In Vitro Metabolism of Aromatic Nitriles

Markus, Bohdan; Kwon, Chul‐Hoon

doi:10.1002/jps.2600831216

Cited by 12 publications

(4 citation statements)

References 21 publications

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“…The prevalence of nitrile-containing pharmaceuticals and the continued stream of potential agents in the clinic attest to the biocompatibility of the nitrile functionality . The nitrile group is not particularly electrophilic toward free nucleophiles, even glutathione, unless activated by adjacent structural elements such as electron withdrawing groups .…”

Section: Introductionmentioning

confidence: 99%

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

et al. 2010

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Section: Introductionmentioning

confidence: 99%

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

et al. 2010

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“…Derivatives 10 and 11 with bromomethyl and chloromethyl groups, respectively, showed good substrate activity for T-synthase, but do not possess CORA activity, possibly due to substitution reaction of benzyl bromide or chloride with high concentrations of amine and thiol groups on proteins in cells. Precursor 12 possessing a nitrile and compounds 13 , 14 , 15 , 16 , and 19 bearing a nitro group on phenyl ring showed better enzymatic acceptor activity than CORA precursor activity, which might be due to these two groups being easy to reduce to amine groups and being consequently metabolized inside the cell. , …”

Section: Resultsmentioning

confidence: 96%

“…Precursor 12 possessing a nitrile and compounds 13, 14, 15, 16, and 19 bearing a nitro group on phenyl ring showed better enzymatic acceptor activity than CORA precursor activity, which might be due to these two groups being easy to reduce to amine groups and being consequently metabolized inside the cell. 36,37 Compound 17, which also possesses a nitro group and an additional methoxy group, was the only tested compound that was not recognized as an acceptor by T-synthase in spite of having a terminal α-linked GalNAc. It is not surprising that this Bn in cells (Figure S6), indicating an inability of compound 17 to cross the Golgi or ER membrane.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Synthesis and Characterization of Versatile O-Glycan Precursors for Cellular O-Glycomics

Zhang

Chernova

et al. 2019

ACS Synth. Biol.

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Protein O-glycosylation is a universal post-translational modification and plays essential roles in many biological processes. Recently we reported a technology termed cellular O-glycome reporter/amplification (CORA) to amplify and profile mucin-type O-glycans of living cells growing in the presence of peracetylated Benzyl-α-GalNAc (Ac 3 GalNAc-α-Bn). However, the application and development of the CORA method are limited by the properties of the precursor benzyl aglycone, which is relatively inert to further chemical modifications. Here we described a rapid parallel microwave-assisted synthesis of Ac 3 GalNAc-α-Bn derivatives to identify versatile precursors for cellular O-glycomics. In total, 26 derivatives, including fluorescent and bioorthogonal reactive ones, were successfully synthesized. The precursors were evaluated for their activity as acceptors for T-synthase and for their ability to function as CORA precursors. Several of the precursors possessing useful functional groups were more efficient than Ac 3 GalNAc-α-Bn as T-synthase acceptors and cellular O-glycome reporters. These precursors will advance the CORA technology for studies of functional O-glycomics.

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“…The two synthesized coumarins, umbelliferone and 4-hydroxycoumarin, are part of the p -coumaric acid metabolic pathway [ 46 ]. Hypoxanthine is a metabolite that is part of the purine degradation pathway in humans, whereas 4-cyanophenol sulfate ( 7 ) has been widely described as a pesticide-derived metabolite after detoxification metabolism in plants [ 47 ].…”

Section: Resultsmentioning

confidence: 99%

Rapid Preparation of a Large Sulfated Metabolite Library for Structure Validation in Human Samples

et al. 2020

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Metabolomics analysis of biological samples is widely applied in medical and natural sciences. Assigning the correct chemical structure in the metabolite identification process is required to draw the correct biological conclusions and still remains a major challenge in this research field. Several metabolite tandem mass spectrometry (MS/MS) fragmentation spectra libraries have been developed that are either based on computational methods or authentic libraries. These libraries are limited due to the high number of structurally diverse metabolites, low commercial availability of these compounds, and the increasing number of newly discovered metabolites. Phase II modification of xenobiotics is a compound class that is underrepresented in these databases despite their importance in diet, drug, or microbiome metabolism. The O-sulfated metabolites have been described as a signature for the co-metabolism of bacteria and their human host. Herein, we have developed a straightforward chemical synthesis method for rapid preparation of sulfated metabolite standards to obtain mass spectrometric fragmentation pattern and retention time information. We report the preparation of 38 O-sulfated alcohols and phenols for the determination of their MS/MS fragmentation pattern and chromatographic properties. Many of these metabolites are regioisomers that cannot be distinguished solely by their fragmentation pattern. We demonstrate that the versatility of this method is comparable to standard chemical synthesis. This comprehensive metabolite library can be applied for co-injection experiments to validate metabolites in different human sample types to explore microbiota-host co-metabolism, xenobiotic, and diet metabolism.

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In Vitro Metabolism of Aromatic Nitriles

Cited by 12 publications

References 21 publications

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

Synthesis and Characterization of Versatile O-Glycan Precursors for Cellular O-Glycomics

Rapid Preparation of a Large Sulfated Metabolite Library for Structure Validation in Human Samples

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