Polar, Functionalized Guanine-O6 Derivatives Resistant to Repair by O6-Alkylguanine-DNA Alkyltransferase: Implications for the Design of DNA-modifying Drugs.
Wheelhouse, Richard T. Bibby, Michael C. Nicolaou, Anna Pletsas, Dimitrios
Wheelhouse, Richard T.
Bibby, Michael C.
Nicolaou, Anna
Pletsas, Dimitrios
Publication Date
2009-07-28
End of Embargo
Supervisor
Rights
Peer-Reviewed
Yes
Open Access status
closedAccess
Accepted for publication
Institution
Department
Awarded
Embargo end date
Collections
Additional title
Abstract
The protein O6-alkylguanine-DNA alkyltransferase (Atase) is responsible for the repair of DNA lesions generated by several clinically important anti-cancer drugs; this is manifest as active resistance in those cancer cell lines proficient in Atase expression. Novel O6-substituted guanine analogues have been synthesized, bearing acidic, basic and hydrogen bonding functional groups. In contrast to existing O6-modified purine analogues, such as methyl or benzyl, the new compounds were found to resist repair by Atase even when tested at concentrations much higher than O6-benzylguanine, a well-established Atase substrate active both in vitro and in vivo. The inactivity of the new purines as covalent substrates for Atase indicates that agents to deliver these groups to DNA would represent a new class of DNA-modifying drug that circumvents Atase-mediated resistance.
Version
No full-text in the repository
Citation
Pletsas, D., Wheelhouse, R.T., Pletsas, V., Nicolaou, A., Jenkins, T.C., Bibby, M.C. and Kyrtopoulos, S.A. (). Polar, Functionalized Guanine-O6 Derivatives Resistant to Repair by O6-Alkylguanine-DNA Alkyltransferase: Implications for the Design of DNA-modifying Drugs. European Journal of Medicinal Chemistry.
Link to publisher’s version
Link to published version
Link to Version of Record
Type
Article