Naturally occurring alkylresorcinols that mediate DNA damage and inhibit its repair

A study Of di- and trihydroxyalkylbenzenes and bis(dihydroxyalkylbenzenes) revealed that several compounds were capable of both mediating Cu2+-depende nt DNA cleavage and strongly inhibiting DNA polymerase beta. The most poten t DNA polymerase beta inhibitors were bis(dihydroxyalkylbenzenes) 5 and 6; compounds 3 and 4 were also reasonably potent. The length of the alkyl subs tituent was found to be a critical element for DNA polymerase beta inhibiti on, since compounds 1 and 2 had shorter substituents than 3 and were comple tely inactive. Lineweaver-Burk plots revealed that 3, 4, and 6 exhibited mi xed inhibition of DNA polymerase beta with respect to both activated DNA an d dTTP. Unsaturated bis(dihydroxyalkylbenzene) 5 was a pure noncompetitive inhibitor with respect to both substrates and associated avidly with the en zyme whether or not it was in complex with its substrate(s). Copper(II)-med iated 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. Chern. Sec. 117 12691-12699] . Unsaturated bis(dihydroxyalkylbenzene) 5 was the next most active DNA cle aving agent, followed by the dihydroxyalkylbenzene 4. The saturated bis(dih ydroxyalkylbenzene) (6) did not cleave DNA well in a cell-free system under the conditions studied but nonetheless potentiated the effects of bleomyci n 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 cell s in the presence of both bleomycin and Cu2+. The same effect was noted to a lesser extent for compound 3 but not for 4 or 6.