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

• Published in: Journal of medicinal chemistry Vol. 39; no. 20; pp. 4073 - 4088
• Main Authors: Holý, Antonín, Dvořáková, Hana, Jindřich, Masojídková, Milena, Buděšínský, Miloš, Balzarini, Jan, Andrei, Graciella, De Clercq, Erik
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 27-09-1996
• Subjects: 3T3 Cells; Adenine - analogs & derivatives; Adenine - chemical synthesis; Adenine - pharmacology; AIDS/HIV; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Transformation, Viral - drug effects; Cytomegalovirus - drug effects; Cytopathogenic Effect, Viral - drug effects; Guanine - analogs & derivatives; Guanine - chemical synthesis; Guanine - pharmacology; Herpesvirus 1, Human - drug effects; Herpesvirus 2, Human - drug effects; Herpesvirus 3, Human - drug effects; HIV-1 - drug effects; HIV-2 - drug effects; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Mice, Inbred C3H; Molecular Structure; Pharmacology. Drug treatments; Purines - chemistry; Sarcoma Viruses, Murine - drug effects; Oncovirinae; Acyclic nucleoside; Herpesviridae; Alphaherpesvirinae; Retroviridae; In vitro; Virus; Azanucleoside; Murine sarcoma virus; Structure activity relation; Type C oncovirus; Bicyclic compound; Lentivirinae; Antiviral; Herpesvirus hominis; Human immunodeficiency virus; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960314q

Reaction of phosphoroorganic synthons with 8-azaadenine, 8-aza-2,6-diaminopurine, and 8-azaguanine using cesium carbonate yielded regioisomeric 8-azapurine N7-, N8-, and 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], and (R)-(2-(phosphonomethoxy)propyl) [(R)-PMP] derivatives. 13C 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 μg/mL, VZV at 0.04−0.4 μg/mL, and MSV (at 0.3−0.6 μg/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 ∼2 μg/mL.