Synthesis and Study of Natural and Non-natural Antiproliferative Agents

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DESCRIPTION (provided by applicant): Our laboratory is developing practical synthetic routes to families of chemically complex natural products that have been shown to inhibit the growth of human cancer cells. In this way, we are able to prepare large numbers of related structures (analogs) for evaluation as new chemotherapeutic agents, compounds with potentially improved properties that would be otherwise unavailable for study. 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 natural products families we study, which in many cases are not known. The dual impacts of this work, providing molecules for target binding and target identification, are of potentially great potential utility in the extraordinarily challenging problem of developing new cancer therapies. Indeed, many of our current front-line small-molecule therapies for cancer are natural products or were derived from natural products lead structures, and many important targets of cancer have been identified through the use of probes prepared by chemical modification of natural products. Among the classes of natural products we are studying are the cortistatins, a family of steroidal alkaloids isolated from a marine sponge that potently inhibit the proliferation of human umbilical vein endothelial cells; the daphniglaucins, unique plant-derived substances that have been shown to inhibit the growth of a lymphoma-derived cell line; the trioxacarcins, bacterial fermentation products with extremely potent inhibitory properties toward growing cancer cells and known to alkylate duplex DNA; salinosporamides, isolates from a marine bacterium that target the proteasome (also targeted by Velcade(R), an approved chemotherapeutic agent for multiple myeloma), and avrainvillamides, fungal natural products shown in our laboratory to target nucleophosmin, a protein whose mutation has been implicated in ~35% of all acute myelogenous lukemias (AMLs) and a novel target for chemotherapeutic intervention. PUBLIC HEALTH RELEVANCE: Many current front-line small-molecule therapies for cancer are natural products, or were derived from natural products as lead structures, and many important targets of cancer have been identified through the use of probes that are structural analogs of natural products; our research seeks to develop highly convergent, highly flexible synthetic routes to five different classes of natural products so as to enable large numbers of analogs to be synthesized and explored as potential leads for cancer therapy. These compounds would not be available for study by any other means. We also seek to use the chemistry we develop to synthesize chemical probes for the identification of the cellular targets of the natural products families we study, in cases where their targets are not known.