Mechanism‐Based Inhibitor of DNA Cytosine‐5 Methyltransferase by a SNAr Reaction with an Oligodeoxyribonucleotide Containing a 2‐Amino‐4‐Halopyridine‐C‐Nucleoside |
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| Authors: | Dr. Kousuke Sato Yuma Kunitomo Yukiko Kasai Shohei Utsumi Prof. Isao Suetake Prof. Shoji Tajima Prof. Satoshi Ichikawa Prof. Akira Matsuda |
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| Affiliation: | 1. Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Tobetsu, Ishikari-gun, Japan;2. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan;3. Laboratory of Epigenetics, Institute for Protein Research, Osaka University, Suita, Osaka, Japan;4. Center for Research and Education on Drug Discovery, Hokkaido University, Kita-ku, Japan |
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| Abstract: | 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 containing XPpG 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. |
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| Keywords: | aromatic substitution DNA methylation epigenetics nucleosides oligonucleotides |
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