PEPTIDES to Imidates and Back-Towards Bioavailibility

这项研究的目标是开发改进的化学方法，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。 我们的目标是开发的化学有其生物合成的起源，其中酶激活酰胺官能团对各种侧链的亲核攻击，导致参与酰胺的正式分子内环化脱水，导致恶唑啉和噻唑啉环的形成。 该提案的三分之一将集中于开发将肽不可逆地转化为杂环并保留Calpha和C β立体化学的合成方法。 多种α-和β-氨基酸的可用性允许合成定制的肽以产生所需的亚氨酸盐、硫代亚氨酸盐和相关结构。 将合成各种侧链保护的和未保护的肽，以检查效率，以及杂环光谱形成的区域和立体选择性。该提案的第二部分将侧重于开发可逆掩蔽肽中酰胺官能团的方法，以使其具有生物可利用性。 酰胺键将被转化为亚胺酯等，具有有利的膜转位性质以促进细胞和/或口服生物利用度，其中随后的水解使肽再生。 中性亚氨酸酯、硫代亚氨酸酯或类似骨架的膜转位性质应由于氢键供体和受体的数量的减少而显著改善，这与肽膜转位能力相关。 阳离子掩蔽酰胺的目的是利用新发现的主动转运系统来介导膜易位。 使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。剩余的具体目标将侧重于评价本项目中生产的杂环和无环亚胺酯和硫代亚胺酯产品的生物活性。 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。 在第一种和第三种情况下，这些化合物将分别在诺华和国家癌症研究所进行筛选。 在第二种情况下，将制备融合的杂环文库，并由我们的Scripps合作者Jamie威廉姆森评估它们与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.