title: Development of rationally designed DNA N6 adenine methyltransferase inhibitors.
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.
authors.affiliation: University of Southampton, School of Chemistry, University Road, Highfield, Southampton SO17 1BJ, UK.
authors.forename: Gerard
authors.initials: G
authors.lastname: Hobley
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: McKelvie
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Harmer
authors.forename: Jason
authors.initials: J
authors.lastname: Howe
authors.forename: Petra C F
authors.initials: PC
authors.lastname: Oyston
authors.forename: Peter L
authors.initials: PL
authors.lastname: Roach
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D012436:S-Adenosylmethionine; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D012436:S-Adenosylmethionine; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific)