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  • In the case of DIA CN the docking results do

    2023-01-24

    In the case of DIA-4CN the docking results do not show any interaction between the iron atom and the inhibitor, presumably due to the reduced ability to form a complex involving the -CONN- moiety versus the bidentate -CONHNH- central group of HYD-4Me. This results in a considerable gap between the isoleucine-histidine-iron complex and the diazene inhibitor, associated with the benzoyl moiety’s approach to the hydrophobic loop in the catalytic domain of LOX. This seems reasonable based on the increased hydrophobic character of the diazene. On this basis we can suggest that iron complexation by HYD-4Me is important for its 15-LOX inhibitory activity, while DIA-4CN acts primarily by blocking the access of the substrate to the α-helical domain of the catalytic site. The docking energies support this notion, as the interaction with HYD-4Me (−4.67kcal/mol) is stronger than with DIA-4CN (−3.66kcal/mol). Because the active site of this oxidoreductase contains a redox active iron atom which is the key to the initial radical generation from the at least doubly unsaturated arachidonic (or linolenic) acid, two different antioxidant capability assays were carried out. These are based on the change of oxidation state of iron and copper, namely, the Ferric Reducing Antioxidant Power (FRAP) and Cupric Reducing Antioxidant Capacity (CUPRAC) assays respectively. The results for the HYD and DIA series are shown in .
    Introduction Lipoxygenases (LOXs) are non-heme, iron containing enzymes that catalyse positional and stereospecific insertion of oxygen (O2) into polyunsaturated fatty acids (PUFAs), such as arachidonic or linoleic donepezil hydrochloride mg [1], [2]. In humans, LOX mediated conversion of PUFAs generates signalling molecules such as leukotrienes, lipoxins and eoxins [3], [4], [5], which play a regulatory role in several inflammatory and respiratory diseases. New classes of inhibitors are needed to explore the lipoxygenases as therapeutic targets. The LOX enzymes are classified as 5-, 8-, 12- and 15-LOX based on their regioselectivity for arachidonic acid metabolism in mammals. In humans, there are two isoforms of 15-LOX, namely 15-LOX-1 and 15-LOX-2 [6]. The enzyme 15-LOX-1 (also referred to as 12/15-LOX) prefers linoleic acid as its major substrate over arachidonic acid [7], [8], which is remarkable since arachidonic acid is preferred by most other mammalian lipoxygenases. Arachidonic acid is converted into 15S-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15(S)-HpETE), which can be reduced to 15(S)-HETE (Fig. 1) [9]. Comparably, linoleic acid is converted into 13S-hydroperoxy-9Z,11E-octadecadienoic acid (13(S)-HpODE), which can be reduced to 13(S)-HODE. The 15-LOX-1 enzyme is predominantly expressed in human airway epithelial cells, reticulocytes, eosinophils, alveolar macrophages, mast cells and dendritic cells, which suggests a major role in airway inflammation [10]. Several studies describe a role for 15-LOX-1 in allergic airway diseases [11], [12], [13] and in chronic airway inflammation [14]. 15-LOX-1 has also been described to play a role in cancer [15], [16], and atherosclerosis [17]. Due to the key role of 15-LOX-1 in several disease processes several types of small molecule inhibitors of this enzyme have been developed. One of the first inhibitors for this enzyme is an indole based compound denoted PD-146176, which is active in the low micromolar range [18]. In a research program by the company Bristol–Myers Squib a series of inhibitors have been developed with potencies in the nanomolar range such as tryptamine-based compounds [19], imidazole-based compounds [20] and pyrazole-based compounds [21]. However, these compound suffer from poor pharmacokinetics in vivo. In addition, 3-aroyl-1-(4-sulfamoylphenyl)thiourea [22] and pyrimidinylthio-pyrimidotriazolothiadiazine [23] derivatives were published as soybean 15-LOX inhibitors with activities in the micromolar range. Recently, our research group described anacardic acid derived salicylates as LOX inhibitors, which also proved to be active in the micromolar range [24], [25], [26].