Polar, functionalized guanine-O6 derivatives resistant to repair by O6-alkylguanine-DNA alkyltransferase: implications for the design of DNA-modifying drugs

Dimitrios Pletsas, Richard T. Wheelhouse, Vassiliki Pletsa, Anna Nicolaou, Terence C. Jenkins, Michael C. Bibby, Soterios A. Kyrtopoulos

    Research output: Contribution to journalArticlepeer-review

    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. © 2006 Elsevier SAS. All rights reserved.
    Original languageEnglish
    Pages (from-to)330-339
    Number of pages9
    JournalEuropean Journal of Medicinal Chemistry
    Volume41
    Issue number3
    DOIs
    Publication statusPublished - Mar 2006

    Keywords

    • DNA repair
    • Drug design
    • O6-alkylguanine-DNA alkyltransferase
    • Purine

    Fingerprint

    Dive into the research topics of 'Polar, functionalized guanine-O6 derivatives resistant to repair by O6-alkylguanine-DNA alkyltransferase: implications for the design of DNA-modifying drugs'. Together they form a unique fingerprint.

    Cite this