title: Naturally occurring alkylresorcinols that mediate DNA damage and inhibit its repair.
abstract: A study of di- and trihydroxyalkylbenzenes and bis(dihydroxyalkylbenzenes) revealed that several compounds were capable of both mediating Cu(2+)-dependent DNA cleavage and strongly inhibiting DNA polymerase beta. The most potent DNA polymerase beta inhibitors were bis(dihydroxyalkylbenzenes) 5 and 6; compounds 3 and 4 were also reasonably potent. The length of the alkyl substituent was found to be a critical element for DNA polymerase beta inhibition, since compounds 1 and 2 had shorter substituents than 3 and were completely inactive. Lineweaver-Burk plots revealed that 3, 4, and 6 exhibited mixed inhibition of DNA polymerase beta with respect to both activated DNA and dTTP. Unsaturated bis(dihydroxyalkylbenzene) 5 was a pure noncompetitive inhibitor with respect to both substrates and associated avidly with the enzyme whether or not it was in complex with its substrate(s). Copper(II)-mediated DNA cleavage was the most pronounced for the trihydroxyalkylbenzene 3, consistent with an earlier report [Singh, U. S., Scannell, R. T., An, H., Carter, B. J., and Hecht, S. M. (1995) J. Am. Chem. Soc. 117, 12691-12699]. Unsaturated bis(dihydroxyalkylbenzene) 5 was the next most active DNA cleaving agent, followed by the dihydroxyalkylbenzene 4. The saturated bis(dihydroxyalkylbenzene) (6) did not cleave DNA well in a cell-free system under the conditions studied but nonetheless potentiated the effects of bleomycin to the greatest extent in cell culture studies. Interestingly, compound 5 produced a reduction in the numbers of viable cells when incubated in the presence of bleomycin and a further reduction in the numbers of viable cells in the presence of both bleomycin and Cu(2+). The same effect was noted to a lesser extent for compound 3 but not for 4 or 6.
authors.affiliation: Departments of Chemistry and Biology, University of Virginia, Charlottesville, Virginia 22901, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Starck
authors.forename: J Z
authors.initials: JZ
authors.lastname: Deng
authors.forename: S M
authors.initials: SM
authors.lastname: Hecht
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D002452:Cell Count / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry; D004249:DNA Damage / Q000187:drug effects; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors; D004260:DNA Repair / Q000187:drug effects; D004269:DNA, Bacterial / Q000037:antagonists & inhibitors* / Q000187:drug effects; D004357:Drug Synergism; D006131:Growth Inhibitors / Q000633:toxicity; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007941:Leukemia P388; D051379:Mice; D012118:Resorcinols / Q000737:chemistry* / Q000633:toxicity; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004269:DNA, Bacterial; D006131:Growth Inhibitors; D012118:Resorcinols; D001761:Bleomycin; D003300:Copper; D019951:DNA Polymerase beta