Analogues of the antiviral acyclonucleoside 9-(4-hydroxy-3-hydroxymethylbutyl)guanine. Part 2. Substitutions on C-1′ and C-3′ of the acyclic N-9 substituent

Abstract

Syntheses of 9-[3,3-bis(hydroxymethyl)butyl]guanine (2), 9-(3-benzyloxymethyl-4-hydroxy-3-hydroxymethylbutyl)guanine (3), 9-(3,4-dihydroxy-3-hydroxymethylbutyl)guanine (4),9-(3-fluoro-4-hydroxy-3-hydroxymethylbutyl)guanine (5), and 9-[4-hydroxy-3,3-bis(hydroxymethyl)butyl]guanine (6) are described. These 3′-substituted analogues of the antiviral acyclonucleoside 9-(4-hydroxy-3-hydroxymethylbutyl)guanine (1) were like the 2′-substituted analogues reported in Part 1 of this series, synthesized by a route involving alkylation of 2-amino-6-chloropurine with protected bromides (8a–d) derived from the appropriately substituted partially protected alcohols (7a–d). Subsequent hydrolysis and deprotection afforded the required 9-substituted guanines.

The preparation of 9-(4-hydroxy-3-hydroxymethyl-1-methoxybutyl)guanine (28) is also described. This 1′-substituted analogue (28) of (1) and its N-7 substituted isomer (29) were synthesized by Lewis acid-catalysed alkylation of trimethylsilylated 2-N-acetylguanine with a hydroxy-protected α-chloro ether (25) and subsequent deprotection of both the hydroxy groups and the 2-amino substituent. All of these acyclonucleosides (2)–(6), (28), and (29), were tested for antiviral activity in cell cultures. The most active compound was the 3′-fluoro derivative (5), which was ca. 3-fold less active than the lead compound (1) against the herpes viruses.