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 immunodefici ency 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 ph osphonic 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 co rresponding S enantiomers were found to be less potent. When evaluated in combination with AZT, ddI, or DABO 603, (R)-8-aza-PMPG gave additi ve, additive, and synergistic anti-HIV-1 effects, respectively.