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Novel synthesis of O(6)-alkylguanine containing oligodeoxyribonucleotides as substrates for the human DNA repair protein, O(6)-methylguanine DNA methyltransferase (MGMT)

The human DNA repair protein O(6)-methylguanine DNA methyltransferase (MGMT) dealkylates mutagenic O(6)-alkylguanine lesions within DNA in an irreversible reaction which results in inactivation of the protein. MGMT also provides resistance of tumours to alkylating agents used in cancer chemotherapy...

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Detalles Bibliográficos
Autores principales: Shibata, Takayuki, Glynn, Nicola, McMurry, T. Brian H., McElhinney, R. Stanley, Margison, Geoffrey P., Williams, David M.
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1435717/
https://www.ncbi.nlm.nih.gov/pubmed/16609128
http://dx.doi.org/10.1093/nar/gkl117
Descripción
Sumario:The human DNA repair protein O(6)-methylguanine DNA methyltransferase (MGMT) dealkylates mutagenic O(6)-alkylguanine lesions within DNA in an irreversible reaction which results in inactivation of the protein. MGMT also provides resistance of tumours to alkylating agents used in cancer chemotherapy and its inactivation is therefore of particular clinical importance. We describe a post-DNA synthesis strategy which exploits the novel, modified base 2-amino-6-methylsulfonylpurine and allows access for the first time to a wide variety of oligodeoxyribonucleotides (ODNs) containing O(6)-alkylguanines. One such ODN containing O(6)-(4-bromothenyl)guanine is the most potent inactivator described to date with an IC(50) of 0.1 nM.