Mechanism‐Based Inhibitor of DNA Cytosine‐5 Methyltransferase by a SNAr Reaction with an Oligodeoxyribonucleotide Containing a 2‐Amino‐4‐Halopyridine‐C‐Nucleoside
Mechanism‐Based Inhibitor of DNA Cytosine‐5 Methyltransferase by a SNAr Reaction with an Oligodeoxyribonucleotide Containing a 2‐Amino‐4‐Halopyridine‐C‐Nucleoside
复制标题
通过与含有 2-氨基-4-卤代吡啶-C-核苷的寡脱氧核糖核苷酸进行 SNAr 反应，实现基于机制的 DNA 胞嘧啶-5 甲基转移酶抑制剂
DOI：
10.1002/cbic.201700688
复制
发表时间：
2018
期刊：
影响因子：
3.2
通讯作者：
A. Matsuda
中科院分区：
文献类型：
--
作者：
K. Sato;Y. Kunitomo;Y. Kasai;S. Usumi;I. Suetake;S. Tajima;S. Ichikwa;A. Matsuda
在染色质中，5-甲基胞嘧啶（mC）代表基因组DNA中的第五个核碱基，起着诱导表观遗传变化的作用。肿瘤细胞表现出异常的DNA甲基化模式，抑制人DNA胞嘧啶-5甲基转移酶（DNMT）是治疗各种癌症的有效策略，DNMT负责在CpG序列中产生mC。在这里，我们描述了2-氨基-4-卤代吡啶-C-核苷（dXP）和含有dXP的寡脱氧核糖核苷酸（ODN）的设计，合成和性能评估作为一种新的基于机制的DNMT抑制剂。设计的含XPpG的ODN通过亲核芳香取代（SNAr）反应与DNMT形成共价键合复合物，并研究其细胞增殖活性。该研究表明，DNA中CpG序列中的dXP可以作为癌症化疗中潜在的核酸药物先导和表观遗传学研究中有用的化学探针。我们的分子设计使用SNAr反应将是有用的DNMT和其他蛋白质-DNA相互作用。
In chromatin, 5‐methylcytosine (mC), which represents the fifth nucleobase in genomic DNA, plays a role as an inducer of epigenetic changes. Tumor cells exhibit aberrant DNA methylation patterns, and inhibition of human DNA cytosine‐5 methyltransferase (DNMT), which is responsible for generating mC in CpG sequences, is an effective strategy to treat various cancers. Here, we describe the design, synthesis, and evaluation of the properties of 2‐amino‐4‐halopyridine‐C‐nucleosides (dXP) and oligodeoxyribonucleotides (ODNs) containing dXP as a novel mechanism‐based inhibitor of DNMTs. The designed ODN containingXPpG forms a complex with DNMTs by covalent bonding through a nucleophilic aromatic substitution (SNAr) reaction, and its cell proliferation activity is investigated. This study suggests that dXP in a CpG sequence of DNA could serve as a potential nucleic acid drug lead in cancer chemotherapy and a useful chemical probe for studies of epigenetics. Our molecular design using a SNAr reaction would be useful for DNMTs and other protein–DNA interactions.