title: Novel post DNA synthesis chemistry for preparing oligonucleotides containing O6-modified purines.
abstract: O6-alkylguanine DNA alkyltransferase (AGT) is a key target for inhibition during cancer chemotherapy. A large number of O6-modified-guanine analogues have been developed as AGT inhibitors, of which benzyl and (4-bromothenyl) have been used clinically. Since the normal AGT substrate is the alkylated guanine in DNA, the inhibition of AGT by oligonucleotides containing these compounds offers a promising therapeutic approach in terms of efficacy. In order to prepare such oligonucleotides, we have synthesised the novel phosphoramidite analogue of the 2'-deoxyriboside of 2-amino-6-methylsulfonylpurine. Following the incorporation of the analogue into DNA, the subsequent nucleophilic displacement of the methylsulfanyl group by alkoxide provides a convenient route to a variety of oligonucleotides containing O6-modified guanines.
authors.affiliation: Centre for Chemical Biology, Department of Chemistry, Richard Roberts Building, University of Sheffield, Sheffield S3 7HF, UK.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shibata
authors.forename: David M
authors.initials: DM
authors.lastname: Williams
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009838:Oligodeoxyribonucleotides; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase