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Towards more specific O6-methylguanine-DNA methyltransferase (MGMT) inactivators.
Lopez, S Margison, Geoffrey P McElhinney, R Cordeiro, A McMurry, T Rozas, I
Lopez, S
Margison, Geoffrey P
McElhinney, R
Cordeiro, A
McMurry, T
Rozas, I
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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.
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Date
2011-03-01
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Article
Citation
Towards more specific O6-methylguanine-DNA methyltransferase (MGMT) inactivators. 2011, 19 (5):1658-65 Bioorg Med Chem