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A Versatile Synthetic Precursor for Introduction of Specific N6-Modifications in 2,6-Diaminopurine Nucleosides:N2-Acetyl-2',3',5'-tri-O-acetyl-N6-(1,2,4-triazol-1-yl)- 2,6-diaminopurine-9--D-ribofuranoside.
1 , 1 , * 2
1  Research Institute of Elemento Organic Chemistry, Nankai University 94 Weijin Road, Tianjin 300071, Peoples Republic of China
2  Laboratory for Drug Design and Synthesis, Department of Chemistry & Biochemistry University of Maryland, Baltimore County (UMBC), 1000 Hilltop Circle Baltimore, Maryland 21250, USA

Abstract: 2,6-Diaminopurines as well as their nucleoside and nucleotide analogues have attracted considerable attention in recent years as potential antiviral and antitumor compounds. Some of these compounds have already been shown to be potent anti-HIV agents, including 2',3'-dideoxy-2,6-diaminopurine-9--D-ribofuranoside (I), the acyclic nucleotide analogue 9-[2-(phosphonylmethoxyethyl)]-2,6-diaminopurine (II), and the three carbocyclic nucleoside analogues ( )-cis-[4'-(2,6-diamino-9H- purin-9-yl)-2-cyclopentenyl]carbinol (III), ( )-cis-[3'-(2,6-diamino-9H-purin-9-yl)cyclopentyl] carbinol (IV), and ( )-9-[2',3'-bis(hydroxymethyl)]cyclobutyl-2,6-diaminopurine (V). As part of a program to improve profiles of drug efficiency and toxicity of 2,6-diaminopurine nucleoside analogues, it became necessary to explore the structure-activity relationships (SAR) via specific modifications at the N6-position of 2,6-diaminopurine ring. However, all available conventional methods to accomplish this goal, including the alkylation of the N6-amino group of 2,6-diaminopurine riboside or the displacement of a halogen group of 2-amino-6-chloropurine riboside yielded intractable mixtures of products and/or poor yields. We report here the synthesis of a versatile, highly reactive precursor (VI), which upon reaction with amine nucleophiles, gave the desired, specifically N6-modified 2,6-diaminopurinepurine nucleosides (VII) in high yields. In addition, the reaction of VI with polymethylenediamines afforded the polymethylene-bridged dimers of 2,6-diaminopurine nucleosides (VIII).
Keywords: 2,6-Diaminopurine Nucleosides, Versatile Synthetic Precursor for Specific N-6 Modifications, Dimers of 2,6-Diaminopurine Nucleosides with Methylene Bridges, Antiviral and Antitumor Compounds