title: Cinnamyl-3,4-dihydroxy-α-cyanocinnamate is a potent inhibitor of 5-lipoxygenase.
abstract: Lipoxygenases (LOs) are iron-containing enzymes that catalyze the conversion of arachidonic acid into hydroperoxyeicosatetraenoic acids (HPETEs) and other bioactive lipid mediators. In mammals, 5-LO, 15-LO, and 12-LO enzymes seem to have distinct roles in pathophysiological contexts, which have emphasized the need for selective inhibitors. Cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) has been proposed as potent and selective inhibitor of platelet-type 12-LO (p12-LO). Here, we re-evaluated the selectivity profile of CDC on LOs, and we show that CDC is a potent and direct inhibitor of 5-LO. CDC reduced 5-LO activity in cell-free assays (purified human recombinant enzyme or leukocyte homogenates), with IC(50) values in the low nanomolar range (9-25 nM) and a selectivity index of approximately 35 and 15 over p12-LO and 15-LO1, respectively. Likewise, CDC inhibited 5-LO product formation in intact human polymorphonuclear leukocytes and monocytes (IC(50) = 0.45-0.8 μM). A lower potency was observed for 15-LO1, whereas p12-LO activity in platelets was hardly affected. In human whole blood, CDC efficiently reduced the formation of 5-LO products, and similar effects were observed for 12(S)-H(P)ETE and 15(S)-H(P)ETE. Finally, CDC (3.5 and 7 mg/kg i.p.) was effective in vivo in the platelet-activating factor-induced shock in mice and reduced formation of the 5-LO product leukotriene B(4) in the rat carrageenan-induced pleurisy after a single oral dose of 10 mg/kg. Together, our data demonstrate that CDC is a potent inhibitor of 5-LO with efficacy in vivo and encourage further development of CDC as the lead compound.
authors: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Jena, Germany. carlo.pergola@uni-jena.de
authors: Carlo
authors: C
authors: Pergola
authors: Bianca
authors: B
authors: Jazzar
authors: Antonietta
authors: A
authors: Rossi
authors: Ulrike
authors: U
authors: Buehring
authors: Susann
authors: S
authors: Luderer
authors: Friederike
authors: F
authors: Dehm
authors: Hinnak
authors: H
authors: Northoff
authors: Lidia
authors: L
authors: Sautebin
authors: Oliver
authors: O
authors: Werz
mesh_terms: D000328:Adult; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D010998:Pleurisy / Q000188:drug therapy / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002109:Caffeic Acids; D016859:Lipoxygenase Inhibitors; C099255:cinnamyl-3,4-dihydroxycyanocinnamate; D001094:Arachidonate 5-Lipoxygenase