title: Towards more specific O6-methylguanine-DNA methyltransferase (MGMT) inactivators.
abstract: Searching for a novel family of inactivators of the human DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) which is known to bind to the DNA minor groove, we have computationally modelled and synthesised two series of 2-amino-6-aryloxy-5-nitropyrimidines with morpholino or aminodiaryl substituents (potential minor groove binders) at the 4-position. Synthesis of these compounds was achieved by successive substitution of each of the two Cl atoms of 2-amino-4,6-dichloro-5-nitropyrimidine by the corresponding amino and aryloxy derivatives. Biochemical evaluation of these compounds as MGMT inactivators showed poor activities, but in general the 4-bromothenyloxy derivatives showed better inactivation than the benzyloxy versions. DNA binding assessment was not possible due to insolubility problems.
authors.affiliation: School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lopez
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Margison
authors.forename: R Stanley
authors.initials: RS
authors.lastname: McElhinney
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cordeiro
authors.forename: T Brian H
authors.initials: TB
authors.lastname: McMurry
authors.forename: Isabel
authors.initials: I
authors.lastname: Rozas
mesh_terms: D003198:Computer Simulation; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D019853:O(6)-Methylguanine-DNA Methyltransferase