DIDEMNINS AND USTILOXINS AS PROBES OF CELL PROLIFERATION

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ABSTRACT: This is a renewal application of a twelve-year program (CA-40081) focusing on the total synthesis of natural products and analogs have potential use as anti-proliferative agents. The compounds we have chosen have been and will continue to be valuable tools for understanding and exploiting the processing which control cell proliferation They are especially important in study anti-proliferative mechanisms which may be novel or poorly understood, and in identifying possible new avenues for therapeutic intervention in proliferative diseases such as cancer. Two separate groups of natural products have been selected for study. We describe first our program to understand further the biological properties of the didemnin family of macrocyclic depsipeptides. Our previous efforts have considerably advanced the synthetic chemistry of these compounds. New initiatives in the didemnin area will focus on synthetic probe molecules: (1) to understand the striking sub-picomolar immunosuppressive activity of certain didemnins, (2) to identify the relevant receptor proteins, (3) to untangle the relationships between apoptotic, cytotoxic, immunosuppressive and protein biosynthesis inhibition activities, and (4) to develop less toxic didemnin pro-drugs. As a new venture, we propose to explore the ustiloxins, macrocyclic peptides which are potent inhibitors of tubulin polymerization. The ustiloxins are poorly understood in terms of tubulin binding site(s), effect(s) on mitosis, and levels of cytotoxicity. The synthetic chemistry of these compounds is also not well-developed. Therefore, we propose two synthetic approaches to the ustiloxins. Our strategy is an outgrowth of our accomplishments in the cyclopeptide alkaloid field. Beyond the initial total synthesis of ustiloxin D, we will disclose a flexible approach suitable for the synthesis of (A) ustiloxin congeners, (B) the closely-related phomopsins, and (C) a set of analogs which will be used to explore binding sites and structure-activity relationships. In addition to their appeal as synthetic targets, the ustiloxins hold promise as important probes for the entire peptide class of anti-tubulin natural products.