Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties

Eleftheriadis, Nikolaos; Poelman, Hessel; Leus, Niek G. J.; Honrath, Birgit; Neochoritis, Constantinos G.; Dolga, Amalia M.; Dömling, Alexander

doi:10.1016/j.ejmech.2016.07.010

Cited by 31 publications

(29 citation statements)

References 57 publications

(49 reference statements)

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“…From the pharmacological point of view, the analysed 1,3,4-tiadiazoles [ 5 , 6 ] substituted with the resorcylic fragment have been observed to have promising anticancer [ 7 , 8 , 9 , 10 ] and neuroprotective [ 11 , 12 , 13 ], anti-oxidative [ 7 ], antifungal and antibacterial activities [ 14 , 15 , 16 , 17 ], anti-inflammatory [ 18 ]. They also show certain very interesting properties as a group of ligands capable of forming complexes with selected D-block metals [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic Studies of Dual Fluorescence in 2-(4-Fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole: Effect of Molecular Aggregation in a Micellar System

et al. 2018

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The article presents the results of spectroscopic studies focused on a selected compound from the 1,3,4-thiadiazole group—2-(4-fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thia-diazole (FABT)—in a micellar system formed by Triton X-100, a non-ionic detergent. Fluorescence measurements revealed the phenomenon of dual fluorescence whose emergence is related to the particular molecular organisation of the compound, which depends both on the concentration of the detergent and, most of all, the concentration of the compound itself. Dual fluorescence of FABT in a micellar system was observed for the compound dissolved in a methanol aqueous system, i.e., an environment wherein the dual fluorescence of the compound had never been reported before. Based on the interpretation of UV-Vis electronic absorption, resonance light scattering (RLS), emission and excitation fluorescence spectra, as well as measurements of dynamic light scattering (DLS) and Principal Component Analysis (PCA), we were able to relate the occurrence of this effect to the process of molecular aggregation taking place between FABT molecules in the micellar system in question. Results of fluorescence spectra measurements and time-correlated single photon counting (TCSPC) indicate that dual fluorescence occurs at detergent concentrations necessary to form micellar systems, which in turn facilitate the process of aggregation of FABT molecules. The correlation between the observed fluorescence effects and the previous measurements performed for analogues from this group suggests the possibility of charge transfer (CT) within the range of detergent concentrations wherein the aforementioned fluorescence effects are observed. It ought to be emphasised that this type of fluorescence effects are relatively easy to induce, which predisposes this groups of fluorophores as ideal fluorescence probes in the context of biological samples.

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Section: Introductionmentioning

confidence: 99%

Spectroscopic Studies of Dual Fluorescence in 2-(4-Fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole: Effect of Molecular Aggregation in a Micellar System

et al. 2018

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“…In this paper, we provide a new strategy to find the potential effective drug target combinations of all three types of drug target combinations involved in our paper. Among the combinations of drug targets we have screened, there are five combinations have been proven to be viable by the corresponding biological experiments, including the combination of 5-LOX and 12-LOX [26], combination of 5-LOX and LTA4H [27], combination of 15-LOX and PLA2 [28], combination of PLA2 and LTA4H [29, 31, 32] and combination of PLA2 and 5-LOX [30]. What’s more, if we can combine the price and doses of drugs, we can have a better optimization.…”

Section: Resultsmentioning

confidence: 99%

“…4. There are thee combinations have been proven to be viable by the corresponding biological experiments, including the combination of 15-LOX and PLA2 [28], combination of PLA2 and LTA4H [29], and combination of PLA2 and 5-LOX [30]. Especially, it has been found that pathway including PLA2 and LTA4H in AA metabolic network is very important for traditional Chinese medicine anti-inflammatory herbal formulae and the treatment of cancers [29, 31, 32].…”

Section: Applying the Strategy Of Screening Drug Target Combinations mentioning

confidence: 99%

Screening drug target combinations in disease-related molecular networks

2019

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Background For treating a complex disease such as cancer, some effective means are needed to control biological networks that underlies the disease. The one-target one-drug paradigm has been the dominating drug discovery approach in the past decades. Compared to single target-based drugs, combination drug targets may overcome many limitations of single drug target and achieve a more effective and safer control of the disease. Most of existing combination drug targets are developed based on clinical experience or text-and-trial strategy, which cannot provide theoretical guidelines for designing and screening effective drug combinations. Therefore, systematic identification of multiple drug targets and optimal intervention strategy needs to be developed. Results We developed a strategy to screen the synergistic combinations of two drug targets in disease networks based on the classification of single drug targets. The method tried to identify the sensitivity of single intervention and then the combination of multiple interventions that can restore the disease network to a desired normal state. In our strategy of screening drug target combinations, we first classified all drug targets into sensitive and insensitive single drug targets. Then, we identified the synergistic and antagonistic of drug target combinations, including the combinations of sensitive drug targets, the combinations of insensitive drug target and the combination of sensitive and insensitive targets. Finally, we applied our strategy to Arachidonic Acid (AA) metabolic network and found 18 pairs of synergistic drug target combinations, five of which have been proven to be viable by biological or medical experiments. Conclusions Different from traditional methods for judging drug synergy and antagonism, we propose the framework of how to enhance the efficiency by perturbing two sensitive targets in a combinatorial way, how to decrease the drug dose and therefore its side effect and cost by perturbing combinatorially a main sensitive target and an auxiliary insensitive target, and how to perturb two insensitive targets to realize the transition from a disease state to a healthy one which cannot be realized by perturbing each insensitive target alone. Although the idea is mainly applied to an AA metabolic network, the strategy holds for more general molecular networks such as combinatorial regulation in gene regulatory networks. Electronic supplementary material The online version of this article (10.1186/s12859-019-2730-8) contains supplementary material, which is available to authorized users.

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“…The reason for this dearth of LOX therapeutics in general is multifaceted, but two limitations in the advancement of LOX-targeting anti-inflammatory inhibitors has been the characterization of the specific role of each LOX isozyme and the difficulty in identifying/developing isoform-selective inhibitors. However, with recent successes, this issue is slowly being overcome [11][12][13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Fatty Acid Allosteric Regulation of C-H Activation in Plant and Animal Lipoxygenases

Offenbacher

Holman

2020

Molecules

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Lipoxygenases (LOXs) catalyze the (per) oxidation of fatty acids that serve as important mediators for cell signaling and inflammation. These reactions are initiated by a C-H activation step that is allosterically regulated in plant and animal enzymes. LOXs from higher eukaryotes are equipped with an N-terminal PLAT (Polycystin-1, Lipoxygenase, Alpha-Toxin) domain that has been implicated to bind to small molecule allosteric effectors, which in turn modulate substrate specificity and the rate-limiting steps of catalysis. Herein, the kinetic and structural evidence that describes the allosteric regulation of plant and animal lipoxygenase chemistry by fatty acids and their derivatives are summarized.

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Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties

Cited by 31 publications

References 57 publications

Spectroscopic Studies of Dual Fluorescence in 2-(4-Fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole: Effect of Molecular Aggregation in a Micellar System

Spectroscopic Studies of Dual Fluorescence in 2-(4-Fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole: Effect of Molecular Aggregation in a Micellar System

Screening drug target combinations in disease-related molecular networks

Fatty Acid Allosteric Regulation of C-H Activation in Plant and Animal Lipoxygenases

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