Towards more specific O6-methylguanine-DNA methyltransferase (MGMT) inactivators
2011; Elsevier BV; Volume: 19; Issue: 5 Linguagem: Inglês
10.1016/j.bmc.2011.01.038
ISSN1464-3391
AutoresSergio López, Geoffrey P. Margison, R. Stanley McElhinney, Alessandra Cordeiro, T. Brian H. McMurry, Isabel Rozas,
Tópico(s)DNA and Nucleic Acid Chemistry
ResumoSearching for a novel family of inactivators of the human DNA repair protein O6-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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