NOVEL ACYCLONUCLEOTIDES - SYNTHESIS AND ANTIVIRAL ACTIVITY OF ALKENYLPHOSPHONIC ACID-DERIVATIVES OF PURINES AND A PYRIMIDINE

A series of phosphonoalkenyl and (phosphonoalkenyl)oxy derivatives of purines and a pyrimidine were synthesized. These compounds are the fir st reported acyclonucleotides which incorporate the alpha,beta-unsatur ated phosphonic acid moiety as the phosphate mimic and include compoun ds 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 b ond. 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 hetero cyclic 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 acyclonucleot ides were tested for activity against herpes simplex types 1 and 2 (HS V-1 and HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), v isna virus, and human immunodeficiency virus type 1 (HIV-1). Guanine d erivatives were moderately to extremely cytotoxic, but the adenines we re less toxic to cells. At the concentrations tested, (Z)-isomers in t he unbranched series had no activity against herpes viruses or HIV-1. (E)-9-[(4-Phosphonobut-3-enyl)oxy]adenine (7d) displayed selective act ivity against HIV-1, (E)-2,6-diamino-9-(4-phosphonobut-3-enyl)purine ( 9) showed selective antiretrovirus activity, and 9-[2-(hydroxymethyl)- 4-phosphonobut-3-enyl]adenine (7c) showed selective antiherpesvirus (V ZV and CMV) activity.