Novel acyclonucleotides: Synthesis and antiviral activity of alkenylphosphonic acid derivatives of purines and a pyrimidine

Article abstract of DOI:10.1021/jm00062a006

A series of phosphonoalkenyl and (phosphonoalkenyl)oxy derivatives of purines and a pyrimidine were synthesized. These compounds are the first reported acyclonucleotides which incorporate the α,β-unsaturated phosphonic acid moiety as the phosphate mimic and include compounds in which the acyclic substituent is attached to N-9 of a purine or N-1 of a pyrimidine by either a nitrogen-carbon or a nitrogen-oxygen bond. The phosphonoalkenyl-substituted compounds 7a-c, 8a-c, 9, 10, and 12 were prepared either by Mitsunobu coupling of alcohols with purine or pyrimidine derivatives or by alternative alkylations of the heterocyclic bases. The (phosphonoalkenyl)oxy derivatives 7d-g, 8d-g, and 11 were synthesized by coupling of alcohols with 9- hydroxypurines or a 1-hydroxypyrimidine under Mitsunobu conditions. The novel acyclonucleotides were tested for activity against herpes simplex types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), visna virus, and human immunodeficiency virus type 1 (HIV-1). Guanine derivatives were moderately to extremely cytotoxic, but the adenines were less toxic to cells. At the concentrations tested, (Z)-isomers in the unbranched series had no activity against herpes viruses or HIV-1. (E)-9- [(4-Phosphonobut-3-enyl)oxy]adenine (7d) displayed selective activity against HIV-1, (E)-2,6-diamino-9-(4-phosphonobut-3-enyl)purine (9) showed selective antiretrovirus activity, and (E)-9-[2-(hydroxymethyl)-4-phosphonobut-3- enyl]adenine (7c) showed selective antiherpesvirus (VZV and CMV) activity.