Nicotine-iminium ions

Brandange, S., and Lindblom, L. The enzyme "aldehyde oxidase" is an iminium oxidase. Reaction with nicotine -iminium ion. 

Obach, R.S., and Van Vunakis, H. Nicotinamide adenine dinucleotide (NAD)-dependent oxidation of nicotine- -iminium ion to... 

Because there is strong evidence that P-450 2A6 is the primary enzyme forming nicotine -iminium ion in adult human liver... 

At this point it is only speculation that addition of biologically relevant sulfur-containing nucleophiles constitutes a detoxication reaction for metabolites of nicotine. Finally, because nucleophilic addition to the nicotine iminium ion is reversible, from a practical standpoint, an addition compound will probably only be formed and detected under conditions where the nucleophile is present in large excess. 

Hibberd and Gorrod incubated nicotine-A-l -(5 )-iminium (152) with hepatic homogenates prepared from mouse, rat, hamster, rabbit, guinea pig, and human fetal liver to demonstrate the involvement of such reactive chemical intermediates in the oxidation of nicotine to cotinine (151) 221). The iminium ion (152) was converted to (151) more rapidly than nicotine, thus confirming the intermediacy of the ion between nicotine and cotinine. A series of inconclusive... 

Nicotine is extensively metabolized to a nnmber of metabolites (Fig. 3) by the liver. Six primary metabolites of nicotine have been identified. Qnantitatively, the most important metabolite of nicotine in most mammalian species is the lactam derivative, cotinine. In humans, about 70-80% of nicotine is converted to cotinine. This transformation involves two steps. The first is mediated primarily by CYP2A6 to produce nicotine-A -iminium ion, which is in equilibrium with 5 -hydroxynicotine. The second step is catalyzed by a cytoplasmic aldehyde oxidase. Nicotine iminiiim ion has received considerable interest since it is an alkylating agent and, as such, could play a role in the pharmacology of nicotine (Shigenaga etal. 1988). 

Brandange S, Lindblom L (1979) The enzyme aldehyde oxidase is animinium oxidase. Reaction with nicotine delta 1(5 ) iminium ion. Biochem Biophys Res Commun 91 991-996 Byrd GD, Chang KM, Greene JM, deBethizy JD (1992) Evidence for urinary excretion of glu-curonide conjugates of nicotine, cotinine, and trans-3 -hydroxycotinine in smokers. Drug Metab Dispos 20 192-197... 

The reaction of iminium ions with dihydropyridines is a method, suggested from biosynthetic studies, for the formation of carbon-carbon bonds to these six-membered heterocycles. The 1,4-dihydropyridine (8), a presumed intermediate from the reaction of ammonia with glutaraldehyde, reacts with the cyclic iminium ion (159) to give, after oxidation, nicotine (160) (72CC1091). Another example of this reaction has provided a total synthesis of olivacine (163). The 1,2-dihydropyridine ring system in (161), generated from its chromium tricarbonyl complex, was observed to undergo an intramolecular cyclization... 

Oxidative reactions at carbon predominate in the biotransformation of cyclic amiiies, and an important consequence of this is often the cleavage of the carbon-nitrogen bond. For example, A-dealkylation of N- alkyl substituted pyrrolidine (or piperidine, morpholine, etc.) involves an initial oxidative attack at the a- alkyl carbon atom to yield an N hydroxyalkyl derivative (carbinolamine), which is then metabolized to a secondary amine and the corresponding aldehyde. The metabolic conversion of nicotine to nornicotine (30 see Scheme 3) probably involves this mechanism, although the iminium ion (31) has also been suggested as an intermediate in the biotransformation (76JMC1168). Carbinolamines are unstable intermediates and have been identified only in a few cases, e.g. A-hydroxymethylcarbazole... 

The major human urinary metabolites of nicotine are cotinine, nicotine A -oxide, and fra s-3 -hydroxycotinine (113). CYP2A6 appears to be the major enzyme responsible for formation of an iminium ion that is the first step in the C-5 oxidation of nicotine to cotinine and also the subsequent... 

