DIDEMNINS--SYNTHETIC STUDIES AND MECHANISM OF ACTION

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The didemnins are cyclic depsipeptides having immunosuppressive, antiviral and antitumor activities. The most potent congeners have exceptional antiproliferative potency (IC50 = 1-10nM) with intact cell viability. The mechanistic basis of the biological activities of didemnins is still uncertain; however, it is believed that didemnins exert their effects through a mechanism which is distinct from that of other immunosuppressive agents such as cyclosporin A, FK-506 or rapamycin. This project seeks to study and clarify the structural and mechanistic basis of the biological properties of the didemnins. The primary goal is the synthesis of novel didemnin analogs containing systematic structural modifications. Testing of these analogs will allow for the further development of a structure-activity relationship (SAR) profile. The second goal is the total synthesis of didemnin congeners which have been recently reported. Synthetic routes to these novel compounds will allow for biological testing and exploration of their potential as medicinal agents. The third goal is the preparation of synthetic didemnin for study by outside collaborators. These investigations will focus on conformational studies of biologically active didemnin analogs and derivatives, as well as interactions between didemnins and receptor proteins. In conclusion, this research is designed to investigate the biological activities of the didemnin cyclic depsipeptides through a program of chemical synthesis and biological evaluation. After the structural and mechanistic issues surround the potent antiproliferative and antitumor activities of didemnins have been clarified, it will be possible to evaluate more thoroughly the medicinal potential of this family of natural products.