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International Journal of Molecular... Feb 2020The identification of molecules whose biological activity can be properly modulated by light is a promising therapeutic approach aimed to improve drug selectivity and...
The identification of molecules whose biological activity can be properly modulated by light is a promising therapeutic approach aimed to improve drug selectivity and efficacy on the molecular target and to limit the side effects compared to traditional drugs. Recently, two photo-switchable diastereomeric benzodiazopyrrole derivatives and have been reported as microtubules targeting agents (MTAs) on human colorectal carcinoma p53 null cell line (HCT 116 p53-/-). Their IC was enhanced upon Light Emitting Diode (LED) irradiation at 435 nm and was related to their form. Here we have investigated the photo-responsive behavior of the acid derivatives of and , namely, and , in phosphate buffer solutions at different pH. The comparison of the UV spectra, acquired before and after LED irradiation, indicated that the conversion of and is affected by the degree of ionization. The apparent rate constants were calculated from the kinetic data by means of fast UV spectroscopy and the conformers of the putative ionic species present in solution (pH range: 5.7-8.0) were modelled. Taken together, our experimental and theoretical results suggest that the photo-conversions of / into the corresponding forms and the thermal decay of / are dependent on the presence of diazonium form of /. Finally, a photo-reaction was detected only for after prolonged LED irradiation in acidic medium, and the resulting product was characterized by means of Liquid Chromatography coupled to High resolution Mass Spectrometry (LC-HRMS) and Nuclear Magnetic Resonance (NMR) spectroscopy.
Topics: Cell Proliferation; Chromatography, Liquid; Colorectal Neoplasms; Diazonium Compounds; HCT116 Cells; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Photochemotherapy; Pyrroles
PubMed: 32069905
DOI: 10.3390/ijms21041246 -
Angewandte Chemie (International Ed. in... May 2020Expanding the toolbox of C-H functionalization reactions applicable to the late-stage modification of complex molecules is of interest in medicinal chemistry, wherein...
Expanding the toolbox of C-H functionalization reactions applicable to the late-stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition-metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C-H bond. However, these high-energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C-H functionalization reactions with diazoacetate derivatives, furnishing sp -sp coupled products with moderate-to-good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition-metal catalyst.
Topics: Alkylation; Catalysis; Cations; Diazonium Compounds; Drug Development; Free Radicals; Hydrocarbons, Aromatic; Metals; Methane; Photochemistry
PubMed: 32068943
DOI: 10.1002/anie.202000684 -
Bioconjugate Chemistry Mar 2020N-Diazirines represent an attractive class of imaging tags for hyperpolarized magnetic resonance imaging (HP-MRI), offering desirable biocompatibility, ease of...
N-Diazirines represent an attractive class of imaging tags for hyperpolarized magnetic resonance imaging (HP-MRI), offering desirable biocompatibility, ease of incorporation into a variety of molecules, and ability to deliver long-lasting polarization. We have recently established hyperpolarization of N-diazirines in organic solvents using SABRE-Shield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH). Yet, the current challenge of SABRE-SHEATH in water, specifically poor polarization efficiency, presents a barrier in examining the practical use of N-diazirines for HP-MRI. Herein, we show that efficient polarization of diverse N-diazirine-labeled molecules in water can be readily achieved by dissolution dynamic nuclear polarization (d-DNP), a hyperpolarization technique used in clinical practice. Hyperpolarization by d-DNP also demonstrates greater enhancement for long-lasting N signals, in comparison with SABRE-SHEATH. Various biologically important molecules are studied in this work, including amino acid, sugar, and drug compounds, demonstrating the great potential of N-diazirines as molecular tags in broad biomedical and clinical applications.
Topics: Diazomethane; Magnetic Resonance Imaging; Nitrogen Isotopes
PubMed: 32023034
DOI: 10.1021/acs.bioconjchem.0c00028 -
ACS Chemical Biology Mar 2020Cathepsin X/Z/P is cysteine cathepsin with unique carboxypeptidase activity. Its expression is associated with cancer and neurodegenerative diseases, although its roles...
Cathepsin X/Z/P is cysteine cathepsin with unique carboxypeptidase activity. Its expression is associated with cancer and neurodegenerative diseases, although its roles during normal physiology are still poorly understood. Advances in our understanding of its function have been hindered by a lack of available tools that can specifically measure the proteolytic activity of cathepsin X. We present a series of activity-based probes that incorporate a sulfoxonium ylide warhead, which exhibit improved specificity for cathepsin X compared to previously reported probes. We apply these probes to detect cathepsin X activity in cell and tissue lysates, in live cells and in vivo, and to localize active cathepsin X in mouse tissues by microscopy. Finally, we utilize an improved method to generate chloromethylketones, necessary intermediates for synthesis of acyloxymethylketones probes, by way of sulfoxonium ylide intermediates. In conclusion, the probes presented in this study will be valuable for investigating cathepsin X pathophysiology.
