title: Polar, functionalized guanine-O6 derivatives resistant to repair by O6-alkylguanine-DNA alkyltransferase: implications for the design of DNA-modifying drugs.
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.
authors.affiliation: School of Pharmacy, University of Bradford, UK.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pletsas
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wheelhouse
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Pletsa
authors.forename: Anna
authors.initials: A
authors.lastname: Nicolaou
authors.forename: Terence C
authors.initials: TC
authors.lastname: Jenkins
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bibby
authors.forename: Soterios A
authors.initials: SA
authors.lastname: Kyrtopoulos
mesh_terms: D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D045643:DNA Repair Enzymes / Q000737:chemistry*; D015195:Drug Design; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D011687:Purines; D006147:Guanine; D004247:DNA; D019853:O(6)-Methylguanine-DNA Methyltransferase; D045643:DNA Repair Enzymes