SYNTHESIS OF BORON ANALOGS OF NATURAL NUCLEOSIDES

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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.