Improvement of SNAr Reaction Rate by an Electron-withdrawing Group in the Cross-linking of DNA Cytosine-5 Methyltransferase by a Covalent Oligodeoxyribonucleotide Inhibitor.
Improvement of SNAr Reaction Rate by an Electron-withdrawing Group in the Cross-linking of DNA Cytosine-5 Methyltransferase by a Covalent Oligodeoxyribonucleotide Inhibitor.
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通过共价寡脱氧核糖核苷酸抑制剂交联 DNA 胞嘧啶 5 甲基转移酶时吸电子基团提高 SNAr 反应速率。
DOI：
10.1002/cbic.201800244
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发表时间：
2018
期刊：
影响因子：
3.2
通讯作者：
S. Ichikawa
中科院分区：
文献类型：
--
作者：
Y;Kasai;K. Sato;S. Utsumi;S. Ichikawa
DNA 胞嘧啶 5-甲基转移酶 (DNMT) 催化 CpG 序列中胞嘧啶残基的 C5 位点的甲基化。在癌细胞中发现了异常的 DNA 甲基化模式。因此，抑制人DNMT是治疗多种癌症的有效策略。 DNMT 抑制剂具有缺电子核碱基，因为该基团有助于 DNMT 中催化 Cys 残基的攻击。最近，我们报道了基于机制的修饰核苷 2-氨基-4-卤代吡啶-C-核苷（dXP）作为 DNMT 抑制剂的合成和性质。为了开发用于寡核苷酸治疗的更有效的 DNMT 抑制剂，需要含有其他核苷类似物的寡脱氧核糖核苷酸 (ODN)，它与 DNMT 反应更快。在此，我们描述了 2-氨基-3-氰基-4-卤代吡啶-C-核苷 (dXPCN) 和含有 dXPCN 的 ODN（作为 DNMT 更具反应活性的抑制剂）的设计、合成和性能评估。设计的核苷dXPCN的亲核芳香取代(SNAr)比dXP更快，并且含有dXPCN的ODN有效地与DNMTs形成复合物。这项研究表明，掺入吸电子基团将是增加 DNMT 亲核试剂反应性的有效方法，同时保持高特异性。
DNA cytosine 5‐methyltransferase (DNMT) catalyzes methylation at the C5 position of the cytosine residues in the CpG sequence. Aberrant DNA methylation patterns are found in cancer cells. Therefore, inhibition of human DNMT is an effective strategy for treating various cancers. The inhibitors of DNMT have an electron‐deficient nucleobase because this group facilitates attack by the catalytic Cys residue in DNMTs. Recently, we reported the synthesis and properties of mechanism‐based modified nucleosides, 2‐amino‐4‐halopyridine‐C‐nucleosides (dXP), as inhibitors of DNMT. To develop a more efficient inhibitor of DNMT for oligonucleotide therapeutics, oligodeoxyribonucleotides (ODNs) containing other nucleoside analogues, which react more quickly with DNMT, are needed. Herein, we describe the design, synthesis, and evaluation of the properties of 2‐amino‐3‐cyano‐4‐halopyridine‐C‐nucleosides (dXPCN) and ODNs containing dXPCN, as more reactive inhibitors of DNMTs. Nucleophilic aromatic substitution (SNAr) of the designed nucleosides, dXPCN, was faster than that of dXP, and the ODN containing dXPCNeffectively formed a complex with DNMTs. This study suggests that the incorporation of an electron‐withdrawing group would be an effective method to increase reactivity toward the nucleophile of the DNMTs, while maintaining high specificity.