Synthesis of acyclowyosine and acyclo-3-methylguanosine, as probes for some chemical and biological properties resulting from the N-3 substitution of guanosine and its analogues

Abstract

Acyclo analogues of wyosine 2 and 3-methylguanosine 3, viz. 9-[(2-hydroxyethoxy)methyl]-3methyl-1, N-2-(prop-1 -ene-1,2-diyl)guanine 5a and 9-[(2-hydroxyethoxy)methyl]-3-methylguanine (3-methylacyclovir, 6a) were synthesized from acyclovir 4. The route to compound 5a involved methylation of the tricyclic acetate 7b with diazomethane-zinc iodide reagent and subsequent deacetylation; tricycle 5a was transformed into compound 6a with N-bromosuccinimide followed by ammonium hydroxide. Direct coupling of 3-methylguanine with the appropriate chain component resulted exclusively in formation of compound 9a, the N-7 regioisomer of 6a. The glycosidic hydrolysis rates of compounds 2 and 3 differed from those of the much less sterically compressed analogues 5a and 6a by less than one order of magnitude. This contrasts with the 10⁵-fold increase in hydrolysis rate of compounds 2 and 3, compared with that of guanosine 1, and suggests that electronic factors must play an important role in the accelerated hydrolysis of 9-substituted 3-methylguanine derivatives. The antiviral activity of acyclovir was virtually abolished following N-3 methylation (6a). The other compounds (2, 3 and 5a) also failed to show any antiviral activity.