Electrophilic nitroalkene-tocopherol derivatives: synthesis, physicochemical characterization and evaluation of anti-inflammatory signaling responses

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.

A novel nitroalkene‐α‐tocopherol analogue inhibits inflammation and ameliorates atherosclerosis in Apo E knockout mice

“…NATOH was synthesized as described previously (Rodriguez‐Duarte et al ., ). Briefly, α‐TOH is transformed into the corresponding bromoacetate derivative 2 by treatment with bromine followed by O ‐acetylation (Scheme ) (Rodriguez‐Duarte et al ., ). Bromoacetate oxidation with N ‐methylmorpholine N ‐oxide yields the corresponding aldehyde 3 .…”

“…Synthesis of NATOH from α-TOH NATOH was synthesized as described previously (Rodriguez-Duarte et al, 2018). Briefly, α-TOH is transformed into the…”

“…The tocopherol used along the study was always (±)‐α‐TOH (Sigma‐Aldrich, St. Louis, MO, USA). Compounds 2 (Southan et al ., ), 3 (Mazzini et al ., ) and NATOH (Rodriguez‐Duarte et al , ) were synthesized according to methods described previously. All other materials were obtained from commercial suppliers and used as received.…”

A Focused Library of NO‐Donor Compounds with Potent Antiproliferative Activity Based on Green Multicomponent Reactions

“…We started the library construction searching for experimental conditions for the eco‐friendly Passerini reaction of aldehyde 1 a , carboxylic acid 2 a (Figure ) and tert‐ butylisonitrile ( 3 a ) to give α‐acyloxyamide 4 a (Table , entries 1–11). Aldehyde 1 a was used as the Boc‐protected phenol instead of the unprotected derivative, as the latter decomposes rapidly.…”

“…Compounds 1 a , 2 a , 2 b , and 4 m were synthesized according to literature methods. All other materials were obtained from commercial suppliers and used as received.…”