Penta- and hexadienoic acid derivatives: a novel series of 5-lipoxygenase inhibitors

Abstract

The synthesis of a series of pentadienoic and hexadienoic acid derivatives is reported. These compounds were tested as inhibitors of 5-lipoxygenase (5 LO) and cyclooxygenase (CO) in vitro and as inhibitors of arachidonic acid (AA) induced ear edema in mice in vivo. Their potency is compared with that of the standard inhibitors nafazatrom, BW 755C, NDGA, KME4, quercetine, and L 652,243. The most potent compound in vivo, diethyl 2-hydroxy-5-(ethylthio)-2(Z),4(Z)-hexadienedioate (20) inhibited AA-induced ear edema when administered topically or orally, with an ED50 value of 0.01 mg/ear and 20 mg/kg, respectively. Among the standard compounds tested, L 652,243 was the most active compound in this test with an ED50 value of 0.01 mg/ear and 1 mg/kg po, but unlike this compound, 20 is a selective inhibitor of 5-LO (IC50 = 2 microM) without any significant activity against CO (IC50 greater than 50 microM). Most of the other compounds in this series are also selective 5-LO inhibitors.

Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review

“…Numerous in vitro studies indicate that a wide range of phenolic compounds might exert anti-inflammatory effects by targeting the 5-LOX pathway ( Table S1 ). Thus, caffeic acid, hydroxytyrosol, resveratrol, curcumin, NDGA and quercetin are compounds with the capacity to reduce the formation of 5-HETE, LTB 4 (and its ω-oxidized metabolites), and Cys-LTs [ 107 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ]. Although desirable, these effects should be considered with caution since inhibition of the 5-LOX pathway could result in higher (pro-inflammatory) COX-2 metabolite levels by shunting the substrate, AA.…”

Demonstrating the Synergy of Synthetic, Mechanistic, and Computational Studies in a Regioselective Aniline Synthesis

“…Reaction of enolates and vinamidinium salts leads to the formation of dienones 7a − h . These dienones are merocyanines based on resonance theory and are typically formed as a ∼3:1 mixture of 3- E : Z isomers . They possess interesting solvato-, thermo-, and photochromic properties due to the potential of valence isomerization to 2 H -pyrans 8a − h…”

“…The experimentally determined rotational barrier for 1,1-diamino-2,2-dicyanoethylene is 11.2 kcal/mol . The initial addition/elimination step of ketone to the vinamidinium leads to a ∼3:1 mixture of 3( E , Z)- isomers of the dienone . Energy differences between the most and the least stable conformations are 9.7 and 7.7 kcal/mol for enol 26 and enamine 28 , respectively .…”

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“…Right mouse ears were topically treated 1 X/d for 5 d with 20 wt% P. nagi ME or intact oil (4 μg in 20 μL acetone) containing 0.5 wt% α-tocopherol and 0.2 wt% palmitoylascorbate as antioxidants [62]. Left ears received 20 μL acetone.…”