PEPTIDES to Imidates and Back-Towards Bioavailibility

这项研究的目标是开发改进的化学方法，将简单的多肽转化为缺少或减少酰胺官能团的产品，在某些情况下是暂时的。我们致力于发展的化学起源于生物合成，在生物合成中，酶激活酰胺官能团，通过各种侧链进行亲核攻击，导致参与的酰胺在分子内进行正式的环脱水，从而形成恶唑啉和噻唑啉环。这项提案的三分之一将专注于开发合成方法，在保留Calpha和Cβ立体化学的情况下将多肽不可逆地转化为杂环。各种α-和β-氨基酸的可获得性使得合成多肽成为可能，以产生所需的酰亚胺、硫代咪酸酯和相关结构。将合成各种侧链保护和非保护的多肽，以考察杂环光谱形成的效率以及区域和立体选择性。该提案的第二部分将侧重于开发方法学，以可逆地掩蔽多肽中的酰胺官能团，使其具有生物利用度。酰胺键将被转化为具有良好的膜转移性能的亚胺酸酯等，以促进细胞和/或口服的生物利用度，其中随后的水解会重新生成多肽。中性酰亚胺、硫代酰亚胺或类似骨架的膜转运性能会因为氢键供体和受体数目的减少而显著改善，这与肽膜转运能力有关。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的转运。使多肽和蛋白质在生物上普遍可用是这一特定目标的长期目标。剩下的具体目标将侧重于评价本项目生产的杂环和非环酰亚胺和硫代亚胺产品的生物活性。我们将集中于抗菌活性，特别是对耐药菌株、RNA结合和抗肿瘤活性的研究。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的筛查。在第二种情况下，将制备融合杂环库，并由我们的斯克里普斯合作者杰米·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.