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The Journal of Organic Chemistry Jan 2023The previously unknown difluoromethyl diazirines and the previously neglected trifluoromethyl-aliphatic diazirines were synthesized and characterized. Model... (Review)
Review
The previously unknown difluoromethyl diazirines and the previously neglected trifluoromethyl-aliphatic diazirines were synthesized and characterized. Model photolabeling experiments and biological studies showed that these compounds could indeed be used as photoaffinity labels.
Topics: Diazomethane; Photoaffinity Labels
PubMed: 36399052
DOI: 10.1021/acs.joc.2c02262 -
Journal of the American Society For... Apr 2023Scaffolds consisting of a peptide, a phthalate linker, and a 4,4-azipentyl group were synthesized and used to study intramolecular peptide-carbene cross-linking in...
Scaffolds consisting of a peptide, a phthalate linker, and a 4,4-azipentyl group were synthesized and used to study intramolecular peptide-carbene cross-linking in gas-phase cations. Carbene intermediates were generated by UV-laser photodissociation at 355 nm of the diazirine ring in mass-selected ions, and the cross-linked products were detected and quantified by collision-induced dissociation tandem mass spectrometry (CID-MS, = 3-5). Peptide scaffolds containing Ala and Leu residues with a C-terminal Gly gave 21-26% yields of cross-linked products, while the presence of the Pro and His residues decreased the yields. Experiments using hydrogen-deuterium-hydrogen exchange, carboxyl group blocking, and analysis of CID-MS spectra of reference synthetic products revealed that a significant fraction of cross-links involved the Gly amide and carboxyl groups. Interpretation of the cross-linking results was aided by Born-Oppenheimer molecular dynamics (BOMD) and density functional theory calculations that allowed us to establish the protonation sites and conformations of the precursor ions. Analysis of long (100 ps) BOMD trajectories was used to count close contacts between the incipient carbene and peptide atoms, and the counting statistics was correlated with the results of gas-phase cross-linking.
Topics: Cations; Hydrogen; Molecular Dynamics Simulation; Peptides; Diazomethane
PubMed: 36881876
DOI: 10.1021/jasms.3c00023 -
Spectrochimica Acta. Part A, Molecular... Jun 2021Triclosan is a commonly used biocide effective against bacterial and fungal infections. However, its overuse in pharmaceutical and personal care products has resulted in...
Triclosan is a commonly used biocide effective against bacterial and fungal infections. However, its overuse in pharmaceutical and personal care products has resulted in its abundance in the natural environment. The detection of triclosan by visual spectroscopy can be carried out using the azo-coupling reaction of diazonium complexes. However, the reaction is also common to other phenolic compounds and aromatic amines, posing significant challenge. In this work, we investigate the azo-coupling reaction of triclosan and several commonly occurring analogous compounds to develop an improved spectroscopic method for the selective determination of triclosan without interference. We find that the azo-coupling reaction between the diazotized derivative and the phenolic compounds is highly dependent on the pH of the reaction media. At pH 7.2, the absorbance of the azo dye product of triclosan shows a peak at 452 nm which has minimal interference from other phenolic azo-dye products with the exception of naphthol. Naphthol shows an interference corresponding to 58% of the analytical signal of equimolar triclosan concentration. To overcome this, we develop an analytical model for the simultaneous determination of triclosan and naphthol from mixed solutions of the compounds. A linear calibration plot from 1.7 to 34 µM was obtained for both triclosan and naphthol with limit-of-detection (LOD) of 0.62 µM and 1.03 µM respectively. The developed protocol was tested for the analysis of water samples collected from various environmental sources spiked with different concentrations of triclosan and naphthol. The samples were enriched by solid-phase-extraction which allowed a 50-fold enhancement in detection of triclosan. The average relative recovery of triclosan in real samples was found to be 98.6% .
Topics: Azo Compounds; Cosmetics; Spectrophotometry; Spectrum Analysis; Triclosan
PubMed: 33684851
DOI: 10.1016/j.saa.2021.119623 -
Proceedings of the National Academy of... Jan 2021Recent technological advances have expanded the annotated protein coding content of mammalian genomes, as hundreds of previously unidentified, short open reading frame...
Recent technological advances have expanded the annotated protein coding content of mammalian genomes, as hundreds of previously unidentified, short open reading frame (ORF)-encoded peptides (SEPs) have now been found to be translated. Although several studies have identified important physiological roles for this emerging protein class, a general method to define their interactomes is lacking. Here, we demonstrate that genetic incorporation of the photo-crosslinking noncanonical amino acid AbK into SEP transgenes allows for the facile identification of SEP cellular interaction partners using affinity-based methods. From a survey of seven SEPs, we report the discovery of short ORF-encoded histone binding protein (SEHBP), a conserved microprotein that interacts with chromatin-associated proteins, localizes to discrete genomic loci, and induces a robust transcriptional program when overexpressed in human cells. This work affords a straightforward method to help define the physiological roles of SEPs and demonstrates its utility by identifying SEHBP as a short ORF-encoded transcription factor.
