Novel series of benzoquinones with high potency against 5-lipoxygenase in human polymorphonuclear leukocytes

European Journal of Medicinal Chemistry
Rosanna FilosaO Werz

Abstract

5-Lipoxygenase (5-LO) is a potential target for pharmacological intervention with various inflammatory and allergic diseases. Starting from the natural dual 5-LO/microsomal prostaglandin E2 synthase (mPGES)-1 inhibitor embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone, 2) that suppresses 5-LO activity in human primary leukocytes with IC50 = 0.8-2 μM, we synthesized 48 systematically modified derivatives of 2. We modified the 1,4-quinone to 1,2-quinone, mono- or bimethylated the hydroxyl groups, and varied the C11-n-alkyl residue (C4- to C16-n-alkyl or prenyl) of 2. Biological evaluation yields potent analogues being superior over 2 and obvious structure-activity relationships (SAR) for inhibition of 5-LO. Interestingly, conversion to 1,2-benzoquinone and bimethylation of the hydroxyl moieties strongly improves 5-LO inhibition in polymorphonuclear leukocytes versus 2 up to 60-fold, exemplified by the C12-n-alkyl derivative 22c (4,5-dimethoxy-3-dodecyl-1,2-benzoquinone) with IC50 = 29 nM. Regarding inhibition of mPGES-1, none of the novel benzoquinones could outperform the parental compound 2 (IC50 = 0.21 μM), and only modest suppressive effects on 12- and 15-LOs were evident. Together, our detailed SAR study reveals 22c as highl...Continue Reading

References

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Jun 14, 2008·The Journal of Pharmacology and Experimental Therapeutics·Andreas KoeberleOliver Werz
Dec 10, 2008·Proceedings of the National Academy of Sciences of the United States of America·Carlo PergolaOliver Werz
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Citations

Dec 29, 2015·European Journal of Medicinal Chemistry·Antonella PedutoRosanna Filosa
Jan 23, 2016·Journal of Medicinal Chemistry·Andreas KoeberleOliver Werz
Nov 12, 2016·European Journal of Medicinal Chemistry·Antonella PedutoRosanna Filosa
Dec 23, 2016·Expert Opinion on Therapeutic Patents·Oliver WerzUlrike Garscha
Jan 24, 2020·Journal of Enzyme Inhibition and Medicinal Chemistry·Xiaole ChenPanpan Wu
Oct 16, 2019·Frontiers in Pharmacology·Renata EspositoBruno D'Agostino
Oct 24, 2019·Mini Reviews in Medicinal Chemistry·Zhaojun ShengWen-Hua Chen
Jul 24, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Pedro Martín-AcostaAna Estévez-Braun
Aug 17, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Zhisheng MiYuanyuan Xie
Jul 16, 2020·Life·Cristina VisentinStefano Ricagno
Apr 30, 2020·Mini Reviews in Medicinal Chemistry·Pragati SilakariPoonam Piplani

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