We found that phenolic compounds, petasiphenol and curcumin (diferuloylmethane), were selective inhibitors of DNA polymerase λ (pol λ) in vitro. In this review, we described the molecular structure and bio-activity (i.e., pol inhibitory activity, antiinflammatory activity and anti-oxidant activity) relationship of phenolic compounds such as petasiphenol, curcumin and 13 chemically synthesized derivatives of curcumin. The inhibitory effect on pol λ (full-length, i.e. intact pol λ including the BRCA1 C-terminus (BRCT) domain) by some derivatives was stronger than that by curcumin, and monoacetylcurcumin (compound (13)) was the strongest pol λ inhibitor of all the compounds tested, achieving 50% inhibition at a concentration of 3.9 μM. Compound (13) did not inhibit the activity of the C-terminal catalytic domain of pol λ including the pol β-like core, in which the proline-rich region and BRCT domain were deleted from its N-terminal region. These curcumin derivatives had anti-12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammatory activity with the same tendency as pol λ inhibitory activity, but compound (13) had no anti-oxidant activity (i.e., DPPH radical-scavenging activity). This compound did not influence the activities of replicative pols such as α, δ and η, and had no effect on repair-related pol activity such as pol β, although the three-dimensional structure of pol β is thought to be highly similar to that of pol λ. Based on these results, the pol λ-inhibitory mechanism of compound (13) and the structure-activity relationship of anti-inflammation are discussed.
Keywords: Curcumin, Monoacetylcurcumin, DNA polymerase λ, DNA polymerase inhibitory activity, Anti-inflammatory activity, Antioxidant activity, Enzyme inhibitor, TPA (12-O-tetradecanoylphorbol-13-acetate)
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