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

摘要

The human DNA repair protein O~6-methylguanine DNA methyliransferase (MGMT) dealkyiates muta-genic O~6-alkylguanine lesions within DNA in an irreversible reaction which results in inactivation of the protein. MGMT also provides resistance of tumours to alkyiating 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 ollgodeoxyribonucieotides (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.