Journal
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS
Volume 39, Issue 8, Pages 1108-1121Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15257770.2020.1764971
Keywords
Tricyclic; O6-methylguanine; oligodeoxyribonucleotide; MGMT; alkyltransferase-like protein
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Funding
- PTDF Nigeria
- EPSRC (Engineering and Physical Sciences Research Council) [GR/M44477]
- BBSRC (Biotechnology and Biological Sciences Research Council) [50/B14708]
- Cancer Research UK
- Government of Thailand
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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.
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