Topics: Amino Acids; Animals; Cathepsins; Cell Culture Techniques; Cell Line; Diazomethane; Enzyme Inhibitors; Fluorescent Dyes; Humans; Hydrocarbons, Fluorinated; Ketones; Kidney; Kinetics; Male; Mice; Mice, Inbred C57BL; Optical Imaging; Protein Domains; Small Molecule Libraries; Structure-Activity Relationship; Substrate Specificity
PubMed: 32022538
DOI: 10.1021/acschembio.9b00961 -
Sensors (Basel, Switzerland) Jan 2020Highly sensitive multicomponent materials designed for the recognition of hazardous compounds request control over interfacial chemistry. The latter is a key parameter...
Highly sensitive multicomponent materials designed for the recognition of hazardous compounds request control over interfacial chemistry. The latter is a key parameter in the construction of the sensing (macro) molecular architectures. In this work, multi-walled carbon nanotubes (CNTs) were deposited on diazonium-modified, flexible indium tin oxide (ITO) electrodes prior to the electropolymerization of pyrrole. This three-step process, including diazonium electroreduction, the deposition of CNTs and electropolymerization, provided adhesively-bonded, polypyrrole-wrapped CNT composite coatings on aminophenyl-modified flexible ITO sheets. The aminophenyl (AP) groups were attached to ITO by electroreduction of the in-situ generated aminobenzenediazonium compound in aqueous, acidic medium. For the first time, polypyrrole (PPy) was electrodeposited in the presence of both benzenesulfonic acid (dopant) and ethylene glycol-bis(2-aminoethylether)-tetraacetic acid (EGTA), which acts as a chelator. The flexible electrodes were characterized by XPS, Raman and scanning electron microscopy (SEM), which provided strong supporting evidence for the wrapping of CNTs by the electrodeposited PPy. Indeed, the CNT average diameter increased from 18 ± 2.6 nm to 27 ± 4.8, 35.6 ± 5.9 and 175 ± 20.1 after 1, 5 and 10 of electropolymerization of pyrrole, respectively. The PPy/CNT/NH-ITO films generated by this strategy exhibit significantly improved stability and higher conductivity compared to a similar PPy coating without any embedded CNTs, as assessed by from electrochemical impedance spectroscopy measurements. The potentiometric response was linear in the 10-3 × 10 mol L Pb(II) concentration range, and the detection limit was 2.9 × 10 mol L at S/N = 3. The EGTA was found to drastically improve selectivity for Pb(II) over Cu(II). To account for this improvement, the density functional theory (DFT) was employed to calculate the EGTA-metal ion interaction energy, which was found to be -374.6 and -116.4 kJ/mol for Pb(II) and Cu(II), respectively, considering solvation effects. This work demonstrates the power of a subtle combination of diazonium coupling agent, CNTs, chelators and conductive polymers to design high-performance electrochemical sensors for environmental applications.
PubMed: 31973054
DOI: 10.3390/s20030580 -
Biosensors Jan 2020This review is divided into two parts; the first one summarizes the main features of surface modification by diazonium salts with a focus on most recent advances, while... (Review)
Review
This review is divided into two parts; the first one summarizes the main features of surface modification by diazonium salts with a focus on most recent advances, while the second part deals with diazonium-based biosensors including small molecules of biological interest, proteins, and nucleic acids.
Topics: Animals; Biosensing Techniques; Diazonium Compounds; Humans; Salts; Surface Properties
PubMed: 31952195
DOI: 10.3390/bios10010004 -
ACS Omega Dec 2019Tyrosine is an attractive target for chemo- and site-selective protein modification. The particular chemical nature of tyrosine residues allows bioconjugation chemistry...
