Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors
| Autor: | 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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| Rok vydání: | 2009 |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Pyrrolidines Methyltransferase Homocysteine Stereochemistry Clinical Biochemistry Pharmaceutical Science DNA Methyltransferase Inhibitor Heterocyclic Compounds 4 or More Rings Biochemistry Structure-Activity Relationship chemistry.chemical_compound S-Adenosyl-L-homocysteine Drug Discovery Humans Structure–activity relationship DNA (Cytosine-5-)-Methyltransferases Enzyme Inhibitors Molecular Biology chemistry.chemical_classification biology Organic Chemistry Enzyme chemistry Enzyme inhibitor biology.protein Molecular Medicine Nucleoside |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 19:2742-2746 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2009.03.132 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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