Figure 7.2 illustrates the phosphorus pentoxide-mediated dehydration of a primary amide to a nitrile, using the transformation of nicotine amide (A) into nicotine nitrile (B) as an example. The reaction of phosphorus pentoxide at the carboxyl oxygen furnishes the partially ring-opened iminium ion E (simplified as F) via the polycyclic iminium ion C. E is deprotonated to give the mixed anhydride G from imidic acid and phosphoric acid. Imidic acids are characterized by the functional group R-C(=NH)-OH. This anhydride is transformed into the nitrile B by an El elimination via the intermediate nitrilium salt D. Nitrilium salts are iV-pro-tonated or V-alkylated nitriles. 

A recent study has employed deuterium labeling to show that the mechanism for the oxidative N-demethylation of nicotine may involve two modes of breakdown for a proposed carbinolamine intermediate, dealkylation with formaldehyde formation and dehydration to an iminium ion.72 The formation of such an sp2-hybrid intermediate may help to explain why both a primary and substantial / -secondary deuterium isotope effect were observed for the N-deethylation of the antiarrhythmic agent, lidocaine.73 In contrast, only a primary isotope effect was observed on the rate of oxidative O-deethylation of deuterated analogs of the analgesic, phenacetin. 77 These results indicate differences in the mechanism of oxidative 0- and N-dealkylation. A final example of the use of secondary deuterium isotope effects in studying enzymes involved in drug metabolism revealed an SN-2-like transition state for the transfer of a methyl group catalyzed by catechol-O-methyl transferase.73... 

In the case of azapetine (12) and nicotine (13), the iminium ion intermediate rather than the carbinolamine appears to be the form of substrate preferred by aldehyde oxidase [63-66]. On the other hand, the ring-opened aldehyde intermediate (aldophosphamide) (14) of cyclophosphamide is oxidized by the enzyme [67], although the isomeric 4-hydroxycyclophos-phamide (15) also undergoes oxidation by a soluble fraction enzyme [11]. Oxidation of the carbinolamine form to a cyclic lactam would not seem to involve nucleophilic enzyme attack, and yet we have shown that the stable pseudobase of 3-methylquinazolin-2-one (16), is an efficient substrate of aldehyde oxidase and competitively inhibits the oxidation of both quaternary and non-quatemized substrates [62]. 

As mentioned previously, there are many Mannich-type cyclizations of acetals that undoubtedly occur via enol ether intermediates and afford -amino acetal products. A prototypical example is presented in Scheme 12. In this sequence, due to Wenkert, the iminium ion precursor is formed by semihydrogenation of a nicotinic ester salt. ... 

At the subcellular level the importance of the P-450 system of microsomes in metabolizing nicotine has been clearly established [98,102]. The first step is oxidation by P-450 at C-5 to give the 1 -5 -iminium ion that is then oxygenated using water as the source of oxygen [103, 104]. A flavoprotein is implicated in this later step, or possibly also in an alternative pathway [104, 105, 106]. The N-demethylation and N-oxide-forming reactions are also catalyzed in microsomes, but the details of these... 

The oxidation of 1,4-dihydropyridines with dimethyldioxirane provides dimeric tetrahydropyridines fused as a 1,4-dioxane. These products can be converted to useful iminium ion precursors and 2-substituted-3-hydroxy-l,2,3,4-tetrahydropyridines <97CC213>. The cycloaddition of 1,4-dihydro- and 1,4,5,6-tetrahydro-nicotinates with cyanoalkenes gives a mixture of regioisomers. No isomerization of the cis/trans relationship is observed with Z- or -but-2-enenitrile indicating a consorted cycloaddition mechanism. Low diastereoselectivity in... 

The required iminium ion can be obtained readily by the condensation of an aldehyde with a butenylamine. For example, heating the butenylamine 276 with pyridine-3-carboxaldehyde and an acid catalyst (camphorsulfonic acid, CSA), gave the acetyl nicotine derivative 277 (3.176). The initial iminium ion 278 rearranges to the new iminium ion 279, which is irreversibly trapped in an intramolecular Mannich reaction to give the pyrrohdine 277. 

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