Design and synthesis of ten biphenyl-neolignan derivatives and their in vitro inhibitory potency against cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4-formation.
A set of ten derivatives of methylhonokiol, an anti-inflammatory active biphenyl-type neolignan from Magnolia grandiflora, has been evaluated for their in vitro cyclooxygenase-1/2 (COX-1/2) inhibitory activity using assays with purified prostaglandin H synthase (PGHS)-1 and PGHS-2 enzymes as well as for their 5-lipoxygenase (5-LOX) mediated LTB(4) formation inhibitory activity using an assay with activated human polymorphonuclear leukocytes. The derivatization reactions included methylation, acetylation, hydrogenation, epoxydation and isomerization. Five of the derivatives are new to science. The most active compound against COX-1 and COX-2 was methylhonokiol with IC(50) values of 0.1 microM, whereas the most active compound against LTB(4) formation was (E)-3'-propenyl-5-(2-propenyl)-biphenyl-2,4'-diol with an IC(50) value of 1.0 microM. Structure-activity relationship studies showed that the polarity of the derivatives plays a crucial role in their activity towards COX-1/2 enzyme and 5-LOX mediated LTB(4) formation.
Schühly
Wolfgang
W
Department of Pharmacognosy, Institute of Pharmaceutical Sciences, Karl-Franzens-Universität Graz, Graz, Austria. wolfgang.schuehly@uni-graz.at
Hüfner
Antje
A
Pferschy-Wenzig
Eva M
EM
Prettner
Elke
E
Adams
Michael
M
Bodensieck
Antje
A
Kunert
Olaf
O
Oluwemimo
Asije
A
Haslinger
Ernst
E
Bauer
Rudolf
R
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001713:Biphenyl Compounds / Q000737:chemistry*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017705:Lignans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D031566:Magnolia / Q000737:chemistry; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001094:Arachidonate 5-Lipoxygenase; D001713:Biphenyl Compounds; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D007975:Leukotriene B4; D017705:Lignans; D011451:Prostaglandin-Endoperoxide Synthases; C010574:biphenyl