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 LTB4 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 IC50 values of 0.1 mu M, whereas the most active compound against LTB4 formation was (E)-3'-propenyl-5-(2-propenyl)-biphenyl-2,4'-diol with an IC50 value of 1.0 mu M. 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 LTB4 formation. (C) 2009 Elsevier Ltd. All rights reserved.