Design of Peptide Hydroxamate‐Based Photoreactive Activity‐Based Probes of Zinc‐Dependent Metalloproteases

The first enantioselective synthesis of a photoreactive (R)-β -phenylalanine is described. In the key step, m-diazirinyl-substituted benzaldehyde is converted to a chiral sulfinimine in a Ti(OEt) 4mediated reaction, followed by diastereoselective enolate addition. The absolute configuration of photo (R)-β -phenylalanine was confirmed by Mosher analysis. The photo amino acid proved to be thermally stable under standard laboratory conditions. Irradiation in toluene afforded cycloheptatriene/norcaradiene valence tautomers, together with carbene benzylation. Quantumchemical calculations indicate a small triplet-singlet gap.

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“…Diazirine 6 also proved to be compatible with enolate addition at low temperature, as it could be expected [32]. When using MeOAc (4 eq.)…”

Section: Synthesissupporting

confidence: 57%

Enantioselective Synthesis and Photoreactivity of a Diazirinyl-substituted (R)-β-Phenylalanine

Schäckermann

Lindel

2014

Zeitschrift Für Naturforschung B

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“…The synthesis started with the coupling of propargylamine to the free carboxylic acid, creating an alkyne handle in amide 2 . This was followed by Fmoc deprotection and coupling of the photoaffinity label 3-{4-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenyl}propanoic acid, leading to compound 3 (Geurink et al, 2010). After Boc-deprotection, succinic anhydride was used to incorporate a carboxylic acid moiety, thereby affording compound 4 .…”

Section: Resultsmentioning

confidence: 99%

“…After 10 minutes, the mixture was concentrated under vacuum, and the piperidine was removed by coevaporations with toluene. This crude mixture was dissolved in 10 ml of DCM, and 3-(4-(3-(trifluoromethyl)-3 H -diazirin-3-yl)phenyl)propanoic acid [304.0 mg, 1.2 mmol, synthesized as described before by Geurink et al (2010)], hexafluorophosphate benzotriazole tetramethyl uronium (448.1 mg, 1.2 mmol), and N , N -diisopropylethylamine (DIPEA; 790 μ l, 4.6 mmol) were added. The total mixture was stirred for 2 hours at RT before it was washed with H 2 O (50 ml), KHSO 4 (1 M, 50 ml), and H 2 O (50 ml).…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Evaluation of a Diazirine Photoaffinity Probe for Ligand-Based Receptor Capture Targeting G Protein–Coupled Receptors

et al. 2018

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Chemoproteomic approaches to identify ligand-receptor interactions have gained popularity. However, identifying transmembrane receptors remains challenging. A new trifunctional probe to aid the nonbiased identification of such receptors was developed and synthesized using a convenient seven-step synthesis. This probe contained three functional groups: 1) an N-hydroxysuccinimide ester for ligand-coupling through free amines, 2) a diazirine moiety to capture the receptor of interest upon irradiation with UV light, and 3) a biotin group which allowed affinity purification of the final adduct using streptavidin. The interaction between the G protein–coupled tachykinin neurokinin 1 (NK1) receptor, expressed in an inducible manner, and the peptidic ligand substance P was used as a test system. Liquid chromatography–mass spectrometry analysis confirmed successful coupling of the probe to substance P, while inositol monophosphate accumulation assays demonstrated that coupling of the probe did not interfere substantially with the substance P–NK1 receptor interaction. Confocal microscopy and western blotting provided evidence of the formation of a covalent bond between the probe and the NK1 receptor upon UV activation. As proof of concept, the probe was used in full ligand-based receptor-capture experiments to identify the substance P–binding receptor via liquid chromatography–tandem mass spectrometry, resulting in the successful identification of only the NK1 receptor. This provides proof of concept toward general utilization of this probe to define interactions between ligands and previously unidentified plasma-membrane receptors.

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“…In this regard, Bischoff et al. developed a photoactivatable probe for the visualization of the active metalloproteases in 2010 [112] . The probe 254 was synthesized via a multistep process using a commercially available precursor 250 , which underwent varieties of reactions and several intermediates, including diaziridine 251 , and photoactivatable intermediate trifluoromethyl‐phenyldiazirines 252 , to deliver photoactivable probe 254 (Scheme 65).…”

Section: Diaziridines As Intermediatesmentioning

confidence: 99%

Recent Advances in the Preparations and Synthetic Applications of Oxaziridines and Diaziridines

et al. 2021

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Oxaziridines and diaziridines have been used as versatile intermediates due to their high ring strain as well as the reactive CÀ O/N bond, for the synthesis of diverse range of nitrogen containing compounds. In the past few decades, numerous novel and handy methodologies on the preparations and utilizations of both the oxaziridines and diaziridines have been developed. In spite of few published reviews in the area (almost a decade back), the synthetic communities have made tremendous progress in their preparations and utilizations. This review has demonstrated the comprehensive advancement in the chemistry of oxaziridines and diaziridines for the last few years (almost a decade). 2.4. Oxaziridines from Ketimines 3. Reactivities of Oxaziridines 3.1. Oxygen Atom Transfer Reactions 3.2. Nitrogen Atom Transfer Reactions 3.3. Rearrangement Reactions of Oxaziridines 3.4. Cycloaddition Reactions 4. Synthesis of Diaziridines 4.1. Diaziridines from Imine Substrates 4.2. Bi-Diaziridines and Monocyclic Diaziridines using Nosyloxycarbamate 4.3. Alkenyl Diaziridines 4.4. Diaziridines using HOSA Reagent 4.5. N-Cyclopropyl Diaziridines 4.6. Synthesis of Diaziridines via Photocatalysis 5. Reactivities of Diaziridines and its Derivatives 6. Diaziridines as Intermediates 7. Conclusions

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Design of Peptide Hydroxamate‐Based Photoreactive Activity‐Based Probes of Zinc‐Dependent Metalloproteases

Cited by 16 publications

References 55 publications

Enantioselective Synthesis and Photoreactivity of a Diazirinyl-substituted (R)-β-Phenylalanine

Enantioselective Synthesis and Photoreactivity of a Diazirinyl-substituted (R)-β-Phenylalanine

Design, Synthesis, and Evaluation of a Diazirine Photoaffinity Probe for Ligand-Based Receptor Capture Targeting G Protein–Coupled Receptors

Recent Advances in the Preparations and Synthetic Applications of Oxaziridines and Diaziridines

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