SYNTHESIS OF BORON ANALOGS OF NATURAL NUCLEOSIDES

该项目旨在探索含硼嘌呤的化学性质 核糖核苷类似物的长期目标是证明， 硼原子在双环中的正确位置 杂环系统导致形成相当稳定和相当 有趣的衍生品 该项目的成果应有助于 举例说明用硼-氧单键取代 天然存在的碳-氮双键，或硼-氮双键 单键形成天然存在的碳-碳双键， 具有独特和有用性质的稳定类似物。 具体而言， 该建议的目标化合物预期是 酶腺苷脱氨酶，凭借硼原子的位置， 该碳原子位置在体内被脱氨基。 的形成 在酶的活性位点的四面体硼酸盐部分提出，和 应该会导致过渡态类似物抑制。 腺苷脱氨酶的抑制剂在增强腺苷脱氨酶活性方面是重要的。 抗肿瘤剂阿糖腺苷的作用。 除了有 针对ADase抑制剂开发的具体目标，本工作将提供一种新的 一类稳定的含硼嘌呤糖苷配基和核苷衍生物， 在各种健康相关领域的研究。 审查 潜在的抗肿瘤、抗菌和特别是抗病毒活性， 这些核苷将引起极大的兴趣。 审查 氢键方案和潜在的纳入到 细胞DNA br RNA库是预期由此产生的其他方面 工作 本提案旨在培养一些代表性成员， 这类新的核苷类似物的量足以 详细检查它们的物理化学性质， 酶活性的测定。 这些类似物的设计 是基于它们与已知的硼杂环的相似性， 水解稳定性和它们的能量稳定位点的硼 在双环的6位（嘌呤环编号）上的原子。 的 用于实现它们的合成的方法是基于顺序的 卤素-金属交换法结合记录的脱水 芳基硼酸化合物的闭环方法。

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.