Synthesis and Study of Natural and Non-natural Antiproliferative Agents

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DESCRIPTION (provided by applicant): In this competitive revision proposal we seek to pursue as a new and additional specific aim the development of practical synthetic routes to the cortistatin family of alkaloids, broadly defined. Our approach is based on a versatile advanced synthetic template from which a diverse array of natural and unnatural cortistatins can be rapidly prepared. Analogs widely variant in the A and D rings, as well as along the skeleton connecting these rings will be prepared. We plan to evaluate the effects of the compounds we prepare upon the growth of HUVECs and thereby to develop a comprehensive profile of structure-activity relationships within the class. We also plan to synthesize molecular probes as tools for the identification of protein target(s) of the cortistatins. We propose to synthesize key intermediates for the production of cortistatins in multi-gram amounts from which we will pursue the preparation of large numbers of cortistatin analogs that otherwise would be inaccessible. This proposal is a competitive revision application. Notice Number: NOT-OD-09-058 n Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revisions Applications PUBLIC HEALTH RELEVANCE: Angiogenesis is the process of new blood vessel growth from existing vasculature, and unregulated angiogenesis has been implicated in a variety of diseases including atherosclerosis, macular degeneration, and many forms of cancer. The development of small-molecule inhibitors of angiogenesis provides one of the most promising avenues of therapy for patients with these illnesses. The overall goal of this project is to develop a means to synthesize in the laboratory analogs of the extremely potent natural angiogenesis inhibitors known as the cortistatins, which may serve as lead structures in pharmaceutical design, as well as biological probes to elucidate the protein target(s) of these compounds in vivo.