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 for binding to 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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-05, Vol.19 (10), p.2747-2751
Main Authors: Saavedra, Oscar M., Isakovic, Ljubomir, Llewellyn, David B., Zhan, Lijie, Bernstein, Naomy, Claridge, Stephen, Raeppel, Franck, Vaisburg, Arkadii, Elowe, Nadine, Petschner, Andrea J., Rahil, Jubrail, Beaulieu, Norman, MacLeod, A. Robert, Delorme, Daniel, Besterman, Jeffrey M., Wahhab, Amal
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
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
Humans
Medical sciences
Pharmacology. Drug treatments
S-Adenosylhomocysteine - chemical synthesis
S-Adenosylhomocysteine - chemistry
S-Adenosylhomocysteine - pharmacology
SAH analogues
Structure-Activity Relationship
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Summary:The inhibitory activity of base-modified SAH analogues and the specificity for binding to 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. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.03.113