Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors |
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Authors: | Ljubomir Isakovic Oscar M. Saavedra David B. Llewellyn Stephen Claridge Lijie Zhan Naomy Bernstein Arkadii Vaisburg Nadine Elowe Andrea J. Petschner Jubrail Rahil Norman Beaulieu France Gauthier A. Robert MacLeod Daniel Delorme Jeffrey M. Besterman Amal Wahhab |
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Affiliation: | 1. MethylGene Inc., Department of Medicinal Chemistry, 7220 rue Frederick-Banting, Montreal, Quebec, Canada H4S 2A1;2. MethylGene Inc., Department of Lead Discovery, 7220 rue Frederick-Banting, Montreal, Quebec, Canada H4S 2A1;3. MethylGene Inc., Department of Pharmacology and Cell Biology, 7220 rue Frederick-Banting, Montreal, Quebec, Canada H4S 2A1 |
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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 N6 alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N6 positions reduced activity against both enzymes. |
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