title: Synthesis and SAR studies of mono O-prenylated coumarins as potent 15-lipoxygenase inhibitors.
abstract: All of the mono isopentenyloxy, -geranyloxy and -farnesyloxy derivatives of coumarin were synthesized and their inhibitory potency against soybean 15-lipoxygenase (SLO) and human 15-lipoxygenase-1 (HLO-1) were determined. Amongst the synthetic analogs, 5-farnesyloxycoumarin showed the most potent inhibitory activity against SLO (IC(50) = 0.8 μM) while 6-farnesyloxycoumarin was the strongest HLO-1 inhibitor (IC(50) = 1.3 μM). The IC(50) variations of the farnesyl derivatives for HLO-1 (1.3 to ∼75 μM) were much higher than that observed for SLO (0.8-5.8 μM). SAR studies showed that hydrogen bonding, CH/π, anion-π and S-OC interactions with Fe(III)-OH, Leu408, Glu357 and Met419 were the distinct intermolecular interactions which can lead to important role of the coumarin substitution site in HLO-1 inhibitory potency, respectively.
authors.affiliation: Biotechnology Research Center and School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Iranshahi
authors.forename: Atena
authors.initials: A
authors.lastname: Jabbari
authors.forename: Ala
authors.initials: A
authors.lastname: Orafaie
authors.forename: Robabeh
authors.initials: R
authors.lastname: Mehri
authors.forename: Soudabeh
authors.initials: S
authors.lastname: Zeraatkar
authors.forename: Taraneh
authors.initials: T
authors.lastname: Ahmadi
authors.forename: Maliheh
authors.initials: M
authors.lastname: Alimardani
authors.forename: Hamid
authors.initials: H
authors.lastname: Sadeghian
mesh_terms: D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry*; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D062105:Molecular Docking Simulation; D017368:Protein Prenylation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D030262:Soybean Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013025:Glycine max / Q000737:chemistry / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D016859:Lipoxygenase Inhibitors; D011994:Recombinant Proteins; D030262:Soybean Proteins; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase