Trapping of metabolically generated electrophilic species with cyanide ion: metabolism of 1-benzylpyrrolidine

Ho, Bert; Castagnoli, Neal

doi:10.1021/jm00176a006

Cited by 49 publications

(31 citation statements)

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“…The formation of glutamic acid derivatives also resembles the metabolic opening of the pyrrolidine fragment of nicotine (II). In an attempt to characterize this oxidative process, the fate of I-benzylpyrrolidine was examined in microsomal incubates of rabbit liver (12). Evidence is presented that the substrate undergoes microsomal oxidation to generate a reactive iminium intermediate which might be formed by ionization of the precursor carbinolamine.…”

Section: Resultsmentioning

confidence: 99%

Fate and disposition of bromocriptine in animals and man. I: Structure elucidation of the metabolites

Maurer¹,

Schreier²,

Delaborde³

et al. 1982

European Journal of Drug Metabolism and Pharmacokinetics

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A total of 16 metabolites of bromocriptine could be isolated from rat bile and incubates of rat liver cell preparations using [6-methyl-14C]bromocriptine as substrate. Separation and purification was achieved by reversed-phase liquid chromatography and preparative thin-layer chromatography in conjunction with radioactivity monitoring. Structure elucidation was based on spectroscopic data (UV, IR, NMR, EI- and FD-MS) and the results of amino acid analysis after acid hydrolysis. Based on the identified metabolites four principal transformation process could be described: -Hydrolytic cleavage of the amide bridge leading to the formation of 2-bromolysergic acid amide (3) and 2-bromolysergic acid (7). -epimerization at position 8 of the bromolysergic acid moiety to the iso-derivatives (isobromocriptine, 2-bromo-isolysergic acid (6), its amide (1), etc.) -regiospecific oxidation at position 8' in the proline fragment generating stereoisomeric 8'-hydroxy-bromocriptines (21-24) -further oxidation of the 8'-hydroxylated derivatives by either the introduction of a second hydroxy group at position 9' to give dihydroxylated derivatives (detected as conjugates with glucuronic acid: metabolites 29, 30 and 31), or the opening of the proline ring under formation of the metabolites 4 and 5 containing glutamic acid instead of proline (7', 8'-seco- 8'-carboxy-bromocriptines). It is suggested that the primary and principal metabolic attack occurs at the proline fragment of the drug. In contrast to the biotransformation of ergoline compounds, none of the bromocriptine metabolites detected showed oxidative transformations in the lysergic acid half of the molecule.

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Section: Resultsmentioning

confidence: 99%

Fate and disposition of bromocriptine in animals and man. I: Structure elucidation of the metabolites

Maurer¹,

Schreier²,

Delaborde³

et al. 1982

European Journal of Drug Metabolism and Pharmacokinetics

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“…Accordingly, the first step of the oxidative attack on 7 yields three iminium cations: two endocyclic (25, 26) and one exocyclic (27). Nucleophilic water molecule can trap these cations to give the corresponding aminoalcohols, as indicated for 27→28.…”

Section: Resultsmentioning

confidence: 99%

“…In this particular case, the main reaction products were two α-aminonitriles (49 and 50 in Scheme 5), counting for about 86% of the reacted 1. They clearly resulted from the iminium cations 44 and 45, respectively, by cyano trapping [7,8,[27][28][29]. Excepting 4, the other reaction products (i.e., 2+7 and 30+BzH) were oxygen-containing compounds, clearly originating from the same iminium cations, escaped from the cyanide anion trapping (i.e., captured by water).…”

Section: Scheme 4 Oxidation By Ruo 4 Of Piperazine Derivative 30 ([Oxmentioning

confidence: 99%

RuO4-mediated oxidation of N-benzylated tertiary amines. 3. Behavior of 1,4-dibenzylpiperazine and its oxygenated derivatives

Petride¹,

Drăghici²,

Florea³

et al. 2006

Open Chemistry

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1,4-Dibenzylpiperazine (1), -2-piperazinone (7), -2,6-piperazinedione (9), and 1-benzoyl-4-benzylpiperazine (30) were oxidized by RuO 4 (generated in situ) by attack at their endocyclic and exocyclic (i.e., benzylic) aminic N -α-C-H bonds to afford various oxygenated derivatives, including acyclic diformamides, benzaldehyde, and benzoic acid. The reaction outcome was complicated by (i) the hydrolysis of diformamides, occurred during the work-up, and (ii) the reaction of benzaldehyde with the hydrolysis-derived amines giving imidazolidines and/or Schiff bases. Benzoic acid resulted from benzaldehyde only. Compounds 7, 30, and 1-benzylpiperazine, but not 9, were transiently formed during the oxidation of 1. In the same reaction conditions, 1,4-dibenzyl-2,3-(or 2,5)-piperazinedione, 1,4-dibenzyl-2,3,6-piperazinetrione, 4-benzoyl-1-benzyl-2-piperazinone, and 1,4-dibenzoylpiperazine were inert. The proposed oxidation mechanism involves the formation of endocyclic and exocyclic iminium cations, as well as of cyclic enamines. The latter intermediates probably result by base-induced deprotonation of the iminium cations, provided an N + −β-proton is available. In the case of 1, the cations were trapped with NaCN as the corresponding α-aminonitriles. The statistically corrected regioselectivity (endocyclic/exocyclic) of the RuO 4 -induced oxidation reaction of 1, 7, and 30 was 1.2-1.3.

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“…Perfusate samples (0.5 ml) were taken from the perfusion media reservoir at 0, 2, 5, 10, 15, 30, 60, 90, 120, 150 and 180 min post dose and analysed for nicotine and any metabolites by HPLC and GC (see below). At the end of each perfusion, the lungs were weighed and stored at -80°C prior to homogenisation using the cyanide trapping technique (14)(15)(16)(17).…”

Section: Nicotine Administrationmentioning

confidence: 99%

“…The use of [14C]-cyanide facilitates the quantitation of such reactive intermediates and has been widely used in studies concerned with the in vitro metabolism of alicyclic amines (6,(14)(15)(16)(17)20). It was of interest to examine whether reactive intermediates derived from nicotine would be present in the lung tissue following the 3 h perfusion period.…”

Section: Cyanide Trapping Techniquementioning

confidence: 99%

Metabolism of (−)-(S)-nicotine in the isolated perfused rabbit lung

Aislaitner

Bello

Tan

et al. 1997

Eur. J. Drug Metab. Pharmacokinet.

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The metabolism of (-)-(S)-nicotine has been investigated following intratracheal administration to the recirculating perfused rabbit lung model. The metabolic products present in the perfusate were identified by co-chromatography (HPLC and GC) with authentic standards and quantified by HPLC. After the 180 min perfusion period, nicotine was found to be metabolically transformed to cotinine (33.7%), 3-hydroxycotinine (10.4%), cotinine-1-N-oxide (3.4%) and nicotine-1'-N-oxide (14.4%). Norcotinine, nornicotine, 3-pyridyl-4-oxo-N-methylbutyramide and an uncharacterised metabolite were also detected in low amounts. Following the perfusion experiment, part of the lung tissue was homogenised in the presence of [14C]-sodium cyanide. Subsequent analysis of the homogenates indicated the formation of 2'-cyanonicotine, 1'-cyanomethylnornicotine and the diastereoisomeric 5'-cyanonicotines.

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Trapping of metabolically generated electrophilic species with cyanide ion: metabolism of 1-benzylpyrrolidine

Cited by 49 publications

References 1 publication

Fate and disposition of bromocriptine in animals and man. I: Structure elucidation of the metabolites

Fate and disposition of bromocriptine in animals and man. I: Structure elucidation of the metabolites

RuO4-mediated oxidation of N-benzylated tertiary amines. 3. Behavior of 1,4-dibenzylpiperazine and its oxygenated derivatives

Metabolism of (−)-(S)-nicotine in the isolated perfused rabbit lung

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