Development of rationally designed DNA N6 adenine methyltransferase inhibitors

Gerard Hobley; Jennifer C McKelvie; Jenny E Harmer; Jason Howe; Petra C F Oyston; Peter L Roach

doi:10.1016/j.bmcl.2012.03.072

Development of rationally designed DNA N6 adenine methyltransferase inhibitors

Bioorg Med Chem Lett. 2012 May 1;22(9):3079-82. doi: 10.1016/j.bmcl.2012.03.072. Epub 2012 Mar 27.

Authors

Gerard Hobley¹, Jennifer C McKelvie, Jenny E Harmer, Jason Howe, Petra C F Oyston, Peter L Roach

Affiliation

¹ University of Southampton, School of Chemistry, University Road, Highfield, Southampton SO17 1BJ, UK.

PMID: 22483584
DOI: 10.1016/j.bmcl.2012.03.072

Abstract

A series of bisubstrate inhibitors for DNA N6 adenine methyltransferase (Dam) have been synthesized by linking an amine analogue of S-adenosylmethionine to an aryl moiety designed to probe the binding pocket of the DNA adenine base. An initial structure-activity relationship study has identified substituents that increase inhibitor potency to the ∼10 μM range and improve selectivity against the human cytosine methyltransferase Dnmt1.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Binding Sites
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Humans
S-Adenosylmethionine
Site-Specific DNA-Methyltransferase (Adenine-Specific) / antagonists & inhibitors*
Structure-Activity Relationship
Substrate Specificity

Substances

Enzyme Inhibitors
S-Adenosylmethionine
Site-Specific DNA-Methyltransferase (Adenine-Specific)