5-azacytosine compounds in medicinal chemistry: current stage and future perspectives.
This review summarizes the basic milestones of the research of 5-azacytosine nucleosides chronologically from their discovery and anticancer activity identification, through to subsequent unveiling of their mechanism of action based on DNA hypomethylation and tumor-suppressor gene reactivation, to the final US FDA approval of 5-azacytidine (Vidaza(®)) and 2'-deoxy-5-azacytidine (Dacogen(®)) for the treatment of myelodysplastic syndromes. 5,6-dihydro-2'-deoxy-5-azacytidine, a compound with anti-HIV activity through lethal mutagenesis, representing a unique mechanism of action among existing anti-retroviral drugs, is discussed together with quite recent discovery of its so far unexpected hypomethylation activity. Special attention is paid to 5-azacytosine acyclic nucleoside analogues and phosphonomethyl derivatives with the emphasis on the new potent anti-DNA virus agent (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine and its prodrug forms. Considering the potential pharmaceutical applications, 5-azacytosine and 5,6-dihydro-5-azacytosine appear to be so far the most effective cytosine mimics for the design of novel antiviral and anti-tumor drug candidates.
Institute of Organic Chemistry & Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, 16610 Prague 6, Czech Republic. marcela@uochb.cas.cz
Marcela
M
Krečmerová
Miroslav
M
Otmar
D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D019175:DNA Methylation / Q000187:drug effects; D055808:Drug Discovery; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy
D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; C013938:5,6-dihydro-5-azacytidine; C039854:5-azacytosine; D003596:Cytosine; D001374:Azacitidine