Novel synthesis of O6-alkylguanine containing oligodeoxyribonucleotides as substrates for the human DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT).
The human DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) dealkylates mutagenic O6-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 O6-alkylguanines. One such ODN containing O6-(4-bromothenyl)guanine is the most potent inactivator described to date with an IC50 of 0.1 nM.
Shibata
Takayuki
T
Department of Chemistry, Centre for Chemical Biology, Richard Roberts Building, University of Sheffield, Sheffield, S3 7HF, UK.
Glynn
Nicola
N
McMurry
T Brian H
TB
McElhinney
R Stanley
RS
Margison
Geoffrey P
GP
Williams
David M
DM
D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry
C403290:O(6)-(4-bromothenyl)guanine; D009838:Oligodeoxyribonucleotides; D009943:Organophosphorus Compounds; C434331:phosphoramidite; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase