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ID: ALA1151876
Journal: Bioorg Med Chem Lett
Title: Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors.
Authors: Isakovic L, Saavedra OM, Llewellyn DB, Claridge S, Zhan L, Bernstein N, Vaisburg A, Elowe N, Petschner AJ, Rahil J, Beaulieu N, Gauthier F, MacLeod AR, Delorme D, Besterman JM, Wahhab A.
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.
CiteXplore: 19364644