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 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-flouro-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 micrograms/mL, VZV at 0.04-0.4 microgram/mL, and MSV (at 0.3-0.6 microgram/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 approximately 2 micrograms/mL.
Holý
A
A
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Praha.
Dvoráková
H
H
Jindrich
J
J
Masojídková
M
M
Budĕsínský
M
M
Balzarini
J
J
Andrei
G
G
De Clercq
E
E
D016475:3T3 Cells; D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002472:Cell Transformation, Viral / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008809:Mice, Inbred C3H; D015394:Molecular Structure; D011687:Purines / Q000737:chemistry*; D009053:Sarcoma Viruses, Murine / Q000187:drug effects
C101734:9-(2-(phosphonomethoxy)-3-hydroxypropyl)-8-azaadenine; C101735:9-(2-(phosphonomethoxy)ethyl)-8-azaguanine; C101736:9-(2-(phosphonomethoxy)propyl)-8-azaguanine; D000998:Antiviral Agents; D011687:Purines; C015008:triazolopyrimidinone; D006147:Guanine; D000225:Adenine