SAR around (l)-S-adenosyl-l-homocysteine, an inhibitor of human DNA methyltransferase (DNMT) enzymes.
The inhibitory activity of base-modified SAH analogues and the specificity of inhibiting human DNMT1 and DNMT3b2 enzymes was explored. The 6-amino group was essential while the 7-N of the adenine ring of SAH could be replaced by CH- without loss of activity against both enzymes. The introduction of small groups at the 2-position of the adenine moiety favors DNMT1 over DNMT3b2 inhibition whereas alkylation of the N(6)-amino moiety favors the inhibition of DNMT3b2 enzyme.
MethylGene Inc., Departments of Medicinal Chemistry, Montreal, Quebec, Canada.
Oscar M
OM
Saavedra
Ljubomir
L
Isakovic
David B
DB
Llewellyn
Lijie
L
Zhan
Naomy
N
Bernstein
Stephen
S
Claridge
Franck
F
Raeppel
Arkadii
A
Vaisburg
Nadine
N
Elowe
Andrea J
AJ
Petschner
Jubrail
J
Rahil
Norman
N
Beaulieu
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; D006801:Humans; D012435:S-Adenosylhomocysteine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D012435:S-Adenosylhomocysteine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C541545:DNA (cytosine-5-)-methyltransferase 3b2, human; C000619380:DNMT1 protein, human