Novel post DNA synthesis chemistry for preparing oligonucleotides containing O6-modified purines

Nucleic Acids Symp Ser (Oxf). 2005:(49):23-4. doi: 10.1093/nass/49.1.23.

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.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Guanine / analogs & derivatives*
  • O(6)-Methylguanine-DNA Methyltransferase / antagonists & inhibitors*
  • Oligodeoxyribonucleotides / chemical synthesis*
  • Oligodeoxyribonucleotides / chemistry

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Oligodeoxyribonucleotides
  • Guanine
  • O(6)-Methylguanine-DNA Methyltransferase