The Mannich Reaction. Mechanistic and Technological Considerations

Thompson, B. Blackburn

doi:10.1002/jps.2600570501

Cited by 85 publications

(19 citation statements)

References 76 publications

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“…No additional trapped metabolites were detected in any of the incubations. Formaldehyde has been shown to react with primary and secondary amine groups in a classic Mannich reaction to form an iminium ion (Thompson, 1968). Consequently, another set of microsomal diltiazem incubations was prepared where incubations proceeded in the presence of 30% v/v H 13 CHO.…”

Section: Resultsmentioning

confidence: 99%

High-Resolution Mass Spectrometry Elucidates Metabonate (False Metabolite) Formation from Alkylamine Drugs during In Vitro Metabolite Profiling

Barbara

Kazmi²,

Muranjan³

et al. 2012

Drug Metab Dispos

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ABSTRACT:In vitro metabolite profiling and characterization experiments are widely employed in early drug development to support safety studies. Samples from incubations of investigational drugs with liver microsomes or hepatocytes are commonly analyzed by liquid chromatography/mass spectrometry for detection and structural elucidation of metabolites. Advanced mass spectrometers with accurate mass capabilities are becoming increasingly popular for characterization of drugs and metabolites, spurring changes in the routine workflows applied. In the present study, using a generic full-scan high-resolution data acquisition approach with a time-offlight mass spectrometer combined with postacquisition data mining, we detected and characterized metabonates (false metabolites) in microsomal incubations of several alkylamine drugs. If a targeted approach to mass spectrometric detection (without fullscan acquisition and appropriate data mining) were employed, the metabonates may not have been detected, hence their formation underappreciated. In the absence of accurate mass data, the metabonate formation would have been incorrectly characterized because the detected metabonates manifested as direct cyanidetrapped conjugates or as cyanide-trapped metabolites formed from the parent drugs by the addition of 14 Da, the mass shift commonly associated with oxidation to yield a carbonyl. This study demonstrates that high-resolution mass spectrometry and the associated workflow is very useful for the detection and characterization of unpredicted sample components and that accurate mass data were critical to assignment of the correct metabonate structures. In addition, for drugs containing an alkylamine moiety, the results suggest that multiple negative controls and chemical trapping agents may be necessary to correctly interpret the results of in vitro experiments.

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Section: Resultsmentioning

confidence: 99%

High-Resolution Mass Spectrometry Elucidates Metabonate (False Metabolite) Formation from Alkylamine Drugs during In Vitro Metabolite Profiling

Barbara

Kazmi²,

Muranjan³

et al. 2012

Drug Metab Dispos

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“…This reaction is a typical Mannich reaction (Thompson, 1968). When acetonitrile or dimethyl sulfoxide was used as solvent in the microsomal incubation, compounds A and dmd.aspetjournals.org B had little turnover, and were metabolically stable.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Novel in Vitro Metabonate From Liver Microsomal Incubations

Surapaneni²,

Zeng³

et al. 2006

Drug Metabolism and Disposition

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ABSTRACT:In vitro drug metabolism studies during the early drug discovery stage are becoming increasingly important. With the increasing demand for high throughput and quick turnaround time for in vitro metabolism studies, however, careful examination of the results and proper design of the experiments are still crucial. In this communication, we report the identification and mechanism of formation of a novel metabonate from incubations of a diamine-containing compound with liver microsomes. The metabonate appeared to be the major product, and its formation was NADPH-and microsomal protein-dependent. Liquid chromatography/mass spectrometry and NMR analysis of the metabonate indicated an extra carbon and unusual formation of an imidazolidine ring. Further studies revealed that this metabonate was not a true biotransformation product from the diamine compound itself in the microsomal incubation, but rather a product resulting from a condensation reaction between the compound and a metabolite of the solvent (alcohol) used in the incubation. When the microsomal incubations contained a small amount of methanol or ethanol as solvent, the alcohols were metabolized to formaldehyde or acetaldehyde, which then condensed with the diamine compound through an imine intermediate to form the metabonate. The compound itself was metabolically stable in vitro when acetonitrile or dimethyl sulfoxide was used as solvent. During the study of in vitro microsomal stability and metabolite identification of amine-containing compounds, the use of alcohol as solvent should be avoided.

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“…Iminium salts are key reactive synthons involved in important organic reactions [1][2][3][4][5][6] that lead to the formation of C-C bonds. In previous studies [7], we reported the preparation of the iminium chlorides of cyclic (thio)ureas through the condensation of the atypical Vilsmeier reagent I and the imidazolidin-2-(thio)one substrates (Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of (acyl)hydrazones and thiosemicarbazones obtained via in situ condensation of iminium salts with nitrogen-containing nucleophiles

et al. 2015

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An unprecedented, highly convergent, high-yielding, one-pot synthesis of (acyl)hydrazones and thiosemicarbazones was carried out by the in situ condensation of isolable iminium chlorides of imidazolidin-2-(thio)one, tetrahydropyrimidin-2-thione and indole derivatives with nitrogen nucleophiles in the presence of a base. The developed reaction procedure is largely advantageous. It is highly parallelizable, no intermediates need to be isolated and minimal sample handling is required during the purification steps. Some relevant reaction parameters including reaction temperature and p[Formula: see text] of the base are discussed. NMR analysis was carried out to assess the stereochemistry of the obtained compounds. The stereochemical outcome of the reaction was found to be affected by the nature of the nitrogen-containing nucleophile being the majority of the derivatives isolated as single geometric isomers. The cytotoxicity and antiviral activities of the prepared compounds have been preliminary assessed. In cell-based screenings some of the derivatives proved to be cytotoxic at low micromolar concentrations and interesting anti-Reo-1 properties have been detected.

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The Mannich Reaction. Mechanistic and Technological Considerations

Cited by 85 publications

References 76 publications

High-Resolution Mass Spectrometry Elucidates Metabonate (False Metabolite) Formation from Alkylamine Drugs during In Vitro Metabolite Profiling

High-Resolution Mass Spectrometry Elucidates Metabonate (False Metabolite) Formation from Alkylamine Drugs during In Vitro Metabolite Profiling

Identification of a Novel in Vitro Metabonate From Liver Microsomal Incubations

Synthesis and biological evaluation of (acyl)hydrazones and thiosemicarbazones obtained via in situ condensation of iminium salts with nitrogen-containing nucleophiles

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