Acyclic Nucleotide Analogs Derived from 8-Azapurines: Synthesis and Antiviral Activity

• DOI: 10.1021/jm960314q
• Publication Date: 2002-07-26T06:00:31Z
• Authors: Antonín Holý; Hana Dvořáková; Jindřich; Milena Masojídková; Miloš Buděšínský; Jan Balzarini; Graciella Andrei; Erik De Clercq
• Keywords: Structure–activity relationship

Reaction of phosphoroorganic synthons with 8-azaadenine, 8-aza-2,6-diaminopurine, and 8-azaguanine using cesium carbonate yielded regioisomeric 8-azapurine N7-, N8-, N9-(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], (R)-(2-(phosphonomethoxy)propyl) [(R)-PMP] 13C NMR spectra were used for structural assignment the regioisomers. None 8-isomers exhibited any antiviral activity against herpesviruses, Moloney murine sarcoma virus (MSV), and/or HIV. 9-(S)-HPMP-8-azaadenine (23) PME-8-azaguanine (65) active HSV-1, HSV-2, CMV at 0.2−7 μg/mL, VZV 0.04−0.4 MSV (at 0.3−0.6 μg/mL). (R)-PMP-8-azaguanine (71a) protected MT-4 CEM cells HIV-1- HIV-2-induced cytopathicity a concentration ∼2 μg/mL.