Oligonucleotide analogues are provided that incorporate 5-aza-cytosine in the oligonucleotide sequence, e.g., in the form of 5-aza-2′-deoxycytidine (decitabine) or 5-aza-cytidine. In particular, oligonucleotide analogues rich in decitabine-deoxyguanosine islets (DpG and GpD) are provided to target the CpG islets in the human genome, especially in the promoter regions of genes susceptible to aberrant hypermethylation. Such analogues can be used for modulation of DNA methylation, such as effective inhibition of methylation of cytosine at the C-5 position. Methods for synthesizing these oligonucleotide analogues and for modulating nucleic acid methylation are provided. Also provided are phosphoramidite building blocks for synthesizing the oligonucleotide analogues, methods for synthesizing, formulating and administering these compounds or compositions to treat conditions, such as cancer and hematological disorders.
提供了含有5-aza-
胞嘧啶的寡核苷酸类似物,例如以5-aza-2'-脱氧
胞嘧啶(
地西他滨)或5-aza-
胞嘧啶的形式出现在寡核苷酸序列中。特别地,提供了含有
地西他滨-脱氧
鸟嘌呤岛(DpG和GpD)的寡核苷酸类似物,以针对人类
基因组中的CpG岛,特别是易于发生异常高甲基化的
基因启动子区域。这样的类似物可用于调节DNA甲基化,例如有效抑制C-5位置的
胞嘧啶的甲基化。提供了合成这些寡核苷酸类似物和调节核酸甲基化的方法。还提供了用于合成寡核苷酸类似物的
磷酰胺酰胺建筑块,以及用于合成、制剂和给药这些化合物或组合物以治疗癌症和血液疾病等疾病的方法。