Institute of Organic Chemistry & Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, 16610 Prague 6, Czech Republic.
Future Med Chem. 2012 May;4(8):991-1005. doi: 10.4155/fmc.12.36.
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.
这篇综述按时间顺序总结了 5-氮杂胞苷核苷的研究基本里程碑，从它们的发现和抗癌活性鉴定，到随后基于 DNA 低甲基化和肿瘤抑制基因重新激活揭示其作用机制，再到美国 FDA 最终批准 5-氮杂胞苷（Vidaza(®)）和 2'-脱氧-5-氮杂胞苷（Dacogen(®)）用于治疗骨髓增生异常综合征。5,6-二氢-2'-脱氧-5-氮杂胞苷通过致死性诱变具有抗 HIV 活性，代表了现有抗逆转录病毒药物中独特的作用机制，与最近发现的其出乎意料的低甲基化活性一起进行了讨论。特别关注 5-氮杂胞苷无环核苷类似物和膦酸甲酯衍生物，重点介绍新型有效的抗 DNA 病毒药物（S）-1-[3-羟基-2-(膦酸甲酯基)丙基]-5-氮杂胞苷及其前药形式。考虑到潜在的药物应用，5-氮杂胞苷和 5,6-二氢-5-氮杂胞苷迄今为止似乎是设计新型抗病毒和抗肿瘤候选药物最有效的胞嘧啶类似物。
