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Synthesis, inhibitory activity and in silico docking of dual COX/5-LOX inhibitors with quinone and resorcinol core
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SYSNO ASEP 0531731 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Synthesis, inhibitory activity and in silico docking of dual COX/5-LOX inhibitors with quinone and resorcinol core Author(s) Šíša, Miroslav (UEB-Q) ORCID
Dvořáková, Marcela (UEB-Q) RID, ORCID
Temml, V. (AT)
Jarošová, Veronika (UEB-Q) ORCID
Vaněk, Tomáš (UEB-Q) RID, ORCID
Landa, Přemysl (UEB-Q) RID, ORCIDNumber of authors 6 Article number 112620 Source Title European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 204, 15 October (2020)Number of pages 11 s. Language eng - English Country FR - France Keywords 5-Lipoxygenase ; Anti-inflammatory activity ; Cyclooxygenase ; Quinones ; Resorcinols Subject RIV CC - Organic Chemistry OECD category Organic chemistry R&D Projects LTC18065 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UEB-Q - RVO:61389030 UT WOS 000573916100027 EID SCOPUS 85088652307 DOI 10.1016/j.ejmech.2020.112620 Annotation Based on the significant anti-inflammatory activity of natural quinone primin (5a), series of 1,4-benzoquinones, hydroquinones, and related resorcinols were designed, synthesized, characterized and tested for their ability to inhibit the activity of cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) enzymes. Structural modifications resulted in the identification of two compounds 5b (2-methoxy-6-undecyl-1,4-benzoquinone) and 6b (2-methoxy-6-undecyl-1,4-hydroquinone) as potent dual COX/5-LOX inhibitors. The IC50 values evaluated in vitro using enzymatic assay were for compound 5b IC50 = 1.07, 0.57, and 0.34 μM and for compound 6b IC50 = 1.07, 0.55, and 0.28 μM for COX-1, COX-2, and 5-LOX enzyme, respectively. In addition, compound 6d was identified as the most potent 5-LOX inhibitor (IC50 = 0.14 μM, reference inhibitor zileuton IC50 = 0.66 μM) from the tested compounds while its inhibitory potential against COX enzymes (IC50 = 2.65 and 2.71 μM for COX-1 and COX-2, respectively) was comparable with the reference inhibitor ibuprofen (IC50 = 4.50 and 2.46 μM, respectively). The most important structural modification leading to increased inhibitory activity towards both COXs and 5-LOX was the elongation of alkyl chain in position 6 from 5 to 11 carbons. Moreover, the monoacetylation in ortho position of bromo-hydroquinone 13 led to the discovery of potent (IC50 = 0.17 μM) 5-LOX inhibitor 17 (2-bromo-6-methoxy-1,4-benzoquinone) while bromination stabilized the hydroquinone form. Docking analysis revealed the interaction of compounds with Tyr355 and Arg120 in the catalytic site of COX enzymes, while the hydrophobic parts of the molecules filled the hydrophobic substrate channel leading up to Tyr385. In the allosteric catalytic site of 5-LOX, compounds bound to Tyr142 and formed aromatic interactions with Arg138. Taken together, we identified optimal alkyl chain length for dual COX/5-LOX inhibition and investigated other structural modifications influencing COX and 5-LOX inhibitory activity. Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2021 Electronic address http://doi.org/10.1016/j.ejmech.2020.112620
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