Acyclic nucleotide analogs derived from 8-azapurines: Synthesis and antiviral activity

Reaction of phosphoroorganic synthons with 8-azaadenine, 8-aza-2,6-diaminopurine, and 8-azaguanine using cesium carbonate yielded regioisomeric 8-azapurine N-7-, N-8-, and N-9-(2-(phosphonomethoxy)alkyl) derivatives. This reaction followed by deprotection afforded isomeric 2-(phosphonomethoxy)ethyl (PME), (S)-(3-hydroxy-2-(phosphonomethoxy)propyl) [(S)-HPMP] (S)-(3-fluoro-2-(phosphonomethoxy)propyl) [(S)-FPMP], (S)-(2-(phosphonomethoxy)propyl) [(S)PMP], and (R)-(2-(phosphonomethoxy)propyl) [(R)-PMP] derivatives. C-13 NMR spectra were used for structural assignment of the regioisomers. None of the 8-isomers exhibited any antiviral activity against herpesviruses, Moloney murine sarcoma virus (MSV), and/or HIV. 9-(S)-HPMP-8-azaadenine (23) and PME-8-azaguanine (65) were active against HSV-1, HSV-2, and CMV at 0.2-7 mu g/mL, VZV at 0.04-0.4 eta g/mL, and MSV (at 0.3-0.6 mu g/mL). PME-8-azaguanine (65) and (R)-PMP-8-azaguanine (71a) protected MT-4 and CEM cells against HIV-1- and HIV-2-induced cytopathicity at a concentration of similar to 2 mu g/mL.