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    Awarded Grants
    Total Synthesis of Apoptolidin and Analogs

    Scientific Abstract:
    Total Synthesis of Apoptolidin and Analogs BACKGROUND: Apoptolidin possesses impressive and selective anti-cancer activity, inducing apoptosis at nanomolar concentrations in cells transfected with the adenovirus E1A oncogene, but not in normal cells or fibroblasts. As a potent inhibitor of F0F1-ATPase and a selective apoptosis-inducing agent, the potential medicinal applications of apoptolidin in cancer treatment are enticing. The compound is accessible through fermentation, but it transacylates readily, even under the mild conditions used in some chemical isolation procedures or biological assays. This instability presents a major obstacle to the development of a useful apoptolidin-based cancer treatment. OBJECTIVES/HYPOTHESIS: Our approach to the apoptolidin aglycone will be maximally convergent. We also anticipate that the carefully planned protection strategy will aid in preventing translactonization to isoapoptolidin, because the orthogonal C-20 protecting group can be left in place until just prior to biological assay. Moreover, the modular experimental design will allow the construction of analogs, including those that address the isomerization concern. SPECIFIC AIMS: (1) To develop and implement an efficient, maximally convergent synthesis to the macrolide of apoptolidin; (2) to construct analogs of apoptolidin that inhibit the deleterious apoptolidin/isoapoptolidin isomerization; and (3) to evaluate these analogs in relation to apoptolidin, by molecular modeling and cytotoxicity assay. STUDY DESIGN: A synthesis that relies on the construction of four quadrants, which are stitched together late in the synthesis and can provide rapid access to numerous structural analogs, is presented. Fifteen steps are proposed in the longest linear sequence, and 36 steps overall. This efficient synthesis incorporates novel methodology, including chemistry developed or under development in the Molander laboratory. CANCER RELEVANCE: Apoptolidin is among the most potent anti-cancer compounds tested by the National Cancer Institute to date. The primary aim of these studies is to carry out an efficient synthesis of this molecule. Upon completion of the apoptolidin aglycone, the long term goal of this work is to incorporate structural diversity into the apoptolidin molecule, both in the macrolactone core and in the carbohydrate appendages. Structure-activity relationship results obtained from assay of these analogs will drive the development of chemotherapeutics that are both potent and stable.

    Lay Abstract:
    Cancer chemotherapy has advanced tremendously in recent decades, but two significant shortcomings persist. First, indiscriminate toxicity of the drugs often causes serious side effects in cancer patients. Secondly, tumor cells can acquire resistance even to the most potent drugs, leading to treatment failure. The discovery of improved cancer therapies can help to overcome these downfalls. One novel strategy being explored is the development of tumor cell-selective drugs. Toward this aim, we plan to study the molecule apoptolidin, one of the most potent anti-cancer compounds tested by the National Cancer Institute to date. Apoptolidin has been shown to effectively kill certain types of cancer cells, while leaving normal cells untouched. Although this compound can be obtained from bacterial cultures, it is quite unstable and becomes deactivated even under mild conditions used for isolation or biological assay. Our primary aim is to devise and implement a practical and efficient total chemical synthesis of apoptolidin. Because apoptolidin can be constructed from defined chemical blocks, a diverse range of similar molecules can be constructed with the ultimate goal of creating a more stable compound.