Synthesis Directed Toward Therapeutic Agents

描述（由申请人提供）：我们的计划是在化学方面的努力，主要解决化学合成中的重要问题。我们致力于设计和优化新的价值反应，甚至独立于特定的目标结构。然而，我们寻找新的合成方法往往受到特定的目标分子或目标结构类型的影响。目标分子的识别，通常从天然产物的大量菜单中提取，也有助于为实验室参与合成以及反应开发中的战略层面问题提供背景。我们在化学水平上选择目标的重要标准是（i）特定分子结构的固有挑战（复杂问题通常会带来冒险的解决方案）和（ii）方法学进步的机会。我们在选择项目时越来越强调潜在的翻译标准。我们有一个普遍的看法，小分子天然产物（SMNPs）作为合成的目标，提供了一个富有成效的平台，发现新的药物的潜在利益和价值的医学。我们也越来越相信，较大的结构（寡糖、多肽、蛋白质和糖蛋白）在化学合成的范围内，但需要注意的是，它们可能比从天然来源获得的对应物更均匀。此外，化学合成提供了获得独特结构的途径，其中可以通过SMNP本身不可用的类型的结构修饰来优化效力、治疗指数和一般功效。目前，我们已经推进了四种候选治疗药物的临床试验，追求上述的转化方式。 在我们的CA103823补助金的最终更新中，我们寻求扩大我们的migrastatin计划，这可能是迄今为止已知的最有前途的抗转移药物。我们希望实现另外两种SMNP：毛晶体和放线菌酸的全合成。此外，我们将总结一项计划，该计划涉及使用PSMA作为针对前列腺癌的疫苗的抗原靶标。其他生物学水平的靶标涉及参与基因调控的蛋白质基序“布罗莫结构域”。上一个赠款期促成了基于异腈化学的重大方法学进展。我们已经能够确定许多化学倾向的异腈，并将其应用于合成肽，包括那些含有叔ammonium键。尽管仍有障碍有待克服，但我们相信，在提案更新中，我们可以利用这些能力来创造我们所设想的“异腈连接”，这将对该领域产生重大影响。此外，我们希望研究其他未探索的可能反应的异腈环加成方式。如果我们成功了，我们所设想的发现可能会在有机合成中产生重大影响。我们非常有信心，上述合成和转化研究可以在最后的时间跨度内基本完成。

DESCRIPTION (provided by applicant): 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.