PEPTIDES to Imidates and Back-Towards Bioavailibility

这项研究的目标是发展改进的化学，将简单的肽转化为缺乏或减少酰胺官能团数量的产品，在某些情况下是暂时的。我们旨在发展的化学源于生物合成，其中酶激活酰胺官能团，通过各种侧链进行亲核攻击，导致参与酰胺的分子内正式环脱水，从而形成恶唑啉和噻唑啉环。该提案的三分之一将集中于开发合成方法，将多肽转化为不可逆的杂环，并保留α和β的立体化学。各种α -和β -氨基酸的可用性允许合成定制的肽，以产生所需的硫代酸盐，硫代酸盐和相关结构。多种侧链保护和无保护肽将被合成，以审查效率，以及区域和立体选择性的形成的杂环光谱。本提案的第二部分将侧重于开发方法，以可逆地掩盖肽中的酰胺功能基团，使其具有生物可利用性。酰胺键将转化为咪酯或类似物，具有有利的膜易位特性，以促进细胞和/或口服生物利用度，随后的水解再生肽。中性酰咪酯、硫代酰咪酯或类似骨架的膜易位性能会因氢键供体和受体数量的减少而显著改善，这与肽膜易位能力有关。阳离子屏蔽酰胺旨在利用新发现的主动运输系统来介导膜易位。使多肽和蛋白质普遍具有生物可利用性是这一特定目标的长期目标。剩余的具体目标将集中于评估该项目生产的杂环和无环亚咪酯和硫代亚咪酯产品的生物活性。我们将专注于抗菌活性，特别是对耐药菌株，RNA结合和抗肿瘤活性。在第一个和第三个病例中，这些化合物将分别提交给诺华公司和国家癌症研究所进行筛选。在第二种情况下，我们将制备融合杂环文库，并由我们的Scripps合作者Jamie Williamson评估它们与RNA靶标的相互作用。

The goal of this research is to develop improved chemistry to transform simple peptides into products lacking or with reduced numbers of amide functional groups, in some cases temporarily. The chemistry we aim to develop has its origins in biosynthesis, wherein enzymes activate amide functional groups towards nucleophilic attack by various side chains leading to the formal intramolecular cyclodehydration of the participating amide resulting in oxazoline and thiazoline ring formation. One third of this proposal will focus on developing synthetic methodology to convert peptides into heterocycles irreversibly with retention of Calpha and Cbeta stereochemistry. The availability of a wide variety of alpha- and beta-amino acids allows the synthesis of peptides tailored to produce the desired imidates, thiomidates and related structures. A variety of side chain protected and unprotected peptides will be synthesized to scrutinize the efficiency, as well as the regio- and stereoselectivity of the formation of a spectrum of heterocycles. The second portion of this proposal will focus on developing methodology to reversibly mask amide functional groups in peptides to make them bioavailable. Amide bonds will be converted to imidate esters, or the like, with favorable membrane translocation properties to facilitate cellular and/or oral bioavailability, where subsequent hydrolysis regenerates the peptide. The membrane translocation properties of neutral imidate, thioimidate or similar backbones should be dramatically improved as a result of the reduction in the number of hydrogen bond donors and acceptors, which correlates with peptide membrane translocation ability. The cationic masked amides aim to take advantage of a newly discovered active transport system to mediate membrane translocation. Making peptides and proteins generally bioavailable is the long term goal of this specific aim. The remaining specific aim will focus on evaluating the biological activity of the heterocyclic and acyclic imidate and thioimidate products produced in this project. We will concentrate on antibacterial activity, particularly towards resistant strains, RNA binding, and antitumor activity. In the first and the third cases, these compounds will be submitted to screens at Novartis and the National Cancer Institute, respectively. In the second case, fused heterocyclic libraries will be prepared and their interactions with RNA targets evaluated by our Scripps collaborator Jamie Williamson.