Our program is an effort in chemistry, primarily addressing issues of importance in chemical synthesis. We work on the design and optimization of new reactions of value, even independent of a particular goal structure. However, our searches for new synthetic methods are often influenced by particular target molecules or target structural types. The identification of target molecules, often drawn from the vast menu of natural products, also helps to provide a context for engaging the lab in strategy level questions in synthesis, as well as in reaction development. Important criteria in our target selections at th chemistry level are (i) inherent challenges of particular molecular structures (complex problems often invite venturesome solutions) and (ii) opportunities for methodology advances. Increasingly, we have emphasized potential translational criteria in our project selections. We have a general view that Small Molecule Natural Products (SMNPs) as targets of synthesis, provide a productive platform for discovery of new agents of potential interest and value in medicine. Increasingly, we also have gained confidence that larger structures (oligosaccharides, polypeptides, proteins and glycoproteins) are within the purview of chemical synthesis with the caveat that they may be more homogeneous than counterparts obtained from natural sources. Moreover, chemical synthesis offers access to unique structures in which potency, therapeutic indices and general efficacy might be optimized via structural modification of a type not available from the SMNP itself. Presently, we have advanced four therapeutic candidates to clinical trials, pursuing the translational modality described above. In this proposed final renewal of our CA103823 grant, we seek to expand upon our migrastatin program, which has led to what is probably the most promising antimetastatic agent thus far known. We hope to realize the total syntheses of two other SMNPs: maoecrystal and actinophyllic acid. In addition, we will bring to conclusion a program involving the use of PSMA as the antigenic target of a vaccine directed to prostate cancer. Other biologic level targets involve the protein motif "bromodomain" which is involved in gene regulation. The previous grant period enabled major methodological advances, based on the chemistry of isonitriles. We have been able to identify many chemical proclivities of isonitriles and applied them to the synthesis of peptides, including those containing tertiary amidic linkages. Though obstacles remain to be overcome, we are confident that in the proposal renewal we can capitalize on these capabilities to create what we envision will emerge as "isonitrile ligation," which can have significant impact on the field. Moreover, we hope to investigate additional unexplored possible reactions of isonitrile cycloaddition modalities. If we are successful, the findings we envision could be of large consequence in organic synthesis. We are quite confident that the synthetic and translational research described above can be substantially completed in this concluding time span.
The proposal brings to bear the resources of target directed organic synthesis to create complex small molecule and biologic level entities with opportunities for translation to medicine. Target structures include: analogs of migrastatin, maoecrystal, actinophyllic acid, a PSMA-based prostate cancer vaccine, follicle stimulating hormone (FSH), and the bromodomain of ATAD2.
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