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Improvement of S N Ar Reaction Rate by an Electron‐Withdrawing Group in the Crosslinking of DNA Cytosine‐5 Methyltransferase by a Covalent Oligodeoxyribonucleotide Inhibitor
Author(s) -
Kasai Yukiko,
Sato Kousuke,
Utsumi Shohei,
Ichikawa Satoshi
Publication year - 2018
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800244
Subject(s) - cytosine , covalent bond , dna , chemistry , methyltransferase , group (periodic table) , polar effect , stereochemistry , biochemistry , medicinal chemistry , organic chemistry , methylation
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 (d X P), 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 (d X P CN ) and ODNs containing d X P CN , as more reactive inhibitors of DNMTs. Nucleophilic aromatic substitution (S N Ar) of the designed nucleosides, d X P CN , was faster than that of d X P, and the ODN containing d X P CN effectively 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.