High‐Throughput Method for Determining the Enantioselectivity of Enzyme‐Catalyzed Hydroxylations Based on Mass Spectrometry

Chen, Yongzheng; Tang, Weng Lin; Mou, Jie; Li, Zhi

doi:10.1002/ange.201001772

Cited by 14 publications

(2 citation statements)

References 97 publications

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“…Modest deuterium labeling (70%) was achieved using only 3 equiv of isopropanol-d 8 (Figure 6). While this level of isotopic enrichment is not sufficient for large-scale production of deuterated therapeutics, it is relevant to preparation of deuterated analogues for applications in drug discovery including characterization of metabolite regiochemistry by HRMS 65,66 and parsing metabolic mechanisms 67 by competitive kinetic isotope effects. The method gave 91% 8c), more activated substrates 68 still underwent significant H/D exchange with as little as 3 equiv of reductant (e.g., 4a, SI Table 6, entry 1).…”

Section: Organic Lettersmentioning

confidence: 99%

Palladium Catalyzed Hydrodefluorination of Fluoro-(hetero)arenes

et al. 2019

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Palladium catalyzed hydrodefluorination was developed for fine-tuning the properties of fluoro-(hetero)aromatic compounds. The robust reaction can be set up in air, requires only commercially available components, and tolerates a variety of heterocycles and functionalities relevant to drug discovery. Given the prevalence of fluorine incorporation around metabolic hotspots, the corresponding deuterodefluorination reaction may prove useful for converting fluorinated libraries to deuterated analogues to suppress the oxidative metabolism by kinetic isotope effects.

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Section: Organic Lettersmentioning

confidence: 99%

Palladium Catalyzed Hydrodefluorination of Fluoro-(hetero)arenes

et al. 2019

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“…Also, combinations of chromatographic and electrophoretic separation methods with MS, such as liquid chromatography (LC)=MS (de Jong et al 2006), LC=tandem mass spectroscopy (MS=MS) (Hows et al 2002), gas chromatography (GC)=MS (Shih et al 2006), frontal affinity chromatography (FAC)=MS (Schriemer et al 1998), or capillary electrophoresis (CE)=MS (Lyubarskaya et al 1998) have been developed for determination of the AChE activity or screening of AChE inhibitors. With various ionization techniques to monitor the contents of substrate and product, mass spectrometry offers great facilities for studying enzyme system (Northen et al 2008;Yamazaki and Takao 2008;Chen et al 2010;Vovk et al 2011). Several reports on determining enzyme activity by MALDI-FTMS have been made from our laboratory (Xu et al 2008;Xu et al 2010;Wang et al 2011;Cai et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Study of Effects of Cigarette Smoke Condensates on Acetylcholinesterase Activity in Human Lung Epithelial Cells by Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Mass Spectrometry

Zhang

Guo

et al. 2012

Analytical Letters

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Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Mass Spectrometry (MALDI-FTMS) is an emerging method for kinetic measurements and inhibitor screening of acetylcholinesterase (AChE). This method is accurate, reproducible, and was successfully applied to the analysis of various biosamples. Recent studies showed the important biological functions of acetylcholinesterase in many kinds of tumors caused by smoking; however, the effect of cigarette smoke condensates (CSCs) on AChE was unclear. Herein, the effects of CSCs on AChE activity in human lung epithelial cells were studied by MALDI-FTMS. The results showed that AChE activity in human lung epithelial cells could be inhibited by CSCs, and inhibition degree on AChE activity depended on the amount of CSCs. Owing to the close relationship of AChE to lung cancer caused by smoking, such findings provide information regarding the relation between the aggressiveness of lung tumor and cigarette smoking.

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Engineering of P450pyr Hydroxylase for the Highly Regio‐ and Enantioselective Subterminal Hydroxylation of Alkanes

Yang

Liu

2014

Angewandte Chemie

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Terminal‐selective cytochrome P450pyr has been successfully engineered through directed evolution for the subterminal hydroxylation of alkanes with excellent regio‐ and enantioselectivity. A sensitive colorimetric high‐throughput screening (HTS) assay was developed for the measurement of both the regioselectivity and the enantioselectivity of a hydroxylation reaction. By using the HTS assay and iterative saturation mutagenesis, sextuple‐mutant P450pyrSM1 was created for the hydroxylation of n‐octane (1) to give (S)‐2‐octanol (2) with 98 % ee and >99 % subterminal selectivity. The engineered P450 is the first enzyme for this type of highly selective alkane hydroxylation, being useful for the CH activation and functionalization of alkanes and the preparation of enantiopure alcohols. Molecular modeling provided structure‐based understanding of the fully altered regioselectivity and the excellent enantioselectivity. Another sextuple‐mutant P450pyrSM2 catalyzed the hydroxylation of propylbenzene (3) to afford (S)‐1‐phenyl‐2‐propanol (4) with 95 % ee and 98 % subterminal selectivity.

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High‐Throughput Method for Determining the Enantioselectivity of Enzyme‐Catalyzed Hydroxylations Based on Mass Spectrometry

Cited by 14 publications

References 97 publications

Palladium Catalyzed Hydrodefluorination of Fluoro-(hetero)arenes

Palladium Catalyzed Hydrodefluorination of Fluoro-(hetero)arenes

Study of Effects of Cigarette Smoke Condensates on Acetylcholinesterase Activity in Human Lung Epithelial Cells by Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Mass Spectrometry

Engineering of P450pyr Hydroxylase for the Highly Regio‐ and Enantioselective Subterminal Hydroxylation of Alkanes

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