Selenium, methylation

Dimethyl selenide is exhaled, and the trimethylselenonium ion is a major urinary metabolite of selenium. Methylation of selenium is a detoxification pathway that is especially important at high selenium doses. 

Excretion of selenium by humans occurs in the urine, feces, expired air, and sweat, but urine and feces are the major routes of elimination. Some of the selenium in feces may be due to bilary excretion (Levander and Baumann 1966a, 1966b). Elimination is reduced in selenium-deficient individuals and may represent a mechanism by which selenium levels are regulated (Martin et al. 1989a Swanson et al. 1991). Methylation is an important mechanism of detoxification for selenium dimethyl selenide is exhaled, and the trimethylselenonium ion is the major urinary metabolite of selenium. Experiments in mice suggest that the hepatic toxicity of selenium may be at least partly due to depression of selenium methylation in the liver, resulting in the accumulation of excess selenides (Nakamuro et al. 2000). 

Chen CL, Whanger PD. 1993. Effect of vitamin B12 status on selenium methylation and toxicity in rats In vivo and in vitro studies. Toxicol Appl Pharmacol 118(l) 65-72. 

Hasegawa T, Mihara M, Nakamuro K, et al. 1996. Mechanisms of selenium methylation and toxicity in mice treated with selenocystine. Arch Toxicol 71 31-38. 

Nakamuro K, Okuno T, Hasegawa T. 2000. Metabolism of selenoamino acids and contribution of selenium methylation to their toxicity. 46(6) 418-421. 

The investigations of Jensen and Schmith (45) indicate that in vitro activity of 2-sulfanilamido and 4-methyl-2-sulfanilamido selenazoles against pneumonia infections is comparable to that of sulfathiazole or sulfadiazine. Frisk (47) found that the activity of the selenium compounds was much lower than that of sulfathiazole. 

The first compounds with a Aj selenazoline structure were mentioned in the literature in 1892 by Michels (55). He prepared 2-methyl-A -selenazoline in the course of his investigations into sulfur and selenium... 

Methylation takes place on the selenium (73). in contrast to the thiazolidines where it occurs on the heterocyclic nitrogen (75). 

Selenium dioxide oxidation of methyl derivatives (Scheme 30). 

Alkyl Isoquinolines. Coal tar contains small amounts of l-methylisoquinoline [1721-93-3] 3-methylisoquinoline [1125-80-0] and 1,3-dimetliylisoquinoline [1721-94-4J. The 1- and 3-methyl groups are more reactive than others in the isoquinoline nucleus and readily oxidize with selenium dioxide to form the corresponding isoquinoline aldehydes (174). These compounds can also be obtained by the hydrolysis of the dihalomethyl group. The 1- and 3-methyhsoquinolines condense with benzaldehyde in the presence of zinc chloride or acetic anhydride to produce 1- and 3-styryhsoquinolines. Radicals formed by decarboxylation of carboxyUc acids react to produce 1-aIkyhsoquinolines. 

Selenocysteine was identified in 1976 (57) in a protein produced by Clostridium stricklandii, and it is thought to be the form in which selenium is incorporated, stoichiometricaHy, into proteins. Studies with rats show that over 80% of the dietary selenium given them is incorporated into proteins, thus selenocysteine takes on metaboHc importance. Selenoproteins having known enzymatic activities contain selenocysteine at the active sites. Two other forms of metabohc selenium are recognized methylated selenium compounds are synthesized for excretion, and selenium is incorporated into some transfer ribonucleic acids (tRNAs) in cultured cells (58). Some of the more important seleno-compounds are Hsted in Table 4. Examples of simple ring compounds are shown in Eigure 4. 

Methylpyridazine can be oxidized with selenium dioxide to give 3-formylpyridazine, and methyl groups attached to any position in pyridazine N-oxides are transformed with pentyl nitrite in the presence of sodium amide in liquid ammonia into the corresponding... 

