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  • Taken together BRP represents a novel chemotype

    2024-05-23

    Taken together, BRP-187 represents a novel chemotype of LT biosynthesis inhibitors with outstanding potency in human PMNL and monocytes activated under pathophysiological relevant conditions and with effectiveness in vivo. Using the PLA that visualizes the in situ interaction between 5-LO and FLAP in intact cells during LT formation, we demonstrate that BRP-187 prevents 5-LO/FLAP complex assembly without blocking 5-LO nuclear redistribution. In light of the unmet need for effective and safe anti-LT drugs and the novel therapeutic indication for FLAP inhibitors, BRP-187 deserves attention and further preclinical assessment of the compound is warranted.
    Conflict of interest statement
    Acknowledgements
    Introduction Leukotrienes (LTs) are inflammatory mediators produced via the 5-lipoxygenase (5-LO) pathway and are linked to diverse inflammatory disorders. Intervention with LTs represents a pertinent pharmacological approach against inflammatory diseases, and anti-LT therapy has been validated in clinical trials of ORY-1001 and allergic rhinitis, with potential in other respiratory and allergic disorders [1], as well as in cardiovascular diseases such as atherosclerosis, myocardial infarction, stroke and abdominal aortic aneurysm [2]. In addition, such inhibitors may be tools for the elucidation of the involvement of 5-LO and LTs in diverse biological processes. Over the last two decades, several studies have shown that quinone derivatives possess a number of biological and pharmacological applications, and hydroquinones are of considerable scientific interest because of their versatile biological activities, where also the corresponding (hydro) quinone may display multiple actions [3]. Our groups have been interested for a long time in the synthesis and the biological evaluation of anti-cancer and anti-inflammatory agents including quinone-based compounds [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Within the context of our investigations towards the synthesis of quinone derivatives with prospects for therapeutic use, we recently studied the natural compound embelin and RF-Id, a synthetic derivative of bolinaquinone (Fig. 1) [7], [8]. The high potency against 5-LO and the promising in vivo efficacy of the corresponding synthesized compounds stimulated us to further modify the structures and thus, to improve the inhibitory potential as well as to investigate SARs of this class of compounds. Starting from embelin, the alkyl chain length in position 3 (n-undecyl residue) was varied by introducing saturated linear n-alkyl residues or isoprenoid side chains. Next, one or two hydroxyl groups were methylated in 2- and 5-position, respectively, and finally, the 2,5-dimethoxy-1,4-benzoquinone core was replaced by a 4,5-methoxy-1,2-benzoquinones backbone (ortho-quinone structures) leading to compounds decorated with the same linear and prenylated chains as for the other groups [10], [11]. We have shown that the increase of the n-alkyl side-chain length determines the 5-LO inhibitory activity in neutrophils stimulated with the Ca2+-mobilizing agent A23187. Thus, ortho-quinones with simple n-undecyl (25) or n-dodecyl (26) and n-tridecyl (27) residues were most potent in intact human neutrophils with IC50 values in the submicromolar range (approx. 50–100 nM) [10], [11]. Starting from this basis and considering that modifications on the quinone scaffold did not affect the polarity of the linear chain as reported in the literature so far, we were interested, whether the presence of a polar group (i.e. hydroxyl) in the n-alkyl chain would affect the potency against ORY-1001 5-LO. Thus, we took into account the marked anti-inflammatory properties of Idebenone (2,3-dimethoxy-5-methyl-6(10-hydroxydecyl)-1,4-benzoquinone) [16], [17], [18], a synthetic analog of coenzyme Q10 (CoQ10), with potent antioxidant activity, able to inhibit the enzymatic metabolism of arachidonic acid by cyclooxygenase and lipoxygenases, with potential anti-inflammatory activity in the central nervous system [18]. Notably, introduction of a polar group into the lipophilic n-alkyl chain may also improve water solubility and thus bioavailability. We therefore envisioned the preparation of quinone derivatives bearing a long (i.e., >C8) hydrophilic chain in order to evaluate the potential of such modification for interference with 5-LO activity. Furthermore, we aimed to obtain broader insights into the relationship between the molecular structure and the biological activity against 5-LO of the most active quinone derivatives (25, 26, 27) and their reduced hydroquinone forms (28, 29, 30). Finally we decided to synthesize different hydroquinones with the same alkyl chain (33, 34), to evaluate if different positions of the hydroxyl group would allow for better interference with 5-LO's active site.