Synthesis and anti-HIV activity of carbocyclic 2',3'-didehydro-2',3'-dideoxy 2,6-disubstituted purine nucleosides

Abstract

(.+-.)-cis-[4-[(2,5-Diamino-6-chloropyrimidinyl)amino]-2-cyclopentenyl]carbinol (5a) was synthesized from 2-amino-4,6-dichloropyrimidine and cis-4-(hydroxymethyl)cyclopentenylamine (2a) by subsequent preparation of the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine (3a) and reduction of the azo moiety with zinc and acetic acid. The carboxyclic analogue of 2''3''-didehydro-2'',3''-dideoxy 2-amino-6-chloropurine (6a) and the corresponding 8-azapurine (9a) were prepared from 5a. The carbocylic 2'',3''-didehydro-2''3''-dideoxy analogues of guanine (7a) and 2,6-diaminopurine (8a), and 8-azaguanine (10a) and 8-aza-2,6-diaminopurine (11) were prepared from 6a and 9a, respectively. The corresponding 2''3''-saturated series of 2-amino-6-substituted-purine carbocyclic nucleosides were prepared following the same scheme starting with cis-4-(hydroxymethyl)cyclopentylamine (2b). Carbocyclic 2'',3''-didehydro-2'',3''-dideoxyguanosine (carbovir, 7a) emerged as a potent and selective anti-HIV agent. Its hydrolytic stability and its ability to inhibit the infectivity and replication of HIV in T-cells at concentrations of approximately 200-400-fold below toxic concentrations make carbovir an excellent candidate for development as a potential antiretroviral agent.