Synthesis and Antiviral Activity of 8-Aza Analogs of Chiral [2-(Phosphonomethoxy)propyl]guanines

• Published in: Journal of medicinal chemistry Vol. 38; no. 20; pp. 4007 - 4013
• Main Authors: Franchetti, Palmarisa, Abu Sheikha, Ghassan, Cappellacci, Loredana, Grifantini, Mario, De Montis, Antonella, Piras, Giovanna, Loi, Anna Giulia, La Colla, Paolo
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-09-1995
• Subjects: AIDS/HIV; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Aza Compounds - chemical synthesis; Aza Compounds - pharmacology; Biological and medical sciences; Cell Line; Guanine - chemical synthesis; Guanine - pharmacology; HIV - drug effects; human immunodeficiency virus 1; Humans; Medical sciences; Pharmacology. Drug treatments; Stereoisomerism; Purine nucleoside; HIV-1 virus; Phosphonic acids; Retroviridae; In vitro; HIV-2 virus; Virus; Structure activity relation; Asymmetric synthesis; Enantiomer; Established cell line; Lentivirinae; Antiviral; Nucleoside; Human immunodeficiency virus; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00020a015

(R)- And (S)-8-aza-9(-)[2-(phosphonomethoxy)propyl]guanine [(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-(tolylsulfonyl) -1,2-propanediol 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 EC50 values of 12 and 4.5 microM, 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.