Synthesis of Antiinfective Agents

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DESCRIPTION (provided by applicant): The long term goals of our laboratory involve the achievement of advances in the capabilities in chemical synthesis and the applications of these advances to problems of biological and even medicinal import. At the chemistry level, we select novel and challenging small molecule natural products structures, which will serve to stimulate and exemplify the value of new strategies and new reaction methodologies. In this facet of our "small molecule" work, we place particular emphasis on conciseness of approach, convergence, and stereocontrol. In parallel we have a program addressed to the chemical synthesis of complex oligosaccharides, in the context of polypeptide or protein like conjugates. In this effort, we place particular emphasis on novel glycosylation protocols and, seek out particular retrosynthetic disconnections and protection strategies which enable conciseness of the synthetic effort. In this program we seek to enlarge upon our capacity to build complex oligosaccharides into the context of substantial polypeptide or even protein settings. For this AI-16943-25-29 grant period, we have identified eight (8) programs for exploration: (1) migrastatin - as its name implies, this compound is reported to prevent tumor cell migration. As such, it might provide the basis for a significant drug candidate in angiogenesis; (2) brasilicardin - an immunosuppressive agent; (3) garsubellin - this compound is exemplary of a fascinating series of non-peptidal small molecules which exhibit neuronal growth factor activity; (4)tashironin - this compound is substantially dissimilar to garsubellin. It also exhibits non-peptidal NGF activity; (5) NG0187 - this compound is a polyoxygenated steroid-like system which also exhibits non-peptidal nerve growth factor activity; (6) Asparagine linked glycopolypeptide constructs which simulate the key structural features of PSA (prostate specific antigen); (7) the synthesis of constructs which simulate the key features of GP120. Aside from the chemical challenge, implicit in this goal is the hope to induce an antibody response which could be of value in progression of the evolution of AIDS disease; (8) A long term goal of the complex glycoconjugate program is the total synthesis of a functional erythropoietin (EPO).