Research paperSynthesis, inhibitory activity and in silico docking of dual COX/5-LOX inhibitors with quinone and resorcinol core
Graphical abstract
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are used for the treatment of common pain as well as for chronic inflammatory diseases such as rheumatoid arthritis. Some of them are over-the-counter drugs and belong to the most widely used pharmaceuticals worldwide. NSAIDs reduce the production of prostaglandins via the inhibition of cyclooxygenase (COX) enzymes. However, chronic intake of non-selective COX inhibitors could result in severe side effects such as gastrointestinal bleeding [1,2]. Besides the inhibition of inducible COX-2 isoform responsible for inflammatory processes, non-selective inhibitors also suppress the activity of COX-1 that plays cytoprotective role in gastrointestinal system. Actually, the role of COX-1 (generally considered as homeostatic) and COX-2 (generally considered as inducible) is complex and depends on many factors such as organ where it actions, developmental stage, stage of inflammatory process etc. The application of selective COX-2 inhibitors (called Coxibs) avoided gastrointestinal complications but their usage resulted in the increased risk of cardiovascular events [3]. One of the reasons is that selective COX-2 inhibitors change homeostasis in the production of vasoactive prostanoids. Coxibs do not affect the production of thromboxane X2 (TXA2) promoting vasoconstriction and platelet aggregation but reduce biosynthesis of prostaglandin I2 (PGI2) that is vasodilator and potent inhibitor of platelet aggregation. Moreover, COX-2 mediates cardioprotective effects of the late phase of ischemic preconditioning and may also play role in angiogenesis [4]. Enzyme 5-lipoxygenase (5-LOX) catalyzes biosynthesis of leukotrienes (LTs) and lipoxins. Leukotriene B4 (LTB4) is important chemotactic and chemokinetic mediator regulating the immune response and inflammatory processes such as arthritis, asthma, and atherosclerosis. The cysteinyl leukotrienes are involved in asthma, allergic rhinitis, and chronic inflammation [5]. Until now, zileuton is only one approved 5-LOX inhibitor for asthma treatment. Moreover, zileuton is associated with adverse effects such as hepatotoxicity and adverse pharmacokinetic profile derived from a short half-life. The inhibition of COXs leads to the increased production of LTs, which could increase asthma. The reason is that both COXs and 5-LOX use as a substrate arachidonic acid (AA) and when the activity of COXs is inhibited AA availability is increased for 5-LOX pathway. Another reason is that the production of vasodilators PGI2 and PGE2 is reduced. Therefore, dual inhibition of COXs and 5-LOX is suggested as a promising approach that should diminish negative effects connected with the inhibition of COXs. Moreover, dual COX/5-LOX inhibition may exhibit better anti-inflammatory activity than NSAIDs because of the influence on inflammatory mediators not affected by COX inhibitors [1]. Previously, we found that some natural benzo- and naphthoquinones are able to inhibit COX as well as 5-LOX catalytic activity in vitro. As the most promising compound was identified benzoquinone primin [6,7]. Benzoquinones were found as potent 5-LOX inhibitors also in other studies. Hydroquinone miconidin acetate isolated from Eugenia hiemalis inhibited human recombinant 5-LOX in vitro [8]. Natural benzoquinone embelin was revealed as potent 5-LOX and microsomal prostaglandin E2 synthase-1 inhibitor [9]. Tests of series of embelin derivatives revealed compounds such as 4,5-dimethoxy-3-dodecyl-1,2-benzoquinone and 5-[(2-naphthyl)methyl]-2-hydroxy-2,5-cyclohexadiene-1,4-dione with significantly higher 5-LOX inhibitory activity than that of the parent compound [10,11]. Further, Peduto et al. optimized alkyl chain pattern of quinones and corresponding hydroquinones that provided the identification of highly potent 5-LOX inhibitors with in vivo anti-inflammatory effect [12]. In our study, we used different synthetic approach and prepared series of derivatives of natural quinone, primin. Obtained compounds were assayed for their ability to inhibit COX-1, COX-2 and 5-LOX catalytic activity as potential dual inhibitors. In addition, in silico docking experiments were employed to elucidate the binding of compounds into catalytic sites of COX as well as 5-LOX enzymes.
Section snippets
Chemistry
For the first set of compounds – benzoquinones, hydroquinones and resorcinols – we have employed synthetic strategy (Scheme 1) developed in our group [13] using Sonogashira cross-coupling as the key step for the aromatic alkylation, thus affording excellent yields of desired compounds 2a-d (60–97%). Different length of side chain was proposed with the aim to investigate its role in inhibitory activity. Hydrogenation on palladium gave quantitative yields of products 3a-d, which subsequently
Conclusions
Rational improvement of the structure of natural benzoquinone primin resulted in the design of derivatives with increased inhibitory activity. Especially, the elongation of the side chain from 5 to 11 carbons increased the inhibitory activity towards 5-LOX and COXs (dual inhibition). The acetylation of (one or both) hydroxyls diminished activity towards COXs, but the activity towards 5-LOX either stayed unchanged, or in the case of monoacetylation, it increased. The data from in vitro enzymatic
General remarks
All reactions requiring anhydrous or inert conditions were carried out under a positive atmosphere of argon in oven-dried glassware. Solutions or liquids were introduced in round bottom flasks using oven dried syringes through rubber septa. All reactions were stirred magnetically using Teflon-coated stirring bars. If needed, reactions were warmed up using electrically-heated silicon oil bath, and the stated temperature corresponds to the temperature of the bath. Organic solutions obtained after
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors gratefully acknowledge the financial support by the grant LT18065 from the Ministry of Education, Youth and Sports of the Czech Republic and networking contribution by the COST Action CM16225 “Realising the therapeutic potential of novel cardioprotective therapies”. Further, Prague OPPK grant CZ.2.16/3.1.00/21519 is honestly acknowledged. V.T. was funded by the FWF Hertha Firnberg fellowship "New ways to counter inflammation" (T-942).
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