Synthesis and antiviral activity of 8-aza analogs of chiral [2-(phosphonomethoxy) propyl]guanines.
(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.
Franchetti
P
P
Dipartimento di Scienze Chimiche, Università di Camerino, Italy.
Sheikha
G A
GA
Cappellacci
L
L
Grifantini
M
M
De Montis
A
A
Piras
G
G
Loi
A G
AG
La Colla
P
P
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D006147:Guanine / Q000138:chemical synthesis* / Q000494:pharmacology; D006678:HIV / Q000187:drug effects*; D006801:Humans; D013237:Stereoisomerism
D000998:Antiviral Agents; D001372:Aza Compounds; D006147:Guanine