Topics: Amino Acid Sequence; Animals; Cattle; Chromatin; Diazomethane; Gene Expression Regulation; Genetic Loci; HEK293 Cells; HeLa Cells; Histones; Humans; K562 Cells; Lysine; Mice; Open Reading Frames; Pan troglodytes; Peptides; Protein Binding; Protein Interaction Mapping; Rats; Sequence Alignment; Sequence Homology, Amino Acid; Transcription, Genetic; Transgenes; Ultraviolet Rays
PubMed: 33468658
DOI: 10.1073/pnas.2021943118 -
ChemPlusChem Feb 2024This work reports the design and synthesis of novel oxadiazole-decorated azobenzenes, structural analysis of the resulting compounds and behavior under light...
This work reports the design and synthesis of novel oxadiazole-decorated azobenzenes, structural analysis of the resulting compounds and behavior under light irradiation. The synthetic strategy involved constructing amino functionalized heterocyclic key intermediates which were used either to yield electrophilic diazonium salts able to react with phenol moieties or as nucleophilic partners in Bayer-Mills reaction with nitroso-substituted derivatives. The amino-derived oxadiazole intermediates were investigated by absorption and emission spectroscopy providing blue and green emitted light. The target oxadiazole-decorated azobenzenes were structurally characterized, including solid-state structures, and subsequently used in irradiation experiments in order to take advantage of the azo group known to provide photoswitching abilities. We noticed quenching of the emissive properties in presence of the azo group; however, all compounds were very stable to repeated cycles of light irradiation. In addition, according to structural diversification we could obtain half-lives of the meta stable isomers within hours to hundreds of hours range. The experimental results were very well correlated with DFT calculations.
PubMed: 37882979
DOI: 10.1002/cplu.202300504 -
Molecules (Basel, Switzerland) Feb 2023In materials (polymer) science and medicinal chemistry, heteroaromatic derivatives play the role of the central skeleton in development of novel devices and discovery of... (Review)
Review
In materials (polymer) science and medicinal chemistry, heteroaromatic derivatives play the role of the central skeleton in development of novel devices and discovery of new drugs. On the other hand, (3-trifluoromethyl)phenyldiazirine (TPD) is a crucial chemical method for understanding biological processes such as ligand-receptor, nucleic acid-protein, lipid-protein, and protein-protein interactions. In particular, use of TPD has increased in recent materials science to create novel electric and polymer devices with comparative ease and reduced costs. Therefore, a combination of heteroaromatics and (3-trifluoromethyl)diazirine is a promising option for creating better materials and elucidating the unknown mechanisms of action of bioactive heteroaromatic compounds. In this review, a comprehensive synthesis of (3-trifluoromethyl)diazirine-substituted heteroaromatics is described.
Topics: Photoaffinity Labels; Diazomethane; Chemistry, Pharmaceutical; Proteins; Nucleic Acids
PubMed: 36771073
DOI: 10.3390/molecules28031408 -
Journal of the American Chemical Society Feb 2022Naturally occurring hydrazones are rare despite the ubiquitous usage of synthetic hydrazones in the preparation of organic compounds and functional materials. In this...
Naturally occurring hydrazones are rare despite the ubiquitous usage of synthetic hydrazones in the preparation of organic compounds and functional materials. In this study, we discovered a family of novel microbial metabolites (tasikamides) that share a unique cyclic pentapeptide scaffold. Surprisingly, tasikamides A-C (-) contain a hydrazone group (C═N─N) that joins the cyclic peptide scaffold to an alkyl 5-hydroxylanthranilate (AHA) moiety. We discovered that the biosynthesis of - requires two discrete gene clusters, with one encoding a nonribosomal peptide synthetase (NRPS) pathway for assembling the cyclic peptide scaffold and another encoding the AHA-synthesizing pathway. The AHA gene cluster encodes three ancillary enzymes that catalyze the diazotization of AHA to yield an aryl diazonium species (diazo-AHA). The electrophilic diazo-AHA undergoes nonenzymatic Japp-Klingemann coupling with a β-keto aldehyde-containing cyclic peptide precursor to furnish the hydrazone group and yield -. The studies together unraveled a novel mechanism whereby specialized metabolites are formed by the coupling of two biosynthetic pathways an unprecedented Japp-Klingemann reaction. The findings raise the prospect of exploiting the arylamine-diazotizing enzymes (AAD) for the synthesis of aryl compounds and modification of biological macromolecules.
Topics: Biosynthetic Pathways; Diazonium Compounds; Hydrazones; Multigene Family; Oligopeptides; Peptide Synthases; Peptides, Cyclic; Streptomyces
PubMed: 35060699
DOI: 10.1021/jacs.1c10369 -
Journal of the American Chemical Society May 2021Diazirines are widely used in photoaffinity labeling (PAL) to trap noncovalent interactions with biomolecules. However, design and interpretation of PAL experiments is...
