Acyclic nucleoside phosphonates with 5-azacytosine base moiety substituted in C-6 position.
Two methods for preparation of 6-substituted derivatives of anti DNA-viral agent 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC) were developed: (1) ammonia mediated ring-opening reaction of diisopropyl esters of HPMP-5-azaC (4) to carbamoylguanidine derivatives followed by ring-closure reaction with orthoesters and (2) condensation reaction of 6-substituted 5-azacytosines with diisopropyl (1S)-[2-hydroxy-1-tosyloxymethyl)ethoxy]methylphosphonate (15). Deprotection of diisopropyl esters to free phosphonic acids was performed with bromotrimethylsilane in acetonitrile followed by hydrolysis. In contrast to parent compound HPMP-5-azaC, a substantial decrease of antiviral activity in case of 6-substituted analogues occurred. Surprisingly, N-3 isomer of 6-methyl-HPMP-5-azaC in the form of isopropyl ester revealed activity against RNA viruses (Sindbis virus).
Krecmerová
Marcela
M
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, vvi, Gilead Sciences & IOCB Research Centre, Flemingovo nám 2, CZ-166 10, Prague 6, Czech Republic. marcela@uochb.cas.cz
Masojídková
Milena
M
Holý
Antonín
A
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology*; D014709:Vero Cells; D014777:Virus Diseases / Q000188:drug therapy; D014780:Viruses / Q000187:drug effects
D000998:Antiviral Agents; D009705:Nucleosides; D063065:Organophosphonates; C039854:5-azacytosine; D003596:Cytosine