Abstract
Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity profile of these inhibitors. A Chloro substituent at the 2-position of 1a, compound 1d, retained potency against DNMT1, while N(6) alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N(6) positions reduced activity against both enzymes.
MeSH terms
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors*
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Homocysteine / analogs & derivatives*
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Homocysteine / chemical synthesis
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Homocysteine / pharmacology
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Humans
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Heterocyclic Compounds, 4 or More Rings
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Pyrrolidines
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Homocysteine
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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DNA (cytosine-5-)-methyltransferase 3b2, human
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DNMT1 protein, human