Oxidation nicotine

Nearly all of the microbial and mammalian transformation studies with this group of alkaloids have been focused on nicotine. Microorganisms have been used to resolve racemic nicotine to make available unnatural (/ )-(+)-nicotine for biological evaluation. Highly significant work has detailed the mechanism of nicotine oxidation in mammals, and has resulted in the identification of reactive intermediates formed as the alkaloid is transformed by hepatic monooxygenases. The chemistry and pharmacology of the pyridine alkaloids is discussed by Strunz and Findlay in Volume 26 of this treatise. 

LuneU E, Molander L, Ekberg K, Wahren J (2000) Site of nicotine absorption from a vapour inhaler-comparison with cigarette smoking. Eur J Clin Pharmacol 55(10) 737-741 MacDougaU JM, Fandrick K, Zhang X, Serafln SV, Cashman JR (2003) Inhibition of human liver microsomal (S)-nicotine oxidation by (—)-menthol and analogues. Chem Res Toxicol 16(8) 988-993... 

The principal metabolites of nicotine are cotinine and nicotine T-N-oxide. There is some evidence that another product of nicotine oxidation is a quarternary nitrogen derivative which may covalently modify proteins. This... 

One approach (M. Wada, Y. Nishara and K.-Y. Akiba, Tetrahedron Letters, 1985, 26, 3267) involves the addition of the 0-silyl derivative (38) of methyl pent-3-ene carboxylate and the salt (39) of methyl nicotinate. Oxidation of the product (40) with DDQ affords the diester (41) which, after protonation, is treated successively with mercury (II) acetate and sodium borohydride to yield the diester (42). Finally this compound when reacted with ammonia in methanol affords ( )-sesbanine. (Scheme 1)... 

Lewis has published several homology models of P450 2A6 (refs [300 302]) and also attempted to rationalize the pattern of nicotine oxidation using molecular orbital calculations . ... 

Naghski, J. Analytical methods Progress on the separation of nicotine oxidation products 4th Tobacco Chemists Research Conference, Program Booklet and Abstracts, Vol. 4, Paper No. 5,1950, p. 1. 

In part, because of the extensive genetic variation and the metabolism of carcinogens, genetic variations have been extensively considered regarding cancer (Sect. 7.4.7, vide infra). P450 2A6 is involved in nicotine oxidation, and Tyn-dale and her group reported that individuals with... 

L-Nicotine oxidation by cell-free extracts of Arthrobacter oxydans yields L-6-hydroxynicotine exclusively. When Arthrobacter oxydans is grown on DL-nicotine, l- and d-6-hydroxynicotine oxidases are produced and have been separated. L-6-Hydroxynicotine oxidase converts L-6-hydroxynicotine to 5-(7-methylaininobutyryl)-2-pyridone (XI1.841) in the presence of oxygen by a mechanism that consists of dehydrogenation followed by hydrolysis of the intermediate enamine (XII-840). ... 

A series of 10 tobacco alkaloids (e.g., (/, 5)-anatabine, (S)-(—)-cotinine, -nicotyrine, -nicotine, and -anabasine, and syn-nicotine- -oxide) were separated on... 

Nicotinic acid is prepared in good tdeld by the oxidation of p picollne with potassium permanganate ... 

Ethyl nicotinate upon treatment with concentrated ammonia solution yields nicotinamide, which gives p-cyanopjTidine upon heating with phosphoric oxide ... 

Section 15 11 Oxidation of alcohols to aldehydes and ketones is a common biological reaction Most require a coenzyme such as the oxidized form of nicotin amide adenine dmucleotide (NAD" )... 

Pyridine A Oxides. Analgesic and antiinflammatory dmgs niflumic acid [4394-00-7] (68) and pranoprofen [52549-17-4] (69) are manufactured from nicotinic acid N-oxide [2398-81 -4]. The antiulcer dmg omeprazole (66) is produced from 2,3,5-trimethylpyridine N-oxide [74409-42-0]. Zinc pyrithione, the zinc salt of pyrithione (45), is a fungicide derived from 2-chloropyridine N-oxide (45). 

Oxidation. The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid [59-67-6] (7) has been accompHshed direcdy in 79% yield using a nitric—sulfuric acid mixture above 220°C (25). A wide variety of oxidants have been used in the preparation of quinoline N-oxide. This substrate has proved to be useful in the preparation of 2-chloroquinoline [612-62-4] and 4-chloroquinoline [611 -35-8] using sulfuryl chloride (26). The oxidized nitrogen is readily reduced with DMSO (27) (see Amine oxides). 

Pyridine carboxamide [98-92-0] (nicotinamide) (1) and 3-pyridine carboxylic acid [59-67-6] (nicotinic acid) (2) have a rich history and their early significance stems not from their importance as a vitamin but rather as products derived from the oxidation of nicotine. In 1867, Huber prepared nicotinic acid from the potassium dichromate oxidation of nicotine. Many years later, Engler prepared nicotinamide. Workers at the turn of the twentieth century isolated nicotinic acid from several natural sources. In 1894, Su2uki isolated nicotinic acid from rice bran, and in 1912 Funk isolated the same substance from yeast (1). 

The alkyl pyridines (6) and (7) can be transformed either to nicotinic acid or nicotinonitrile. In the case of nicotinic acid, these transformations can occur by either chemical or biological means. From an industrial standpoint, the majority of nicotinic acid is produced by the nitric acid oxidation of 2-meth5i-5-ethylpyridine. Although not of industrial significance, the air oxidation has also been reported. Isocinchomeronic acid (10) (Fig. 2) is formed as an intermediate. 

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