Synthesis Directed Toward Therapeutic Agents

描述(由申请者提供)：我们的项目是化学方面的努力，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目标分子或目标结构类型的影响。目标分子的鉴定通常来自大量的天然产物，这也有助于为实验室参与合成和反应开发的策略层面的问题提供背景。我们在化学水平上选择目标的重要标准是(I)特定分子结构的内在挑战(复杂的问题往往需要冒险的解决方案)和(Ii)方法学进步的机会。我们越来越多地在项目选择中强调潜在的翻译标准。我们普遍认为，小分子天然产物(SMNPs)作为合成的目标，为发现新的具有潜在兴趣和医学价值的药物提供了一个富有成效的平台。我们也越来越相信，更大的结构(寡糖、多肽、蛋白质和糖蛋白)属于化学合成的范畴，但需要注意的是，它们可能比从自然来源获得的对应结构更均一。此外，化学合成提供了获得独特结构的途径，在这种结构中，效力、治疗指数和一般疗效可以通过SMNP本身无法获得的结构修饰来优化。目前，我们已经有四个候选治疗药物进入临床试验，追求上述转换方式。在我们CA103823授权的最后一次更新中，我们寻求扩大我们的米曲司汀计划，该计划可能是迄今为止最有希望的抗转移剂。我们希望实现另外两种SMNPs的全合成：毛晶和放线叶酸。此外，我们还将结束一个使用PSMA作为前列腺癌疫苗抗原靶的项目。其他生物水平的靶标包括与基因调控有关的蛋白质基序“溴域”。在前一批赠款期间，在异腈化学的基础上取得了重大的方法学进展。我们已经能够识别异腈的许多化学倾向，并将它们应用于多肽的合成，包括那些含有叔胺基键的多肽。尽管仍有障碍需要克服，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设想的“异腈结扎”，这可能会对该领域产生重大影响。此外，我们希望研究其他未知的异腈环加成方式的可能反应。如果我们成功了，我们设想的发现可能会对有机合成产生重大影响。我们非常有信心，上述综合和翻译研究可以在最后这段时间内基本完成。

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.