Towards more specific O6-methylguanine-DNA methyltransferase (MGMT) inactivators

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 5; pp. 1658 - 1665
• Main Authors: Lopez, Sergio, Margison, Geoffrey P., Stanley McElhinney, R., Cordeiro, Alessandra, McMurry, T. Brian H., Rozas, Isabel
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.03.2011; Elsevier
• Subjects: 5-Nitropyrimidine; Biological and medical sciences; chemistry; Computer Simulation; DNA; DNA repair; Docking; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Inhibitory Concentration 50; Medical sciences; MGMT; Miscellaneous; O-Methylguanine-DNA Methyltransferase - antagonists & inhibitors; PaTrin2; Pharmacology. Drug treatments; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Docking; PaTrin2; 5-Nitropyrimidine; MGMT; DNA repair; Nitro compound; Benzophenone derivatives; Morpholine derivatives; Inactivation; Modeling; Thiophene derivatives; Enzymatic activity; Structure activity relation; Molecular model; Repair; Chemical synthesis; Ether; Enzyme; Transferases; Benzene derivatives; Aniline derivatives; Ketone; DNA; Pyrimidine derivatives; Aromatic amine
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.01.038

Searching 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.