Inhibitory effects of sulfobacin B on DNA polymerase and inflammation.
The sulfonolipid, sulfobacin B, is isolated from Chryseobacterium sp. and functions both as a von Willebrand factor receptor antagonist and a DNA polymerase (pol) α inhibitor. Previously, we chemically synthesized sulfobacin B by starting from L-cysteine. In this study, we investigated the inhibitory effects of chemically synthesized sulfobacin B on the activity of pols and other DNA metabolic enzymes. Sulfobacin B selectively inhibited the activity of all animal pol species: Among the pols tested, the inhibitory effect of the compound on pol λ activity was the strongest with IC50 values of 1.6 µM. However, sulfobacin B did not influence the activity of plant or prokaryotic pols, or that of the other DNA metabolic enzymes such as primase of pol α, RNA polymerase, polynucleotide kinase or deoxyribonuclease I. As we previously found a positive relationship between pol λ inhibition and anti-inflammation, we examined whether sulfobacin B could inhibit inflammatory responses. The compound caused a marked reduction in 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation in the mouse ear. In a cell culture system using mouse macrophages, sulfobacin B strongly inhibited the production of tumor necrosis factor (TNF)-α and the action of nuclear factor-κB induced by lipopolysaccharide (LPS). In an in vivo mouse model of LPS-induced acute inflammation, the intraperitoneal injection of sulfobacin B to mice led to the suppression of serum TNF-α production. These results indicate that sulfobacin B is a potential chemotherapeutic agent for inflammation.
Maeda
Jun
J
Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Kobe, Hyogo 650-0017, Japan.
Nishida
Masayuki
M
Takikawa
Hirosato
H
Yoshida
Hiromi
H
Azuma
Takeshi
T
Yoshida
Masaru
M
Mizushina
Yoshiyuki
Y
D017738:Alkanesulfonic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019384:Nucleic Acid Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D017738:Alkanesulfonic Acids; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; C096616:sulfobacin B; D004259:DNA-Directed DNA Polymerase