51 research outputs found
Vitamin E metabolites as potent inhibitors of 5-lipoxygenase
International audienc
Modifications and hybrids of 1,2,3,4‑tetrahydropyridinium salts and their antiprotozoal potencies
The antiprotozoal activity of 1-benzyltetrahydropyridin-4-yliden iminium salts is reported. This paper describes the preparation of a series of analogs from dihydropyridines or dihydrothiopyrans as educts. The new compounds were investigated for their activity against Plasmodium falciparum NF54, a causative organism of Malaria tropica and Trypanosoma brucei rhodesiense, the causative organism of Human African Trypanosomiasis (sleeping sickness). Several structure-activity relationships were detected. Both the substituents in ring positions 1 and 4 of the tetrahydropyridinium moiety had a strong impact on the antiprotozoal activities as well as on the cytotoxicity of compounds against L-6 cells (rat skeletal myoblasts). All new compounds were characterized using FT-IR spectroscopy, HRMS, and NMR spectroscopy
Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation.
Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (27a), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E2 synthase-1. Compound 27a is metabolized by sulfation and β-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead
Semisynthetic and Natural Garcinoic Acid Isoforms as New mPGES-1 Inhibitors
Over the last twenty years, tocotrienol analogues raised great interest because of their higher level and larger domain of biological activities when compared with tocopherols. Amongst the most promising therapeutic application, anti-inflammatory potency has been evaluated through the inhibition of various mediators of inflammation. Here, we worked on the isolation of two natural isoforms of garcinoic acid (i.e., δ and γ) from two different sources, respectively, Garcinia kola seeds and Garcinia amplexicaulis bark. We also developed semisynthetic strategies to access the other two non-natural α- and β-garcinoic acid isoforms. In the next stage of our work, microsomal prostaglandin E2 synthase was defined as a target to evaluate the anti-inflammatory potential of the four garcinoic acid isomers. Both dimethylated isoforms, β- and γ-garcinoic acid, exhibited the lowest IC50, 2.8 µM and 2.0 µM, respectively. These results showed that the affinity of tocotrienol analogues to microsomal prostaglandin E2 synthase-1 most probably contributes to the anti-inflammatory potential of this class of derivatives
Discovery of New Liver X Receptor Agonists by Pharmacophore Modeling and Shape-Based Virtual Screening
Agonists
of liver X receptors (LXR) α and β are important
regulators of cholesterol metabolism, but agonism of the LXRα
subtype appears to cause hepatic lipogenesis, suggesting LXRβ-selective
activators are attractive new lipid lowering drugs. In this work,
pharmacophore modeling and shape-based virtual screening were combined
to predict new LXRβ-selective ligands. Out of the 10 predicted
compounds, three displayed significant LXR activity. Two activated
both LXR subtypes. The third compound activated LXRβ 1.8-fold
over LXRα
Potent inhibition of human 5-lipoxygenase and microsomal prostaglandin E-2 synthase-1 by the anti-carcinogenic and anti-inflammatory agent embelin
Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) possesses anti-inflammatory and anti-carcinogenic properties in vivo, and these features have been related to interference with multiple targets including XIAPs, NF kappa B, STAT-3, Akt and mTOR. However, interference with these proteins requires relatively high concentrations of embelin (IC50 > 4 mu M) and cannot fully explain its bioactivity observed in several functional studies. Here we reveal human 5-lipoxygenase (5-LO) and microsomal prostaglandin E-2 synthase (mPGES)-1 as direct molecular targets of embelin. Thus, embelin potently suppressed the biosynthesis of eicosanoids by selective inhibition of 5-LO and mPGES-1 with IC50 = 0.06 and 0.2 mu M, respectively. In intact human polymorphonuclear leukocytes and monocytes, embelin consistently blocked the biosynthesis of various 5-LO products regardless of the stimulus (fMLP or A23187) with IC50 = 0.8-2 mu M. Neither the related human 12- and 15-LO nor the cyclooxygenases-1 and -2 or cytosolic phospholipase A(2) were significantly affected by 10 mu M embelin. Inhibition of 5-LO and mPGES-1 by embelin was (I) essentially reversible after wash-out, (II) not impaired at higher substrate concentrations, (III) unaffected by inclusion of Triton X-100, and (IV) did not correlate to its proposed antioxidant properties. Docking simulations suggest concrete binding poses in the active sites of both 5-LO and mPGES-1. Because 5-LO- and mPGES-1-derived eicosanoids play roles in inflammation and cancer, the interference of embelin with these enzymes may contribute to its biological effects and suggests embelin as novel chemotype for development of dual 5-LO/mPGES-1 inhibitors. (C) 2013 Elsevier Inc. All rights reserved
Finding New Molecular Targets of Familiar Natural Products Using In Silico Target Prediction
Natural products comprise a rich reservoir for innovative drug leads and are a constant source of bioactive compounds. To find pharmacological targets for new or already known natural products using modern computer-aided methods is a current endeavor in drug discovery. Nature's treasures, however, could be used more effectively. Yet, reliable pipelines for the large-scale target prediction of natural products are still rare. We developed an in silico workflow consisting of four independent, stand-alone target prediction tools and evaluated its performance on dihydrochalcones (DHCs)-a well-known class of natural products. Thereby, we revealed four previously unreported protein targets for DHCs, namely 5-lipoxygenase, cyclooxygenase-1, 17β-hydroxysteroid dehydrogenase 3, and aldo-keto reductase 1C3. Moreover, we provide a thorough strategy on how to perform computational target predictions and guidance on using the respective tools
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