Synthesis of 5‐(Fluorophenyl)tocopherols as Novel Dioxin Receptor Antagonists

Abstract

γ‐Tocopherol, a component of the essential nutrient mixture commonly designated as vitamin E, was chemically combined with differently substituted monofluoro‐ and difluorophenyl moieties to produce potential antagonists for the human aryl hydrocarbon receptor (AhR). 5‐Iodo‐γ‐tocopherol was a very reliable starting material for the Pd‐catalyzed reaction with (fluorophenyl)boronic acids (Suzuki coupling). The ortho‐ and meta‐fluoro‐substituted derivatives showed conformational isomerism due to restricted rotation around the interaromatic bond. This effect was investigated by NMR spectroscopy. Three of the derivatives showed very high potency in assays and are promising candidates for further testing.

Xanthohumol ameliorates 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin–induced cellular toxicity in cultured MC3T3‐E1 osteoblastic cells

“…In this study, we found that TCDD exposure caused osteoblast cytotoxicity and oxidative stress, whereas xanthohumol mitigated these effects. Kloser et al (2011) demonstrated that antioxidants such as tocopherol are antagonistic to TCDD and have been found to decrease the concentration of nitrogen peroxide and decrease damage to single-stranded DNA (Alsharif & Hassoun, 2004). Several studies have demonstrated that ROS produced during oxidative stress initiated signaling cascades leading to cytotoxicity and autophagy (Kim et al, 2007;Scherz-Shouval et al, 2007).…”

The protective action of tocopherol and acetylsalicylic acid on the behavior of rats treated with dioxins

“…The improving effect obtained after a long-term use of TCP in both tests can be justified by a protective role of this vitamin on the phospholipids of cell membranes, mitochondrial membranes, as well as reduced activity of free radicals and nitric oxide, and lower level of TNF concentration, which is also confirmed by studies of other authors. [50][51][52] Administration of ASA in ASA (F) group also resulted in shorter response times, which confirms the positive effect of ASA on neurotransmission. Similar results are presented in the studies by Gong et al, Wang and Lu et al 40,53,54 This study confirms that ASA is an antagonist of the glycine receptor and it reduces the inhibitory effect of GABA, releases glutamate from presynaptic terminals, resulting in the facilitation effect, which induces the hyperreactivity.…”

Indirect study of the effect of α-tocopherol and acetylsalicylic acid on the mineral composition of bone tissue in the offspring of female rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin: long-term observations

“…36,47,63 The anti-inammatory properties of ASA constitute a valuable addition to the antagonistic effect of this drug on the aryl hydrocarbon receptor. 36,38 It is worth mentioning that in the literature there is only a small amount of data concerning the inuence of TCDD on the content of magnesium, zinc and iron in bones. 64 It was shown that the administration of TCDD contributed to changes in the content of magnesium in the cytosol of liver cells.…”

“…It has been shown in recent studies that two well-known substances, a-tocopherol and acetylsalicylic acid (ASA), have properties that can reduce the effects of dioxins poisoning. 3,31,36,38,39 Nowadays, monitoring the constant exposure of humans and animals to dioxins and their inuence on bone mineralization is essential for the prevention of dioxin intoxication and the development of effective pharmacological treatment methods…”