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Electrophilic nitroalkene-tocopherol derivatives: synthesis, physicochemical characterization and evaluation of
Jorge Rodriguez-Duarte1,2,3, Rosina Dapueto1,2,3, Germán Galliussi1,3
1Laboratory of Vascular Biology and Drug Development, Institut Pasteur de Montevideo, Montevideo, Uruguay.
Abstract:
Inflammation plays a major role in the onset and development of chronic non-communicable diseases like obesity, cardiovascular diseases and cancer. Combined, these diseases represent the most common causes of death worldwide, thus development of novel pharmacological approaches is crucial. Electrophilic nitroalkenes derived from fatty acids are formed endogenously and exert anti-inflammatory actions by the modification of proteins involved in inflammation signaling cascades. We have developed novel nitroalkenes derived from α-tocopherol aiming to increase its salutary actions by adding anti-inflammatory properties to a well-known nutraceutical. We synthesized and characterized an α-tocopherol-nitroalkene (NATOH) and two hydrosoluble analogues derived from Trolox (NATxME and NATx0). We analyzed the kinetics of the Michael addition reaction of these compounds with thiols in micellar systems aiming to understand the effect of hydrophobic partition on the reactivity of nitroalkenes. We studied NATxME in vitro showing it exerts non-conventional anti-inflammatory responses by inducing Nrf2-Keap1-dependent gene expression and inhibiting the secretion of NF-κB dependent pro-inflammatory cytokines. NATxME was also effective in vivo, inhibiting neutrophil recruitment in a zebrafish model of inflammation. This work lays the foundation for the rational design of a new therapeutic strategy for the prevention and treatment of metabolic and inflammation-related diseases.
Insights
Novel nitroalkenes derived from alpha-tocopherol (a vitamin E form) show potent anti-inflammatory effects. These compounds offer a promising strategy for treating metabolic and inflammation-related diseases.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Inflammation is a key factor in chronic diseases like obesity, cardiovascular disease, and cancer.
- Electrophilic nitroalkenes, naturally occurring fatty acid derivatives, possess anti-inflammatory properties by modifying signaling proteins.
- Alpha-tocopherol (vitamin E) is a well-known nutraceutical with beneficial properties.
Purpose of the Study:
- To develop novel alpha-tocopherol-derived nitroalkenes with enhanced anti-inflammatory activity.
- To investigate the reactivity and anti-inflammatory mechanisms of these novel compounds.
- To explore their therapeutic potential for metabolic and inflammation-related diseases.
Main Methods:
- Synthesis and characterization of alpha-tocopherol-nitroalkene (NATOH) and its hydrosoluble analogues (NATxME, NATx0).
- Analysis of Michael addition reaction kinetics with thiols in micellar systems.
- In vitro studies of NATxME's effects on Nrf2-Keap1 and NF-κB signaling pathways.
- In vivo evaluation of NATxME in a zebrafish model of inflammation.
Main Results:
- Novel alpha-tocopherol-derived nitroalkenes (NATOH, NATxME, NATx0) were successfully synthesized.
- NATxME demonstrated in vitro anti-inflammatory effects by inducing Nrf2-Keap1-dependent gene expression.
- NATxME inhibited NF-κB dependent pro-inflammatory cytokine secretion and neutrophil recruitment in vivo.
Conclusions:
- Alpha-tocopherol-derived nitroalkenes represent a promising new class of anti-inflammatory agents.
- NATxME exhibits potent anti-inflammatory activity through modulation of key cellular pathways.
- These findings support the development of a novel therapeutic strategy for metabolic and inflammatory diseases.
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