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

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 13; pp. 4459 - 4465
• Main Authors: SCHÜHLY, Wolfgang, HÜFNER, Antje, PFERSCHY-WENZIG, Eva M, PRETTNER, Elke, ADAMS, Michael, BODENSIECK, Antje, KUNERT, Olaf, OLUWEMIMO, Asije, HASLINGER, Ernst, BAUER, Rudolf
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 01.07.2009
• Subjects: Arachidonate 5-Lipoxygenase - metabolism; Biological and medical sciences; Biphenyl Compounds - chemistry; Bones, joints and connective tissue. Antiinflammatory agents; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Humans; Leukocytes - metabolism; Leukotriene B4 - antagonists & inhibitors; Leukotriene B4 - metabolism; Lignans - chemical synthesis; Lignans - chemistry; Lignans - pharmacology; Magnolia - chemistry; Medical sciences; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - metabolism; Structure-Activity Relationship; Prostaglandin-endoperoxide synthase; Enzyme; SAR; Cyclooxygenase 2; Antiinflammatory agent; Cyclooxygenase 1; In vitro; Cyclooxygenase; Leukotriene B4; Structure activity relation; Biphenyl derivatives; Arachidonate 5-lipoxygenase; Epoxide; Phenols; Lignan; Honokiol derivatives; Oxidoreductases; Lipoxygenase; Chemical synthesis; Anti-inflammatory
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.05.018

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.