Diazirines are widely used in photoaffinity labeling (PAL) to trap noncovalent interactions with biomolecules. However, design and interpretation of PAL experiments is challenging without a molecular understanding of the reactivity of diazirines with protein biomolecules. Herein, we report a systematic evaluation of the labeling preferences of alkyl and aryl diazirines with individual amino acids, single proteins, and in the whole cell proteome. We find that alkyl diazirines exhibit preferential labeling of acidic amino acids in a pH-dependent manner that is characteristic of a reactive alkyl diazo intermediate, while the aryl-fluorodiazirine labeling pattern reflects reaction primarily through a carbene intermediate. From a survey of 32 alkyl diazirine probes, we use this reactivity profile to rationalize why alkyl diazirine probes preferentially enrich highly acidic proteins or those embedded in membranes and why probes with a net positive charge tend to produce higher labeling yields in cells and in vitro. These results indicate that alkyl diazirines are an especially effective chemistry for surveying the membrane proteome and will facilitate design and interpretation of biomolecular labeling experiments with diazirines.
Topics: Amino Acids; Binding Sites; Diazomethane; Diazonium Compounds; Humans; Hydrogen-Ion Concentration; Photoaffinity Labels; Protein Conformation; Proteins; Proteome; Voltage-Dependent Anion Channel 1
PubMed: 33876925
DOI: 10.1021/jacs.1c02509 -
Journal of Flow Chemistry 2024Azo compounds find use in many areas of science, displaying crucial properties for important applications as photoconductive organic pigments, fluorescent quenchers,... (Review)
Review
Azo compounds find use in many areas of science, displaying crucial properties for important applications as photoconductive organic pigments, fluorescent quenchers, paints, cosmetics, inks, and in the large and valuable dye industry. Due to the unstable intermediates, and the exothermic and fast reactions used in their synthesis, high value azo compounds are excellent candidates for continuous flow manufacturing. This comprehensive review covers the progress made to date on developing continuous flow systems for azo synthesis and reflects on the main challenges still to be addressed, including scale up, conversion, product purity, and environmental impact. The further development of integrated continuous flow processes has the potential to help tackle these challenges and deliver improved methods for azo compound generation.
PubMed: 38882391
DOI: 10.1007/s41981-024-00307-2 -
Antibiotics (Basel, Switzerland) Dec 2022The drug-resistance problem is widely spread and becoming more common in community-acquired and nosocomial strains of bacteria. Therefore, finding new antimicrobial...
The drug-resistance problem is widely spread and becoming more common in community-acquired and nosocomial strains of bacteria. Therefore, finding new antimicrobial agents remains an important drug target. From this perspective, new derivatives of benzothiazole were synthesized and evaluated for their antimicrobial activity and ability to inhibit the DHPS enzyme. The synthesis was carried out by the reaction of benzothiazole -arylsulphonylhydrazone with -aryl-2-cyano-3-(dimethylamino)acrylamide, -aryl-3-(dimethylamino)prop-2-en-1-one, arylaldehydes or diazonium salt of arylamine derivatives, which led to the formation of -arylsulfonylpyridones (yield 60-70%) and - (yield 50-60%)-(2-(benzo[]thiazole-2-yl)-3-arylacryloyl-4-methylsulfonohydrazide - (yield 60-65%) 4-(benzo[]thiazole-2-yl)-5-aryl-1-pyrazol-3(2)-one - (yield 65-75%), and -(2-(benzo[]thiazol-2-yl)-2-(2-arylhydrazono)acetyl)-4-arylsulfonohydrazide - (yield 85-70%). The antimicrobial evaluations resulted into a variety of microbial activities against the tested strains. Most compounds showed antimicrobial activity against with an MIC range of 0.025 to 2.609 mM. The most active compound, , exhibited superior activity against the strain with an of MIC 0.025 mM among all tested compounds, outperforming both standard drugs ampicillin and sulfadiazine. The physicochemical-pharmacokinetic properties of the synthesized compounds were studied, and it was discovered that some compounds do not violate rule of five and have good bioavailability and drug-likeness scores. The five antimicrobial potent compounds with good physicochemical-pharmacokinetic properties were then examined for their inhibition of DHPS enzyme. According to the finding, three compounds, -, had IC values comparable to the standard drug and revealed that compound was the most active compound with an IC value of 7.85 μg/mL, which is comparable to that of sulfadiazine (standard drug) with an IC value of 7.13 μg/mL. A docking study was performed to better understand the interaction of potent compounds with the binding sites of the DHPS enzyme, which revealed that compounds - are linked by two arene-H interactions with Lys220 within the PABA pocket.
PubMed: 36551457
DOI: 10.3390/antibiotics11121799