The direct combination of selenium and acetylene provides the most convenient source of selenophene (76JHC1319). Lesser amounts of many other compounds are formed concurrently and include 2- and 3-alkylselenophenes, benzo[6]selenophene and isomeric selenoloselenophenes (76CS(10)159). The commercial availability of thiophene makes comparable reactions of little interest for the obtention of the parent heterocycle in the laboratory. However, the reaction of substituted acetylenes with morpholinyl disulfide is of some synthetic value. The process, which appears to entail the initial formation of thionitroxyl radicals, converts phenylacetylene into a 3 1 mixture of 2,4- and 2,5-diphenylthiophene, methyl propiolate into dimethyl thiophene-2,5-dicarboxylate, and ethyl phenylpropiolate into diethyl 3,4-diphenylthiophene-2,5-dicarboxylate (Scheme 83a) (77TL3413). Dimethyl thiophene-2,4-dicarboxylate is obtained from methyl propiolate by treatment with dimethyl sulfoxide and thionyl chloride (Scheme 83b) (66CB1558). The rhodium carbonyl catalyzed carbonylation of alkynes in alcohols provides 5-alkoxy-2(5//)-furanones (Scheme 83c) (81CL993). The inclusion of ethylene provides 5-ethyl-2(5//)-furanones instead (82NKK242). The nickel acetate catalyzed addition of r-butyl isocyanide to alkynes provides access to 2-aminopyrroles (Scheme 83d) (70S593). 

The second alkaloid solanocapsidine, C2gH4404N2, m.p. S05° (approx.), is amorphous. It was used for a selenium dehydrogenation experiment and yielded Diels s hydrocarbon, y-methylci/ciopentenophenanthrene (picrate, m.p. 117°) and a mixture of bases from which 2-methyl-5-ethylpyridine (picrate, m.p. 162°) and 4-methyl-2-ethylpyridine (picrate, m.p. 125°) were isolated. 

Jacobs and Craig have made an extended study of the selenium dehydrogenation products of cevine and in addition to cevanthrol and eevanthridine have obtained the following thirteen substances Bases, j3-picoline, 5-methyl-2-ethylpyridinc, 5-methyl-2-hydroxyethylpyridine, base, CgHgON (pierate, m.p. 151-2°), base, CgHjgN (pierate, m.p. 150-1°), base, CggHigN, m.p. 233-5° (methiodide, m.p. 285-290°), base, m.p. 229-230° (methiodide, m.p. 295° (dec.) )... 

The selenium-dehydrogenation products of fsorubijervine have not yet been fully examined, but the two structurally significant products, 5-methyl-2-ethylpyridine and a hydrocarbon, m.p. 135-6°, yielding... 

Ketohydroxycassanic acid, C20H32O4, has also been used for another mode of degradation by Ruzicka, Dalma and Scott (1941). On oxidation by chromic acid in acetic acid it yields diketocassanic acid, C20H30O4, m.p. 225°, [a]u ° — 44° (EtOH), which forms a methyl ester, m.p. 108°, (EtOH), and is reduced by sodium amyloxide at 220° to cassanic acid, C20H34O2, m.p. 224°, [a]f - - 3° (CHCI3), which on selenium dehydrogenation also yields 1 7 8-trimethylphenanthrene. 

The methyl group m 3-methyl-4,5,6,7-tetrafluoroindoles is oxidized to an aldehydic or a hydroxymethyl group with high selectivity by selenium dioxide [90] (equation 83)... 

The chalcogene heterocycles have been used as stable precursors for sulfur-said selenium-cantaining hetero-l,3-dienes in cycloaddition reactions 3//-l,2,4-Thiaselenazoles are a convenient source of 4,4-bis(trifluoromethyl)-l-thia-3-aza-buta-1,3-dienes, and 3//-diselenazoles are a convenient source of 4,4-bis(trifluoromethyl)-l-selena-3-azabuta-l,3-dienes as well as bis(tnfluoro-methyl)-substrtuted nitrile ylides [137]... 

Intramolecular chalcogen interactions may also stabilize reactive functional groups enabling the isolation of otherwise unstable species or their use as transient intermediates, especially in the case of selenium and tellurium. For example, tellurium(II) compounds of the type ArTeCl are unstable with respect to disproportionation in the absence of such interactions. The diazene derivative 15.23 is stabilized by a Te N interaction. Presumably, intramolecular coordination hinders the disproportionation process. Other derivatives of the type RTeX that are stabilized by a Te N interaction include 8-(dimethylamino)-l-(naphthyl)tellurium bromide, 2-(bromotelluro)-A-(p-tolyl)benzylamine, and 2-[(dimethylammo)methyl]phenyltellunum iodide. Intramolecular donation from a nitrogen donor can also be used to stabilize the Se-I functionality in related compounds." ... 

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