Synthesis and Biological Properties of 9-(2, 4-Dihydroxybutyl) Adenine and Guanine: New Analogues Of 9-(2, 3-Dihydroxyprqpyl)adenine (Dhpa) and 9-(2-Hydroxyethoxymethyl)guanine (Acyclovir)

Abstract

New analogues of antiviral agents 9-(2, 3-dihy-droxyproply) adenine (DHPA, 1a.) and 9-(2-hydroxyethoxymethyl) guanine (acyclovir, Ib) - compounds Ic and Id were prepared and their biological activity was investigated. Racemic 1, 2, 4-butanetriol (2) was converted to the corresponding benzylidene derivative (3a) by acetalation with benzalde-hyde and triethyl orthoformate. Acetal 3a and p-toluene- sul-fonyl chloride in pyridine gave the corresponding p-toluenes fonate 3b. Alkylation of adenine 5a via sodium salt of 5a with 3b in dimethylformamide or in the presence of tetra-n-butylammonium fluoride in tetrahydrofuran gave intermediate 6a. Reaction of 2-amino-6-chloropurine (5b) with 3b effected by K₂CO₃ in dimethylsulfoxide gave compound 6b and a smaller amount of 7-alkylated proauct 7. A similar transformation catalyzed by tetra-n-butylammonium fluoride afforded only intermediate 5b. Acid-catalyzed de-protection (hydrolysis) of 6b and 6a gave the title compounds Ic and Id. The S-enantiomer of Ic was deaminated with adenosine deaminase. Our results argue against the presence of a methyl group-binding site of adenosine deaminase. Compounds Ic and Id exhibited little or no activity in antiviral assays with several DNA and RNA viruses.