Approaches to the Preparation of 4‐Benzyloxy‐2‐(α,α,α‐D3)methylphenol, a Building Block for Labeled δ‐Tocopherol, and a New Synthesis ofR,R,R‐5‐D3‐α‐Tocopherol

Mazzini, Francesco; Mandoli, Alessandro; Salvadori, Piero; Netscher, Thomas; Rosenau, Thomas

doi:10.1002/ejoc.200400535

Cited by 8 publications

(12 citation statements)

References 20 publications

(11 reference statements)

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“…Purification by column chromatography (Hex:EtOAc, 10:1) afforded 2a (1.24 g, 72% yield from 1a) as yellow dense oil. Analytical data are consistent with those given in the literature 31 , 40 , 48 . 1 H NMR (400 MHz, CDCl 3 ): δ 4.42 (bs, 2 H), 2.80 (t, J 6.6 Hz, 2 H), 2.41 (s, 3 H), 2.14 (s, 3 H), 2.04 (s, 3 H), 1.91–1.77 (m, 2 H), 1.59–1.07 (m, 24 H), 0.90–0.86 (m, 12 H).…”

Section: Methodssupporting

confidence: 90%

“…After stirring overnight at room temperature, the solvent was evaporated under reduced pressure and the crude residue purified by column chromatography (Hex:EtOAc, 15:1), affording 3a (1.01 g, 93%) as yellow dense oil. Analytical data are consistent with those given in the literature 31 , 40 , 48 . 1 H NMR (400 MHz, CDCl 3 ): δ 10.29 (s, 1 H), 3.12 (m, 2 H), 2.39 (s, 3 H), 2.21 (s, 3 H), 2.09 (s, 3 H, ArCH3), 2.09–1.63 (m, 2 H), 1.41–1.08 (m, 24 H), 0.90–0.86 (m, 12 H).…”

Section: Methodssupporting

confidence: 90%

“…Alpha-tocopherol or Trolox methyl ester were transformed to the corresponding bromoacetate by treatment with bromine followed by O -acetylation 28 , 29 . Then, the 6- O -acetyl-5a-bromo derivative 2 oxidation with N -methylmorpholine N -oxide yields the corresponding aldehyde 3 as described in the literature 30 , 31 . Finally, condensation of 3 with nitromethane, in the presence of ammonium acetate, gave the desired nitroalkene 4a (NATOH) or 4b (NATxME) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Rodríguez-Duarte

Dapueto

Galliussi

et al. 2018

Sci Rep

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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.

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Section: Methodssupporting

confidence: 90%

Section: Methodssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

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

Rodríguez-Duarte

Dapueto

Galliussi

et al. 2018

Sci Rep

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“…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.…”

Section: Methodsmentioning

confidence: 99%

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

Rodríguez-Duarte

Galliussi

Dapueto

et al. 2019

British J Pharmacology

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Background and purpose Atherosclerosis is characterized by chronic low‐grade inflammation with concomitant lipid accumulation in the arterial wall. Anti‐inflammatory and anti‐atherogenic properties have been described for a novel class of endogenous nitroalkenes (nitrated‐unsaturated fatty acids), formed during inflammation and digestion/absorption processes. The lipid‐associated antioxidant α‐tocopherol is transported systemically by LDL particles including to the atheroma lesions. To capitalize on the overlapping and complementary salutary properties of endogenous nitroalkenes and α‐tocopherol, we designed and synthesized a novel nitroalkene‐α‐tocopherol analogue (NATOH) to address chronic inflammation and atherosclerosis, particularly at the lesion sites. Experimental approach We synthesized NATOH, determined its electrophilicity and antioxidant capacity and studied its effects over pro‐inflammatory and cytoprotective pathways in macrophages in vitro. Moreover, we demonstrated its incorporation into lipoproteins and tissue both in vitro and in vivo, and determined its effect on atherosclerosis and inflammatory responses in vivo using the Apo E knockout mice model. Key results NATOH exhibited similar antioxidant capacity to α‐tocopherol and, due to the presence of the nitroalkenyl group, like endogenous nitroalkenes, it exerted electrophilic reactivity. NATOH was incorporated in vivo into the VLDL/LDL lipoproteins particles to reach the atheroma lesions. Furthermore, oral administration of NATOH down‐regulated NF‐κB‐dependent expression of pro‐inflammatory markers (including IL‐1β and adhesion molecules) and ameliorated atherosclerosis in Apo E knockout mice. Conclusions and implications In toto, the data demonstrate a novel pharmacological strategy for the prevention of atherosclerosis based on a creative, natural and safe drug delivery system of a non‐conventional anti‐inflammatory compound (NATOH) with significant potential for clinical application.

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“…In the same way, considering the recent findings after the CEHCs metabolites discovery and characterization [32,61], efforts were made to obtain labeled CEHCs analogues, leading to the preparation of d 2 -␥-CEHC [55,79], d 3 -␥-CEHC [79] and d 3 -␣-CEHC [80]. There are very few reports regarding deuterated tocotrienols [81,82] and ␦-T [83]. Several metabolic studies have been carried out on animals or humans fed with deuterated tocopherol derivatives, extracting plasma and tissues and analyzing the distribution, concentration and formation of metabolites of the labeled material.…”

Section: In Vivo Administration Of Labeled Analoguesmentioning

confidence: 98%

Analytical strategies to assess the functional metabolome of vitamin E

Torquato

Orsola

Giusepponi

et al. 2016

Journal of Pharmaceutical and Biomedical Analysis

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Approaches to the Preparation of 4‐Benzyloxy‐2‐(α,α,α‐D₃)methylphenol, a Building Block for Labeled δ‐Tocopherol, and a New Synthesis ofR,R,R‐5‐D₃‐α‐Tocopherol

Cited by 8 publications

References 20 publications

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

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

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

Analytical strategies to assess the functional metabolome of vitamin E

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