SYNTHESIS AND ANTIVIRAL ACTIVITY OF 8-AZA ANALOGS OF CHIRAL [2-(PHOSPHONOMETHOXY)PROPYL]GUANINES

(R)- And (S)-8-aza-9-[2-(phosphonomethoxy)propyl] [(R)- and (S)-8-aza-PMPG] were synthesized and tested in vitro for anti-human immunodeficiency virus (HIV) activity. The synthesis of the above compounds and of (R)-9-[2-(phosphonomethoxy)propyl]guanine [(R)-PMPG] was carried out through the alkylation of 8-azaguanine or guanine with (R)- and (S)2-O-[(diisopropylphosphono)methyl]-1-O-(followed by deprotection of the phosphonic moiety. A different, even more convenient synthesis of (R)-8-aza-PMPG starting from 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone and (R)-[2-[(diisopropylphosphono)methoxy]propyl]amine is also reported. Both (R)-8-aza-PMPG and (R)-PMPG demonstrated anti-HIV activity in the MTT assay with EC(50) values of 12 and 4.5 mu M, respectively. The corresponding S enantiomers were found to be less potent. When evaluated in combination with AZT, ddI, or DABO 603, (R)-8-aza-PMPG gave additive, additive, and synergistic anti-HIV-1 effects, respectively.