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dc.contributor.authorLopez, S
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorMcElhinney, R
dc.contributor.authorCordeiro, A
dc.contributor.authorMcMurry, T
dc.contributor.authorRozas, I
dc.date.accessioned2011-12-02T15:20:31Z
dc.date.available2011-12-02T15:20:31Z
dc.date.issued2011-03-01
dc.identifier.citationTowards more specific O6-methylguanine-DNA methyltransferase (MGMT) inactivators. 2011, 19 (5):1658-65 Bioorg Med Chemen
dc.identifier.issn1464-3391
dc.identifier.pmid21320783
dc.identifier.doi10.1016/j.bmc.2011.01.038
dc.identifier.urihttp://hdl.handle.net/10541/192872
dc.description.abstractSearching 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.
dc.language.isoenen
dc.subject.meshComputer Simulation
dc.subject.meshEnzyme Activation
dc.subject.meshEnzyme Inhibitors
dc.subject.meshHumans
dc.subject.meshInhibitory Concentration 50
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase
dc.subject.meshPyrimidines
dc.titleTowards more specific O6-methylguanine-DNA methyltransferase (MGMT) inactivators.en
dc.typeArticleen
dc.contributor.departmentSchool of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland.en
dc.identifier.journalBioorganic & Medicinal Chemistryen
html.description.abstractSearching 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.


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