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

Abstract 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.