The novel natural product YM-26567-1 [(+)-trans-4-(3-dodecanoyl-2,4,6- trihydroxyphenyl)-7-hydroxy-2-(4-hydroxyphenyl)chroman]: a competitive inhibitor of group II phospholipase A2.
(+)-trans-4-(3-dodecanoyl-2,4,6-trihydroxyphenyl)-7-hydroxy-2-(4- hydroxyphenyl)chroman (YM-26567-1), a novel natural product isolated from the fruit of Horsfieldia amygdaline, dose-dependently inhibited group II phospholipase A2 (PLA2) prepared from rabbit platelet with an IC50 value of 6.7 microM (4.6-9.6 microM, n = 4). In contrast to irreversible PLA2 inhibitors such as manoalide and p-bromophenacyl bromide, the PLA2 inhibition of YM-26567-1 was independent of preincubation time. Lineweaver-Burk analysis revealed that YM-26567-1 behaved as a competitive inhibitor of rabbit platelet PLA2 with a Ki value of 1.6 +/- 0.3 microM (n = 5). Although YM-26567-1 also competitively inhibited group I PLA2 derived from porcine pancreas, the Ki value was approximately 10-fold greater for porcine pancreas than for rabbit platelet PLA2. In vivo, topical application of YM-26567-1 to the mouse ear inhibited 12-O-tetradecanoylphorbol-13-acetate (1 micrograms/ear)-induced mouse ear edema in a dose-dependent manner with a 50% effective dose of 28 micrograms/ear (13-63 micrograms/ear, n = 10/dose), but did not improve arachidonic acid (4 mg/ear)-induced mouse ear edema at 1 mg/ear. These results suggest that YM-26567-1 is a competitive PLA2 inhibitor showing a higher affinity for group II than group I PLA2, and that it may act as a potent anti-inflammatory compound through its direct inhibition of PLA2.
Miyake
A
A
Molecular and Cellular Pharmacology Department, Yamanouchi Pharmaceutical Co. Ltd., Tokyo, Japan.
Yamamoto
H
H
Takebayashi
Y
Y
Imai
H
H
Honda
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology; D001667:Binding, Competitive; D002839:Chromans / Q000494:pharmacology*; D004487:Edema / Q000517:prevention & control; D007700:Kinetics; D051379:Mice; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D011817:Rabbits; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002839:Chromans; C078775:YM 26567-1; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2; D013755:Tetradecanoylphorbol Acetate