents, with potentially improved therapeutic or pharmacokinetic properties. The synthetic routes we are developing also allow us to prepare chemical probes that are useful for the identification of the cellular targets of the families of natural products that we study, wich in many cases are unknown. Our research thus aims to address two critical challenges facing the development of novel cancer therapies by both providing new molecules for evaluation as well as elucidating the cellular mechanisms underpinning their biological activities. Indeed, many current front-line small-molecule therapies for cancer are natural products or are derivatives of natural products, and many important cellular targets for therapeutic intervention have been identified through the use of probes prepared by the chemical modification of such molecules. Among the classes of natural products we are studying are the trioxacarcins, bacterial fermentation products with extremely potent inhibitory properties toward growing cancer cells and known to alkylate duplex DNA; avrainvillamides, fungal natural products shown in our laboratory to target nucleophosmin and exportin-1, two proteins known to play key roles in the initiation and progression of acute myelogenous lukemia (AML) and emerging targets for chemotherapeutic intervention; and tetracyclines, bacterial fermentation products initially developed as antibiotics that also exhibit poorly understood anti-cancer and anti-inflammatory activities in human cells.