Constrained ( l-)- S-adenosyl- l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2009-05, Vol.19 (10), p.2742-2746
• Main Authors: Isakovic, Ljubomir, Saavedra, Oscar M., Llewellyn, David B., Claridge, Stephen, Zhan, Lijie, Bernstein, Naomy, Vaisburg, Arkadii, Elowe, Nadine, Petschner, Andrea J., Rahil, Jubrail, Beaulieu, Norman, Gauthier, France, MacLeod, A. Robert, Delorme, Daniel, Besterman, Jeffrey M., Wahhab, Amal
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Constrained SAH analogues; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNMT1 inhibitors; DNMT3b2 inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; Heterocyclic Compounds, 4 or More Rings - chemical synthesis; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Homocysteine - analogs & derivatives; Homocysteine - chemical synthesis; Homocysteine - pharmacology; Humans; Medical sciences; Pharmacology. Drug treatments; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.03.132

Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2 S,4 S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine. Optimization of 1a changed the selectivity profile of these inhibitors. Chloro substitution at the 2-position, compound 1b, retained potency against DNMT1 while N 6 alkylation, compound 7a, conserved DNMT3b2 activity. Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2 S,4 S)-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.