Synthesis of oligodeoxyribonucleotides containing a tricyclic thio analogue of  O  6 -methylguanine and their recognition by MGMT and Atl1.
Promutagenic  O  6 -alkylguanine adducts in DNA are repaired in humans by  O  6 -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  O  6 -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.
Abdu K, Aiertza MK, Wilkinson OJ, Senthong P, Craggs TD, Povey AC, Margison GP, Williams DM