Synthese von hantelförmigen DNA‐Inibitoren für die humane DNA‐Methyltransferase Dnmt1

Kuch, David; Schermelleh, Lothar; Manetto, Susanne; Leonhardt, Heinrich; Carell, Thomas

doi:10.1002/ange.200702055

Cited by 3 publications

(2 citation statements)

References 37 publications

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“…After treatment of C2C12 myoblast cells with the dumbbells, they showed colocalization with Dnmt1. [44] Here we report the ability of short highly modified doublestranded oligonucleotides to inhibit the prokaryotic methyltransferase M.HhaI and the eukaryotic methyltransferase Dnmt1 in vitro. The concept is depicted schematically in Figure 1.…”

Section: Introductionmentioning

confidence: 97%

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Phosphorothioation of Oligonucleotides Strongly Influences the Inhibition of Bacterial (M.HhaI) and Human (Dnmt1) DNA Methyltransferases

2009

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Methyltransferase inhibitors: Short double-stranded oligonucleotides that have a hemimethylated target sequence and 5-fluoro-2'-deoxycytidine as a suicide inhibitor as well as their phosphorothioated analogues were tested for their ability to inhibit the bacterial methyltransferase M.HhaI and the human Dnmt1 in vitro.The cytidine analogue 5-fluoro-2'-deoxycytidine (dC(F)) is a mechanism-based inhibitor of DNA methyltransferases. We report the synthesis of short 18-mer dsDNA oligomers containing a triple-hemimethylated CpG motive as a recognition sequence for the human methyltransferase Dnmt1. The DNA strands carry within these CpG islands dC(F) building blocks that function as mechanism-based inhibitors of the analyzed methyltransferases. In addition, we replaced the phosphodiester backbones at defined positions by phosphorothioates. These hypermodified DNA strands were investigated as inhibitors of the DNA methyltransferases M.HhaI and Dnmt1 in vitro. We could show that both methylases behave substantially differently in respect to the amount of DNA backbone modification.

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Section: Introductionmentioning

confidence: 97%

“…[44] Opposite the dC M dG islands dC F nucleobases were placed as suicide substrate in the counterstrand, as is shown in Figure 1. The full sequences are listed in Figure 2.…”

Section: Introductionmentioning

confidence: 99%

Phosphorothioation of Oligonucleotides Strongly Influences the Inhibition of Bacterial (M.HhaI) and Human (Dnmt1) DNA Methyltransferases

2009

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Mechanism‐Based Inhibitor of DNA Cytosine‐5 Methyltransferase by a S_NAr Reaction with an Oligodeoxyribonucleotide Containing a 2‐Amino‐4‐Halopyridine‐C‐Nucleoside

et al. 2018

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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 (d P) and oligodeoxyribonucleotides (ODNs) containing d P as a novel mechanism-based inhibitor of DNMTs. The designed ODN containing PpG forms a complex with DNMTs by covalent bonding through a nucleophilic aromatic substitution (S Ar) reaction, and its cell proliferation activity is investigated. This study suggests that d P 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 S Ar reaction would be useful for DNMTs and other protein-DNA interactions.

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Improvement of S_NAr Reaction Rate by an Electron‐Withdrawing Group in the Crosslinking of DNA Cytosine‐5 Methyltransferase by a Covalent Oligodeoxyribonucleotide Inhibitor

et al. 2018

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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 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 P ) and ODNs containing d P , as more reactive inhibitors of DNMTs. Nucleophilic aromatic substitution (S Ar) of the designed nucleosides, d P , was faster than that of d P, and the ODN containing d P 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.

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Synthese von hantelförmigen DNA‐Inibitoren für die humane DNA‐Methyltransferase Dnmt1

Cited by 3 publications

References 37 publications

Phosphorothioation of Oligonucleotides Strongly Influences the Inhibition of Bacterial (M.HhaI) and Human (Dnmt1) DNA Methyltransferases

Phosphorothioation of Oligonucleotides Strongly Influences the Inhibition of Bacterial (M.HhaI) and Human (Dnmt1) DNA Methyltransferases

Mechanism‐Based Inhibitor of DNA Cytosine‐5 Methyltransferase by a S_NAr Reaction with an Oligodeoxyribonucleotide Containing a 2‐Amino‐4‐Halopyridine‐C‐Nucleoside

Improvement of S_NAr Reaction Rate by an Electron‐Withdrawing Group in the Crosslinking of DNA Cytosine‐5 Methyltransferase by a Covalent Oligodeoxyribonucleotide Inhibitor

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Synthese von hantelförmigen DNA‐Inibitoren für die humane DNA‐Methyltransferase Dnmt1

Cited by 3 publications

References 37 publications

Phosphorothioation of Oligonucleotides Strongly Influences the Inhibition of Bacterial (M.HhaI) and Human (Dnmt1) DNA Methyltransferases

Phosphorothioation of Oligonucleotides Strongly Influences the Inhibition of Bacterial (M.HhaI) and Human (Dnmt1) DNA Methyltransferases

Mechanism‐Based Inhibitor of DNA Cytosine‐5 Methyltransferase by a SNAr Reaction with an Oligodeoxyribonucleotide Containing a 2‐Amino‐4‐Halopyridine‐C‐Nucleoside

Improvement of SNAr Reaction Rate by an Electron‐Withdrawing Group in the Crosslinking of DNA Cytosine‐5 Methyltransferase by a Covalent Oligodeoxyribonucleotide Inhibitor

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Mechanism‐Based Inhibitor of DNA Cytosine‐5 Methyltransferase by a S_NAr Reaction with an Oligodeoxyribonucleotide Containing a 2‐Amino‐4‐Halopyridine‐C‐Nucleoside

Improvement of S_NAr Reaction Rate by an Electron‐Withdrawing Group in the Crosslinking of DNA Cytosine‐5 Methyltransferase by a Covalent Oligodeoxyribonucleotide Inhibitor