title: Enzymatic Studies of Isoflavonoids as Selective and Potent Inhibitors of Human Leukocyte 5-Lipo-Oxygenase.
abstract: Continuing our search to find more potent and selective 5-LOX inhibitors, we present now the enzymatic evaluation of seventeen isoflavones (IR) and nine isoflavans (HIR), and their in vitro and in cellulo potency against human leukocyte 5-LOX. Of the 26 compounds tested, 10 isoflavones and 9 isoflavans possessed micromolar potency, but only three were selective against 5-LOX (IR-2, HIR-303, and HIR-309), with IC50 values at least 10 times lower than those of 12-LOX, 15-LOX-1, and 15-LOX-2. Of these three, IR-2 (6,7-dihydroxy-4-methoxy-isoflavone, known as texasin) was the most selective 5-LOX inhibitor, with over 80-fold potency difference compared with other isozymes; Steered Molecular Dynamics (SMD) studies supported these findings. The presence of the catechol group on ring A (6,7-dihydroxy versus 7,8-dihydroxy) correlated with their biological activity, but the reduction of ring C, converting the isoflavones to isoflavans, and the substituent positions on ring B did not affect their potency against 5-LOX. Two of the most potent/selective inhibitors (HIR-303 and HIR-309) were reductive inhibitors and were potent against 5-LOX in human whole blood, indicating that isoflavans can be potent and selective inhibitors against human leukocyte 5-LOX in vitro and in cellulo.
authors.affiliation: Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago, Chile, Casilla 442, Correo 2, Santiago, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Mascayano
authors.affiliation: Laboratorio de Investigación Científica Emory Black, Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago, Chile, Casilla 442, Correo 2, Santiago, Chile.
authors.forename: Victoria
authors.initials: V
authors.lastname: Espinosa
authors.affiliation: Laboratorio de Investigación Científica Emory Black, Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago, Chile, Casilla 442, Correo 2, Santiago, Chile.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sepúlveda-Boza
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, 95064.
authors.forename: Eric K
authors.initials: EK
authors.lastname: Hoobler
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, 95064.
authors.forename: Steve
authors.initials: S
authors.lastname: Perry
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, 95064.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Diaz
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, 95064.
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007962:Leukocytes / Q000201:enzymology*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D012756:Sheep
chemical_list: D005419:Flavonoids; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human
keywords: IC50 values, structure-activity relationship; human lipo-oxygenase; isoflavans derivative; steered molecular dynamics