Tyrosine is an attractive target for chemo- and site-selective protein modification. The particular chemical nature of tyrosine residues allows bioconjugation chemistry with reactive aryl diazonium salts via electrophilic aromatic substitution to produce diazo compounds. In this work, we describe the preparation of Cu- and Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-diazonium salts as building blocks for azo coupling chemistry with tyrosine and tyrosine-containing peptides and proteins under mild conditions. 2--(4-aminobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (-NH-Bn-NOTA) was used to form the corresponding Cu- and Ga-labeled complexes, followed by diazotization with NaNO in the presence of HCl. Cu- and Ga-labeled NOTA complexes were prepared in high radiochemical yields >80% starting from 20 μg of -NH-Bn-NOTA. Conversion of -NH-Bn-NOTA complexes into diazonium salts followed by azo coupling with l-tyrosine afforded Cu- and Ga-labeled tyrosine in radiochemical yields of 80 and 56%, respectively. Azo coupling with tyrosine-containing hexapeptide neurotensin NT(8-13) afforded Cu- and Ga-labeled NT(8-13) in radiochemical yields of 45 and 11%, respectively. Azo coupling of Cu-labeled NOTA-diazonium salt with human serum albumin (HSA) gave Cu-labeled HSA in radiochemical yields of 20%. The described azo coupling chemistry represents an innovative and versatile bioconjugation strategy for selective targeting of tyrosine residues in peptides and proteins.
PubMed: 31891090
DOI: 10.1021/acsomega.9b03248 -
Journal of Enzyme Inhibition and... Dec 2020A series of compounds incorporating 3-(3-(2/3/4-substituted phenyl)triaz-1-en-1-yl) benzenesulfonamide moieties were synthesised and their chemical structure was...
A series of compounds incorporating 3-(3-(2/3/4-substituted phenyl)triaz-1-en-1-yl) benzenesulfonamide moieties were synthesised and their chemical structure was confirmed by physico-chemical methods. Carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the compounds were evaluated against human isoforms hCA I and II. K values of these sulphonamides were in the range of 21 ± 4-72 ± 2 nM towards hCA I and in the range of 16 ± 6-40 ± 2 nM against hCA II. The 4-fluoro substituted derivative might be considered as an interesting lead due to its effective inhibitory action against both hCA I and hCA II (Ks of 21 nM), a profile rarely seen among other sulphonamide CA inhibitors, making it of interest in systems where the activity of the two cytosolic isoforms is dysregulated.
Topics: Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Dose-Response Relationship, Drug; Humans; Molecular Structure; Structure-Activity Relationship; Sulfonamides; Triazenes
PubMed: 31813300
DOI: 10.1080/14756366.2019.1700240 -
Angewandte Chemie (International Ed. in... Jan 2020Diazomethane is one of the most versatile reagents in organic synthesis, but its utility is limited by its hazardous nature. Although alternative methods exist to...
Diazomethane is one of the most versatile reagents in organic synthesis, but its utility is limited by its hazardous nature. Although alternative methods exist to perform the unique chemistry of diazomethane, these suffer from diminished reactivity and/or correspondingly harsher conditions. Herein, we describe the repurposing of imidazotetrazines (such as temozolomide, TMZ, the standard of care for glioblastoma) for use as synthetic precursors of alkyl diazonium reagents. TMZ was employed to conduct esterifications and metal-catalyzed cyclopropanations, and results show that methyl ester formation from a wide variety of substrates is especially efficient and operationally simple. TMZ is a commercially available solid that is non-explosive and non-toxic, and should find broad utility as a replacement for diazomethane.
Topics: Antineoplastic Agents; Cyclopropanes; Diazomethane; Esterification; Humans; Models, Molecular; Nitrogen Mustard Compounds
PubMed: 31793158
DOI: 10.1002/anie.201911896 -
Nature Communications Nov 2019Coupling reactions of amines and alcohols are of central importance for applications in chemistry and biology. These transformations typically involve the use of a...
Coupling reactions of amines and alcohols are of central importance for applications in chemistry and biology. These transformations typically involve the use of a reagent, activated as an electrophile, onto which nucleophile coupling results in the formation of a carbon-nitrogen or a carbon-oxygen bond. Several promising reagents and procedures have been developed to achieve these bond forming processes in high yields with excellent stereocontrol, but few offer direct coupling without the intervention of a catalyst. Herein, we report the synthesis of chiral donor-acceptor azetines by highly enantioselective [3 + 1]-cycloaddition of enoldiazoacetates with aza-ylides and their selective coupling with nitrogen and oxygen nucleophiles via 3-azetidinones to form amino acid derivatives, including those of peptides and natural products. The overall process is general for a broad spectrum of nucleophiles, has a high degree of electronic and steric selectivity, and retains the enantiopurity of the original azetine.
Topics: Amino Acids; Azetidines; Azetines; Catalysis; Chemistry Techniques, Synthetic; Cycloaddition Reaction; Diazonium Compounds; Indicators and Reagents; Stereoisomerism
PubMed: 31757976
DOI: 10.1038/s41467-019-13326-8