Solanapyrone A, a phytotoxin and enzyme inhibitor isolated from a fungus (SUT 01B1-2) selectively inhibits the activities of mammalian DNA polymerase beta and lambda (pol beta and lambda) in vitro. The IC50 values of the compound were 30 microm for pol beta and 37 microm for pol lambda. Because pol beta and lambda are in a family and their three-dimensional structures are thought to be highly similar to each other, we used pol beta to analyze the biochemical relationship with solanapyrone A. On pol beta, solanapyrone A antagonistically competed with both the DNA template and the nucleotide substrate. BIAcore analysis demonstrated that solanapyrone A bound selectively to the N-terminal 8-kDa domain of pol beta. This domain is known to bind single-stranded DNA, provide 5'-phosphate recognition of gapped DNA, and cleave the sugar-phosphate bond 3' to an intact apurinic/apyrimidinic (AP) site (i.e. AP lyase activity) including 5'-deoxyribose phosphate lyase activity. Solanapyrone A inhibited the single-stranded DNA-binding activity but did not influence the activities of the 5'-phosphate recognition in gapped DNA structures and the AP lyase. Based on these results, the inhibitory mechanism of solanapyrone A is discussed.

Traditional Chinese medicinal plants are a treasure house for screening novel inhibitors of DNA polymerases and DNA topoisomerases from mammals; in the present study, nine lanostanetype triterpene acids were found in sclerotium of Poria cocos. Among the nine compounds, only dehydroebriconic acid could potently inhibit DNA topoisomerase II (topo II) activity (IC₅₀=4.6 μM), while the compound moderately inhibited the activities of DNA polymerases α, β, γ, δ, ɛ, η, iota;, κ and λ only from mammals, to similar extents. Another compound, dehydrotrametenonic acid, also showed moderate inhibitory effects against topo II (IC₅₀=37.5 μM) and weak effects against all the polymerases tested. Both compounds showed no inhibitory effect against topo I, higher plant (cauliflower) DNA polymerase I (α‐like polymerase) or II (βlike polymerase), calf thymus terminal deoxynucleotidyl transferase, human immunodeficiency virus type‐1 reverse transcriptase, prokaryotic DNA polymerases such as the Klenow fragment of E. coli DNA polymerase I, Taq DNA polymerase and T4 DNA polymerase, or DNA metabolic enzymes such as T7 RNA polymerase, T4 polynucleotide kinase and bovine deoxyribonu‐clease I. These findings suggest that dehydroebriconic acid and dehydrotrametenonic acid should be designated as topo II‐preferential inhibitors, although they also moderately inhibited all the mammalian DNA polymerases tested. Both dehydrotrametenonic acid and dehydroebriconic acid could prevent the growth of human gastric cancer cells, and their LD₅₀ values were 63.6 and 38.4 μM, respectively. The cells were halted at the G1 phase in the cell cycle. The relation between the structure of triterpene acids and their inhibitory activities is discussed.

We previously reported that phenolic compounds, petasiphenol and curcumin (diferuloylmethane), were a selective inhibitor of DNA polymerase λ (pol λ) in vitro. The purpose of this study was to investigate the molecular structural relationship of 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‐ terminal [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. The compound did not influence the activities of replicative pols such as α, δ, and ɛ. It had no effect on pol β activity either, although the three‐dimensional structure of pol β is thought to be highly similar to that of pol λ. 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 BRCT motif was deleted from its N‐terminal region. MALDI‐TOF MS analysis demonstrated that compound 13 bound selectively to the N‐terminal domain of pol λ, but did not bind to the C‐terminal region. Based on these results, the pol λ‐inhibitory mechanism of compound 13 is discussed.