Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors.
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.
MethylGene Inc., Department of Medicinal Chemistry, Montreal, Quebec, Canada.
Ljubomir
L
Isakovic
Oscar M
OM
Saavedra
David B
DB
Llewellyn
Stephen
S
Claridge
Lijie
L
Zhan
Naomy
N
Bernstein
Arkadii
A
Vaisburg
Nadine
N
Elowe
Andrea J
AJ
Petschner
Jubrail
J
Rahil
Norman
N
Beaulieu
France
F
Gauthier
A Robert
AR
MacLeod
Daniel
D
Delorme
Jeffrey M
JM
Besterman
Amal
A
Wahhab
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D011759:Pyrrolidines; D006710:Homocysteine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C541545:DNA (cytosine-5-)-methyltransferase 3b2, human; C000619380:DNMT1 protein, human