Acetyl-a-tocopherol

The only chromane known from lichens Erioderma phaeorhizum) is acetyl-a-tocopherol (381) 348). The chromone siphulin (382) was synthesized by reaction of 2-hydroxy-4-benzyloxy-6-n-heptylacetophe-none with 2-carboxy-3,5-dibenzyloxyhomophthalate in the presence of NaH to give tri-O-benzylprotosiphulin this yielded siphulin after acid-induced dehydration and hydrogenolysis 461) (see Scheme 129). 

Stabilization of the zwitterionic intermediate in o-QM formation can also occur intramolecularly. In this case, the stabilizing moieties must be able to dissipate the positive charge at the benzylic group by a resonance effect and prevent rotation of the exocyclic methylene group by a steric blocking. One example for such a temporary stabilization is the nitration of a-tocopheryl acetate (25) by concentrated HNO3, which produced 6-0-acetyl-5-nitro-a-tocopherol (27) in quite good yields,48 the... 

FIGURE 6.21 Synthesis of 6-0-acetyl-5-nitro-a-tocopherol (27) and four resonance forms of the cationic intermediate (26). 

Various hydroxyl and amino derivatives of aromatic compounds are oxidized by peroxidases in the presence of hydrogen peroxide, yielding neutral or cation free radicals. Thus the phenacetin metabolites p-phenetidine (4-ethoxyaniline) and acetaminophen (TV-acetyl-p-aminophenol) were oxidized by LPO or HRP into the 4-ethoxyaniline cation radical and neutral V-acetyl-4-aminophenoxyl radical, respectively [198,199]. In both cases free radicals were detected by using fast-flow ESR spectroscopy. Catechols, Dopa methyl ester (dihydrox-yphenylalanine methyl ester), and 6-hydroxy-Dopa (trihydroxyphenylalanine) were oxidized by LPO mainly to o-semiquinone free radicals [200]. Another catechol derivative adrenaline (epinephrine) was oxidized into adrenochrome in the reaction catalyzed by HRP [201], This reaction can proceed in the absence of hydrogen peroxide and accompanied by oxygen consumption. It was proposed that the oxidation of adrenaline was mediated by superoxide. HRP and LPO catalyzed the oxidation of Trolox C (an analog of a-tocopherol) into phenoxyl radical [202]. The formation of phenoxyl radicals was monitored by ESR spectroscopy, and the rate constants for the reaction of Compounds II with Trolox C were determined (Table 22.1). 

The tocopherols can be separated by a number of methods one is to esterify them with a lower alcohol followed by washing, vacuum distillation and saponification alternatively, fractional liquid-liquid extraction may be used. The product can then be further purified by molecular distillation, extraction or crystallisation. This process produces a product high in y- and (5-tocopherols but these can be converted into the more useful a-tocopherol by methylation. If required a-toco-pherol acetate can be made by acetylating the a-tocopherol. 

Figure 11 Biosynthesis of isoprenoid type cofactors. 18, Heme a 39, pyridoxal 5 -phosphate 43, 1-deoxy-D-xylulose 5-phosphate 46, thiamine pyrophosphate 83, acetyl-CoA 84, (S)-3-hydroxy-3-methylglutaryl-CoA 85, mevalonate 86, isopentenyl diphosphate (IPP) 87, dimethylallyl diphosphate (DMAPP) 88, pyruvate 89, D-glyceraldehyde 3-phosphate 90, 2C-methyl-D-erythritol 4-phosphate 91, 2C-methyl-erythritol 2,4-cyclodiphosphate 92, 1-hydroxy-2-methyl-2-( )-butenyl 4-diphosphate 93, polyprenyl diphosphate 94, cholecalciferol 95, fS-carotene 96, retinol 97, ubiquinone 98, menaquinone 99, a-tocopherol.

In order to prepare C -labeled d-a-tocopherol we started from natural d-7-tocopherol (Fig. 6) and introduced the C -methyl group into the 5-position by use of the Mannich reaction. Condensation of d-y-tocopherol with radioactive paraformaldehyde in the presence of diethylamine followed by catalytic reduction gave d-a-tocopherol. This was acetylated to methyl-C Mabeled d-a-tocopherol acetate (specific activity 1.7 tc/mg Fig. 6). 

Haloperidol, a dopamine receptor antagonist, was cytotoxic to mouse clonal hippocampal HT22 cells in a concentration-dependent manner and caused death by oxidative stress as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazo-lium bromide (Post et al. 1998). The addition of haloperidol to HT22 cells led to an increase in intracellular peroxides and a rime-dependent drop in the intracellular glutathione levels. Haloperidol-induced oxidative cell death was prevented by melatonin, its precursor N-acetyl serotonin, and most effectively by a-tocopherol. 

A process is described for preparing a-tocopherol or tocopheryl acetate by cyclocondensation of trimethylhydroquinone wilii phytol or isophytol in the presence of an acid catalyst in liq. or SCCO2, optionally followed by acetylation. 

Some of die first agents tested in ALS models were antioxidants. Correlative increases in oxidative markers in and around affected tissues strongly inplicated oxidative injury as a coirponent of overall neuronal loss in MND and ALS (4,10,11). Logic dictated diat, even if oxidative injury is secondary to the primary insult, antioxidants could be beneficial, and a number of such agents were tried, including ascorbate (vitamin C), tocopherol (vitamin E), cysteine, and N-acetyl-cysteine (8,12-14). The fact that tiiese conpounds are relatively safe dietary supplements made them natural choices and they were among the first conpounds tested in both mice and humans. 

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