SYNTHESIS OF BORON ANALOGS OF NATURAL NUCLEOSIDES

该项目旨在探索含硼嘌呤的化学。 核糖核苷类似物，其长期目标是证明 硼原子在双环中的合理位置 杂环体系导致形成了相当稳定和安静的 有趣的衍生品。这一项目的成果将有助于 举例说明用硼-氧单键取代 自然生成的碳-氮双键，或硼-氮的 天然碳-碳双键的单键，以提供 稳定的类似物，具有独特和有用的特性。具体地说， 这项提议的目标化合物有望成为血管活性物质的抑制剂 腺苷脱氨酶，通过将硼原子放置在 在体内被脱氨的碳原子位置。形成一种新的 提出了该酶活性部位的四面体硼酸盐部分，并 应该导致被称为过渡态类似物抑制的过程。 腺苷脱氨酶的抑制剂在增强 抗肿瘤药物阿糖腺苷的作用。除 针对ADase抑制剂的开发，本工作将提供一种新的 一类稳定的含硼嘌呤苷元和核苷衍生物， 在各种与健康相关的领域学习。对…的考试 具有潜在的抗肿瘤、抗细菌、特别是抗病毒活性 这些核苷将会引起人们的极大兴趣。对…的考试 氢键方案和并入到 细胞dna br rna池是预计由此产生的其他方面。 工作。目前的建议旨在使一些有代表性的成员 这类新的核苷类似物的数量足以 对它们的物理化学性质进行了详细的检查，并 还有酶活性的测定。这些类比的设计 是基于它们与已知的已证实的硼杂环的相似性 硼的水解性及其能量稳定轨迹 双环上6位(嘌呤环编号)的原子。这个 用于实现它们的合成的方法是基于顺序的 结合文献记载的脱水剂的卤素-金属交换法 芳基硼酸化合物的环合成方法学。

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.