Kinetic and structural investigations of novel inhibitors of human epithelial 15-lipoxygenase-2

Tsai, Wan‐Chen; Gilbert, Nathaniel C.; Ohler, Amanda; Armstrong, Michelle; Perry, Steve; Kalyanaraman, Chakrapani; Yasgar, Adam; Rai, Ganesha; Simeonov, Anton; Jadhav, Ajit; Standley, Melissa; Lee, Hsiau‐Wei; Crews, Phillip; Iavarone, Anthony T.; Jacobson, Matthew P.; Neau, David; Offenbacher, Adam R.; Newcomer, Marcia E.; Holman, Theodore R.

doi:10.1016/j.bmc.2021.116349

Cited by 20 publications

(30 citation statements)

References 53 publications

(73 reference statements)

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“…At the other end of the molecule, methylsulfonylpiperazine moiety interacts with Phe192 via π–sulfur contact. The results from molecular docking studies suggest that the potential inhibitory activity is a non-redox mechanism and competes with a substrate to bind the active site [ 28 , 49 , 50 , 51 , 52 ].…”

Section: Resultsmentioning

confidence: 99%

Interactions of N-Mannich Bases of Pyrrolo[3,4-c]pyrrole with Artificial Models of Cell Membranes and Plasma Proteins, Evaluation of Anti-Inflammatory and Antioxidant Activity

et al. 2023

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Despite the widespread and easy access to NSAIDs, effective and safe treatment of various inflammatory disorders is still a serious challenge because of the severe adverse effects distinctive to these drugs. The Mannich base derivatives of pyrrolo[3,4-c]pyrrole are potent, preferential COX-2 inhibitors with a COX-2/COX-1 inhibitory ratio better than meloxicam. Therefore, we chose the six most promising molecules and subjected them to further in-depth research. The current study presents the extensive biological, spectroscopic and in silico evaluation of the activity and physicochemical properties of pyrrolo[3,4-c]pyrrole derivatives. Aware of the advantages of dual COX–LOX inhibition, we investigated the 15-LOX inhibitory activity of these molecules. We also examined their antioxidant effect in several in vitro experiments in a protection and regeneration model. Furthermore, we defined how studied compounds interact with artificial models of cell membranes, which is extremely important for drugs administered orally with an intracellular target. The interactions and binding mode of the derivatives with the most abundant plasma proteins—human serum albumin and alpha-1-acid glycoprotein—are also described. Finally, we used computational techniques to evaluate their pharmacokinetic properties. According to the obtained results, we can state that pyrrolo[3,4-c]pyrrole derivatives are promising anti-inflammatory and antioxidant agents with potentially good membrane permeability.

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Section: Resultsmentioning

confidence: 99%

Interactions of N-Mannich Bases of Pyrrolo[3,4-c]pyrrole with Artificial Models of Cell Membranes and Plasma Proteins, Evaluation of Anti-Inflammatory and Antioxidant Activity

et al. 2023

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“…Deuterated, pepsin-digested samples of h12-LOX were analyzed using a 1200 series LC system (Agilent, Santa Clara, CA) that was connected in-line with the LTQ Orbitrap XL mass spectrometer (Thermo), as described by our laboratory previously [ 19 , 29 ]. Mass spectral data corresponding to the HDX measurements were analyzed using HDX Workbench [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

Biochemical and hydrogen-deuterium exchange studies of the single nucleotide polymorphism Y649C in human platelet 12-lipoxygenase linked to a bleeding disorder

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Yamaguchi

et al. 2023

Archives of Biochemistry and Biophysics

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“…The only inhibitors known to date that specifically inhibit ALOX15B with micromolar potency were synthesized based on the concept of a U-shaped substrate binding cavity ( Jameson et al, 2014 ; Tsai et al, 2021a ). The respective inhibitors (MLS000327069, MLS000327186, and MLS000327206) are described to have a 50-fold higher selectivity for ALOX15B versus human ALOX5, ALOX12, ALOX15, cyclooxygenase (COX)-1 and COX-2, without affecting redox activity ( Tsai et al, 2021a ). Besides recombinant enzyme preparations, inhibition of ALOX15B was studied in a cell assay that used ALOX15B-overexpressing HEK293T cells.…”

Section: Inhibition Of Alox15bmentioning

confidence: 99%

Arachidonate 15-lipoxygenase type B: Regulation, function, and its role in pathophysiology

2022

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As a lipoxygenase (LOX), arachidonate 15-lipoxygenase type B (ALOX15B) peroxidizes polyenoic fatty acids (PUFAs) including arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and linoleic acid (LA) to their corresponding fatty acid hydroperoxides. Distinctive to ALOX15B, fatty acid oxygenation occurs with positional specificity, catalyzed by the non-heme iron containing active site, and in addition to free PUFAs, membrane-esterified fatty acids serve as substrates for ALOX15B. Like other LOX enzymes, ALOX15B is linked to the formation of specialized pro-resolving lipid mediators (SPMs), and altered expression is apparent in various inflammatory diseases such as asthma, psoriasis, and atherosclerosis. In primary human macrophages, ALOX15B expression is associated with cellular cholesterol homeostasis and is induced by hypoxia. Like in inflammation, the role of ALOX15B in cancer is inconclusive. In prostate and breast carcinomas, ALOX15B is attributed a tumor-suppressive role, whereas in colorectal cancer, ALOX15B expression is associated with a poorer prognosis. As the biological function of ALOX15B remains an open question, this review aims to provide a comprehensive overview of the current state of research related to ALOX15B.

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Kinetic and structural investigations of novel inhibitors of human epithelial 15-lipoxygenase-2

Cited by 20 publications

References 53 publications

Interactions of N-Mannich Bases of Pyrrolo[3,4-c]pyrrole with Artificial Models of Cell Membranes and Plasma Proteins, Evaluation of Anti-Inflammatory and Antioxidant Activity

Interactions of N-Mannich Bases of Pyrrolo[3,4-c]pyrrole with Artificial Models of Cell Membranes and Plasma Proteins, Evaluation of Anti-Inflammatory and Antioxidant Activity

Biochemical and hydrogen-deuterium exchange studies of the single nucleotide polymorphism Y649C in human platelet 12-lipoxygenase linked to a bleeding disorder

Arachidonate 15-lipoxygenase type B: Regulation, function, and its role in pathophysiology

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