TOTAL SYNTHESIS OF THE CYTOTOXIN UCS1025A AND DERIVATIVES THEREOF FOR USE AS ANT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Telomerase inhibitors are a distinctive class of cytotoxic compounds that have found recent success as chemotherapies. One of the newest members of this class, UCS1025A, is a pentacyclic polyketide that contains a unique furropyrrolizidine subunit. This compound has been identified as both a telomerase inhibitor and an antibiotic. However, its oxidized derivative, UCS1025B, shows minimal activity in each of these assays. This presents the medicinal chemist with a unique insight into the structure-activity relationship of these molecules and merits further exploration. Therefore, the primary objective of this proposal will be the development of a practical synthetic sequence that can be used to produce gram quantities of UCS1025A. Furthermore, the sequence will allow for the facile production of simple derivatives of the parent compound, so structure-activity relationships can be determined. Once synthesized, UCS1025A and its derivatives will be tested for their ability to inhibit telomerase both in vitro and in vivo. The ultimate goal of this project will be the development of a novel telomerase inhibitor that could be used as a chemotherapeutic agent.