MOLECULAR METAPHORS IN BIOORGANIC CHEMISTRY

生物有机化学中的分子隐喻

• 批准号: 3302888
• 负责人: MICHAEL C PIRRUNG
• 金额: $ 14.12万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3302888
• 关键词: Fusarium; carboxylate; chelating agents; chemical binding; chemical group; chemical structure; chemical synthesis; enol; enzyme inhibitors; enzyme model; enzyme structure; enzyme substrate analog; glutamate receptor; isocitrate dehydrogenase; ketoacid; malate dehydrogenase; metalloenzyme; mycotoxins; nuclear magnetic resonance spectroscopy; phosphoenolpyruvate; pyruvate decarboxylase; pyruvate kinase; racemization; stereoisomer; triose phosphate isomerase

The long term goal of this research is to develop functional groups ("molecular metaphors") which can be used to replace existing functional groups in, primarily, small molecules which interact with biological targets. These metaphors can be used in the design of new molecules to act as enzyme inhibitors, receptor antagonists, etc., and may also prove useful in the elucidation of some functions of biological targets. Along with the design element, specific methods for the synthesis of the metaphors in the biological context in which they are to be applied must be developed. The ultimate embodiment of this work would be a "kit" of structures (and simple procedures to prepare them) which could be plugged, cassette-like, into a molecule of interest to modify its properties in a predictable way. This will enable chemists to more efficiently make new pharmaceuticals. This grant focuses on two functional groups widely distributed in biological molecules, enols and carboxylate groups, generally, but alpha-keto acids and their enols, specifically. It is intended to develop the vinyl fluoride functionality as an equivalent for enols, and to use this equivalence to develop inhibitors and stereochemical probes for enol-utilizing enzymes. The hypothesis that the stereochemistry of enzyme-bound enol intermediates can be elucidated by study of the properties of vinyl fluoride analogues will be tested. It is also intended to elucidate the basis for inhibition of pyruvate dehydrogenase complex by the natural product moniliformin. The inhibition of other pyruvate/thiaminpyrophosphate enzymes by moniliformin and analogues will be evaluated. The ability of squaric and deltic acid structures to substitute for carboxyl groups in enol-utilizing enzymes and in receptors will be studied. Methods for preparation of squaric and deltic acid derivatives will also be developed in this part of the project.

这项研究的长期目标是开发功能团 （“分子隐喻”）可用于取代现有的功能 主要是与生物相互作用的小分子中的基团 目标。 这些隐喻可用于设计新分子以发挥作用 作为酶抑制剂、受体拮抗剂等，也可能被证明是有用的 阐明生物靶标的某些功能。 随着 设计元素，隐喻合成的具体方法 必须开发它们应用的生物学背景。 这 这项工作的最终体现将是一个结构“套件”（以及简单的 准备它们的程序）可以像盒式磁带一样插入 感兴趣的分子以可预测的方式改变其性质。 这 将使化学家能够更有效地制造新药物。 这笔赠款重点关注广泛分布在 通常是生物分子、烯醇和羧酸基团，但是 特别是α-酮酸及其烯醇。 其目的是开发 氟乙烯官能团作为烯醇的等价物，并使用 这相当于开发抑制剂和立体化学探针 烯醇利用酶。 假设立体化学 酶结合的烯醇中间体可以通过研究来阐明 将测试氟乙烯类似物的性质。 它还旨在阐明抑制丙酮酸的基础 由天然产物念珠菌素脱氢酶复合物。 抑制作用 其他丙酮酸/硫胺焦磷酸酶的串珠福明和 将评估类似物。 方酸和三角酸的能力 取代烯醇利用酶中的羧基的结构和 将研究受体中的情况。 方晶石的制备方法 该项目还将开发三角酸衍生物。