Synthesis of oligodeoxyribonucleotides containing a tricyclic thio analogue of O6-methylguanine and their recognition by MGMT and Atl1

Kabir Abdu, Miren Karmele Aiertza Otxotorena, Oliver J. Wilkinson, Pattama Senthong, Timothy D. Craggs, Andrew Povey, Geoffrey Margison, David Williams

Research output: Contribution to journalArticlepeer-review

Abstract

Promutagenic O6-alkylguanine adducts in DNA are repaired in humans by O6-methylguanine-DNA-methyltransferase (MGMT) in an irreversible reaction. Here we describe the synthesis of a phosphoramidite that allows the preparation of oligodeoxyribonucleotides (ODNs) containing a novel tricyclic thio analogue of O6-methylguanine in which the third ring bridges the 6-thio group and C7 of a 7-deazapurine. These ODNs are very poor substrates for MGMT and poorly recognised by the alkyltransferase-like protein, Atl1. Examination of the active sites of both MGMT and Atl1 suggest large steric clashes hindering binding of the analogue. Such analogues, if mutagenic, are likely to be highly toxic.
Original languageEnglish
JournalNucleosides, Nucleotides and Nucleic Acids
Publication statusAccepted/In press - 1 May 2020

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