br Perspective AA LA and other PUFAs
Perspective AA, LA and other PUFAs and their lipid metabolites play an important role in human diseases. 12/15-LOX which is the metabolic enzyme of them plays an important role in the pathogenesis-related diseases such as atherosclerosis, diabetic nephropathy, neurological diseases and other pathological processes related to growth, migration, oxidative stress, extracellular matrix production and inflammatory factor expression. Conventionally, the signal pathway of 12/15-LOX is thought to be mainly apoptosis. In recent years, researchers find that 12/15-LOX is not only involved in autophagy but also ferroptosis which is a newly defined cell death. Figuring out the way how 12/15-LOX play a part in human disease helps to discover new drug targets and develop new drugs. We discuss the possibility of 12/15-LOX that it may serve as a potential target for disease treatment. And the relationship between 12/15-LOX, diseases and the relevant types of cell death need to be further explored. It turned out that 12/15-LOX inhibitors including baicalein, PD146176, N-benzyl-N-hydroxy-5-phenylpentamidine (BHPP), nordihydroguaiaretic 487 mg (NDGA) have protective effects on the cell and animal models of various diseases (Table 1). However, more clinical studies are needed to confirm its role in the drug efficacy.
Conflicts of interest
Acknowledgments This work is partially financially supported by the National Natural Science Foundation of China (Nos. 81671293 and 81302750) and Hunan Natural Science Foundation (No. 2017JJ3479).
Lipoxygenases (LOXs) catalyze the production of eicosanoid leukotrienes and lipoxins, both biosynthesized from arachidonic acid (AA) derived from the cell membrane, and important biological mediators of inflammatory processes. This family of enzymes is well conserved among mammalian species and catalyzes stereo- and regiospecific introduction of dioxygen into the polyunsaturated chain of AA as hydroperoxide, which finally is converted to the hydroxyl group. Due to this activity, the name of this enzyme is often preceded by the number of the carbon atom in the AA chain which undergoes oxidation. Thus, using the usual acronym, 5-LOX, 12-LOX and 15-LOX isoforms introduce an oxygen atom at positions C-5, C-12 and C-15 respectively. Some benzothiophene derivatives and esters of caffeic acid have been reported to be potent inhibitors of 5-LOX. Examples of these are the commercial Zileuton (IC=0.4μM) and CAPE (IC=0.13μM). Likewise, some phenylhydrazones inhibit the dual cyclooxygenase/peroxidase activity of prostaglandin synthase, phenylhydrazide derivatives selectively inhibit cycloxygenase-2, and pyrazole carboxamides inhibit 15-lipoxygenase-1, but until now we are not aware of any systematic studies of these compounds as 15-LOX inhibitors. The same is true for the related diazene derivatives. During the last decades a growing interest has arisen to develop new, greener synthetic strategies whereby the amount of residual waste becomes progressively smaller, and a many such reactions can be found in the literature. An interesting example of a green oxidation of arylhydrazides was proposed by Hashimoto, where a phthalocyanine was used as the oxidant. Another example of a green strategy applicable to our work was reported by Metro, who prepared different amide derivatives by mechanochemical means. Specifically, the latter procedure was used to obtain the first set of compounds in this research. The aim of the present work was to study the effects of two different structural features on the inhibitory behavior of two families of inhibitors: the influence of the oxidation of the central nitrogen-nitrogen single bond of phenylhydrazides, and the systematic substitution of the position of the -phenyl moiety. Both series proposed here were prepared using short and clean procedures, and some of the resulting compounds proved to be fairly potent inhibitors of 15-LOX. shows the synthesis of both series. The first step is the preparation of phenylhydrazide derivatives (HYD series) where both moieties, hydrazine and benzoic acid, where connected by a solvent-free reaction carried out by grinding the reactants in a simple mortar. The oily material prepared by this method was rinsed with pure water affording a white or yellowish white solid that was crystallized in ethanol to obtain fine needles in almost every case. This procedure is an environmentally friendly coupling reaction, with easy recovery of the desired compounds and negligible formation of side products. The second step in is the oxidation of the former substances with potassium ferricyanide. This reaction was carried out by shaking two immiscible solutions, one containing the substituted hydrazide dissolved in dichloromethane, and the other, the ferricyanide in a strongly basic aqueous solution. Using this simple experimental setup, the formation of diazene is easily detectable by the change of color in the organic phase from colorless to red, keeping the inorganic iron in aqueous solution. Further purification of the oily red products was not needed. Both reactions represent simple and clean methods for the rapid preparation of phenylhydrazides and their phenylcarbonylazo analogs in high yields.