Fused Pyrimidine (IsoA) Nucleosides:Design and Synthesis

University Of Maryland Balt Co Campus, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Despite promising leads in the search for new chemotherapeutic agents, the emergence of resistance to presently used treatments, as well as the lack of a single candidate to be identified and retained as a cure for cancer, clearly points to the need for continued biological investigations. It is well recognized that nucleosides are the fundamental building blocks of many biological systems and as a result, modified nucleosides have provided the impetus for a plethora of investigations due to their inherent structural resemblance to the naturally occurring nucleosides. There exists an intricately intertwined relationship between purine and pyrimidine nucleotide metabolism, cell proliferation and tumor cell differentiation. Because of this relationship, inhibition of key enzymes in nucleotide metabolism and DNA synthesis can be used as a chemotherapeutic approach to treating cancer. In this regard, the biological role of DNA methylation involves either inhibition or enhancement of DNA binding proteins. DNA encodes information by forming specific patterns of methylation, and since gene expression is determined by "reading" these patterns during DNA-protein interactions, disruption of DNA methylation becomes an attractive target for therapy. Disruption of DNA methylation can be accomplished in several ways, in particular, by inhibition of DNA methyltransferase (DNA MeTase) and/or S-adenosylhomocysteine hydrolase (SAHase), both established cellular targets for antiviral, antiparasitic and anticancer agents. Modified nucleosides, in particular the carbocyclic nucleosides. have exhibited significant inhibitory activity against SAHase and DNA MeTase. We propose herein the synthesis and biological investigation of a novel series of carbocyclic nucleosides that possess key structural features that will endow them with potent inhibitory properties against the aforementioned enzymes. We believe this inhibition will result in meaningful biological activity, as well as to induce cell differentiation.