TY - JOUR
T1 - Naturally occurring alkylresorcinols that mediate DNA damage and inhibit its repair
AU - Starck, Shelley R.
AU - Deng, Jing Zhen
AU - Hecht, Sidney M.
PY - 2000/3/7
Y1 - 2000/3/7
N2 - A study of di- and trihydroxyalkylbenzenes and bis(dihydroxyalkylbenzenes) revealed that several compounds were capable of both mediating Cu2+-dependent DNA cleavage and strongly inhibiting DNA polymerase β. The most potent DNA polymerase β 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 β 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 β 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 Cu2+. The same effect was noted to a lesser extent for compound 3 but not for 4 or 6.
AB - A study of di- and trihydroxyalkylbenzenes and bis(dihydroxyalkylbenzenes) revealed that several compounds were capable of both mediating Cu2+-dependent DNA cleavage and strongly inhibiting DNA polymerase β. The most potent DNA polymerase β 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 β 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 β 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 Cu2+. The same effect was noted to a lesser extent for compound 3 but not for 4 or 6.
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U2 - 10.1021/bi991509d
DO - 10.1021/bi991509d
M3 - Article
C2 - 10694411
AN - SCOPUS:0034052127
SN - 0006-2960
VL - 39
SP - 2413
EP - 2419
JO - Biochemistry
JF - Biochemistry
IS - 9
ER -