Development of Chemical Tools to Monitor and Control Isoaspartyl Peptide Methyltransferase Activity

Kimura, Yusuke; Komatsu, Toshimitsu; Yanagi, Kouichi; Hanaoka, Kenjiro; Ueno, Takahiro; Terai, Takuya; Kojima, Hirotatsu; Okabe, Takayoshi; Nagano, Tetsuo; Urano, Yasuteru

doi:10.1002/anie.201608677

Cited by 11 publications

(9 citation statements)

References 35 publications

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“…In recent years, inhibitors against hSHMT have attracted much attention because they could lead to the development of anticancer drugs and molecular tools for clarifying physiological phenomena related to one-carbon metabolism 1,2,4–8 . With promising molecular probes for hSHMT activity detection now in hand, HTS for hSHMT inhibitors using hSHMT molecular probes 1 and 2 was carried out 41 .…”

Section: Resultsmentioning

confidence: 99%

Design strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction

et al. 2019

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Serine hydroxymethyltransferase (SHMT) is an enzyme that catalyzes the reaction that converts serine to glycine. It plays an important role in one-carbon metabolism. Recently, SHMT has been shown to be associated with various diseases. Therefore, SHMT has attracted attention as a biomarker and drug target. However, the development of molecular probes responsive to SHMT has not yet been realized. This is because SHMT catalyzes an essential yet simple reaction; thus, the substrates that can be accepted into the active site of SHMT are limited. Here, we focus on the SHMT-catalyzed retro-aldol reaction rather than the canonical serine–glycine conversion and succeed in developing fluorescent and 19F NMR molecular probes. Taking advantage of the facile and direct detection of SHMT, the developed fluorescent probe is used in the high-throughput screening for human SHMT inhibitors, and two hit compounds are obtained.

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Section: Resultsmentioning

confidence: 99%

Design strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction

et al. 2019

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“…The synthesis of this compound 17 is usually quite tedious. To date the only preparation described in the literature resulted in a 22 % yield . Here the synthesis of Fmoc‐O 2 Oc‐Bt 16 , followed by reaction with fluoresceinamine 13 in the presence of TFA (1 equiv.…”

Section: Resultsmentioning

confidence: 99%

Unexpected Reactivity of N‐Acyl‐Benzotriazoles with Aromatic Amines in Acidic Medium (ABAA Reaction)

2018

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Despite the large number of methods for the synthesis of amides, formation of the amide bond from aromatic amines has always been a challenge for organic chemists due to their weak nucleophile character. We describe here a new efficient method of amide formation from N‐Acyl‐Benzotriazoles and Aromatic Amines (ABAA reaction) including aniline derivatives, in acidic conditions. This reaction is selective for aromatic amines, since aliphatic amines did not react under the same experimental conditions. Using the ABAA reaction, we have synthesized a series of aromatic amide compounds including labelled enzyme substrates, in excellent yield. The ABAA reaction also allowed the one‐pot synthesis of Nordiazepam, which is a precursor of the anxiolytic Diazepam (Valium®). This procedure opens new ways of synthesis of amides from aromatic amines, as well as of heterocyclic structures.

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“…Enzymatically activatable probes allow for high-contrast imaging and provide a readout of the enzyme activity by virtue of their fluorescence ‘turn-on’ response. They have been successfully used in the detection of bacterial infection [ 18 ] and disease biomarkers [ 59 ], organelle-specific drug delivery [ 60 ], characterization of enzyme inhibitors [ 61 , 62 ], etc. Targeted probes cover a wider range of proteins which are ligandable.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Fluorescence imaging of drug target proteins using chemical probes

Zhu

Hamachi

2020

Journal of Pharmaceutical Analysis

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Fluorescence imaging can provide valuable information on the expression, distribution, and activity of drug target proteins. Chemical probes are useful small-molecule tools for fluorescence imaging with high structural flexibility and biocompatibility. In this review, we briefly introduce two classes of fluorescent probes for the visualization of drug target proteins. Enzymatically activatable probes make use of the specific enzymatic transformations that generally produce a fluorogenic response upon reacting with target enzymes. Alternatively, specific imaging can be conferred with a ligand that drives the probes to target proteins, where the labeling relies on noncovalent binding, covalent inhibition, or traceless labeling by ligand-directed chemistry.

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Development of Chemical Tools to Monitor and Control Isoaspartyl Peptide Methyltransferase Activity

Cited by 11 publications

References 35 publications

Design strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction

Design strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction

Unexpected Reactivity of N‐Acyl‐Benzotriazoles with Aromatic Amines in Acidic Medium (ABAA Reaction)

Fluorescence imaging of drug target proteins using chemical probes

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