SYNTHESIS OF BORON ANALOGS OF NATURAL NUCLEOSIDES

天然核苷硼类似物的合成

• 批准号: 3468215
• 负责人: MICHAEL GROZIAK
• 金额: $ 9.39万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3468215
• 关键词: adenosine deaminase; antineoplastics; antiviral agents; boron; chemical structure; chemical substitution; drug design /synthesis /production; enzyme activity; enzyme inhibitors; heterocyclic compounds; hydrogen bond; nucleoside analog

The project is designed to explore the chemistry of boron-containing purine ribonucleoside analogs with the long-term objective of demonstrating that the judicious positioning of the boron atom in the bicyclic ring heterocyclic system results in the formation of reasonably stable and quite interesting derivatives. The results of this project should serve to illustrate the concept of substituting a boron-oxygen single bond for a naturally-occurring carbon-nitrogen double bond, or of a boron-nitrogen single bond for a naturally-occurring carbon-carbon double bond to provide stable analogs possessing unique and useful properties. In specific, the target compounds of this proposal are expected to be inhibitors of the enzyme adenosine deaminase, by virtue of the placement of the boron atom at that carbon-atom position which is deaminated in vivo. The formation of a tetrahedral borate moiety at the enzyme's active site is proposed, and should result in the process known as transition-state analog inhibition. Inhibitors of adenosine deaminase are of importance in potentiating the effect of the antitumor agent arabinosyl-adenosine. In addition to the specific aim of developing ADase inhibitors, this work will provide a new class of stable boron-containing purine aglycon and nucleoside derivatives, for study in a variety of health-related areas. The examination of potential antitumor, antibacterial, and especially antiviral activities of these nucleosides will be of great interest. The examination of hydrogen-bonding schemes and the potential for incorporation in to the cellular DNA br RNA pools are other aspects expected to arise from this work. The present proposal seeks to prepare some representative members of this new class of nucleoside analogs in sufficient quantities for a detailed examination of their physicochemical properties and for a determination of enzymatic activity as well. The design of these analogs is based upon their similarity to known boron heterocycles of proven hydrolytic stability and upon their energy-stabilizing locus of the boron atom at the 6-position (purine ring numbering) of the bicyclic ring. The methods to be used in achieving their synthesis are based upon a sequential halogen-metal exchange methodology coupled with documented dehydrative ring-closure methodologies of arylboronic acid compounds.

该项目旨在探索含硼的嘌呤的化学反应 核糖核苷类似物的长期目标证明 硼原子在双环环中的明智定位 杂环系统导致形成合理的稳定和完全 有趣的衍生物。 该项目的结果应用于 说明将硼 - 氧单键取代的概念 天然存在的碳氮双键或硼氮键 单键，用于自然出现的碳碳双键以提供 具有独特且有用的特性的稳定类似物。 具体而言 预计该提案的目标化合物将是抑制剂 酶腺苷脱氨酶，借助硼原子的放置 该碳原子位置在体内被脱离。 形成 提出了酶的活性部位的四面体硼酸盐部分，并 应导致称为过渡态类似抑制的过程。 腺苷脱氨酶的抑制剂在增强该抑制剂方面很重要 抗肿瘤剂阿拉伯 - 腺苷的作用。 除了 开发ADASE抑制剂的具体目的，这项工作将提供新的 一系列含硼硼的嘌呤胶质和核苷衍生物， 在各种与健康相关的地区进行研究。 检查 潜在的抗肿瘤，抗菌，尤其是抗病毒活性 这些核苷将引起极大的兴趣。 检查 氢键方案，并有可能融入到 细胞DNA BR RNA池是从中产生的其他方面 工作。 本提案旨在为一些代表成员做好准备 这类新的核苷类似物，足够量 详细检查其理化特性和 酶活性也确定。 这些类似物的设计 基于它们与已知的硼杂环相似 水解稳定性及其在硼的能量稳定基因座上 在双环环的6位（嘌呤环编号）处原子。 这 用于实现其合成的方法是基于顺序的 卤素金属交换方法与有记录的脱水结合 芳基硼酸化合物的环闭合方法。