Acid/base-triggered photophysical and chiroptical switching in a series of helicenoid compounds

International audienceA series of molecules that possess two quinolines, benzoquinolines, or phenanthrolines connected in a chiral fashion by a biaryl junction along with their water-soluble derivatives was developed and characterized. The influence of the structure on the basicity of the nitrogen atoms in two heterocycles was examined and the photophysical and chiroptical switching activity of the compounds upon protonation was studied both experimentally and computationally. The results demonstrated that changes in the electronic structure of the protonated vs. neutral species, promoting a bathochromic shift of dominant electronic transitions and alternation of their character from π-to-π* to charge-transfer-type, when additionally accompanied by the high structural flexibility of a system, leading to changes in conformational preferences upon proton binding, produce particularly pronounced modifications of the spectral properties in acidic medium. The latter combined with reversibility of the read-out make some of the molecules in this series very promising multifunctional pH probes

An unusual functional group interaction and its potential to reproduce steric and electrostatic features of the transition states of peptidolysis

International audienceThe donor–acceptor interaction between a tertiary amine and an aldehyde, first observed among a select class of alkaloïds, was deliberately established in a peptidomimetic (1a–c) to mimic features of the two principal transition states of peptide hydrolysis. Compounds 1a–c show preferential adoption in methanol and water of a ‘folded’ conformation displaying the interaction. Proportions of the folded form in MeOH range from 45% to 70% and can reach 84% in buffer. Significantly, three tendencies for the folded/unfolded equilibrium are observed: increasing solubility and polarity of the medium and decreasing temperature results in a higher extent of folding. In the absence of any parameter set available for this weak bond, no modeling studies were conducted to aid in the design of 1a–c. The successful straightforward synthesis of 1 and its folding and inhibition results with HIV-1 peptidase using FRET technology encourage studies to further preorganize candidate molecules and to screen the structure space by modeling and parallel combinatorial chemistry

On the inhibition of HIV-1 protease by hydrazino-ureas displaying the N→CO interaction

International audienceTo create novel HIV-1 protease (HIV PR) inhibitors, we have extended our investigations of the N→Cdouble bond; length as m-dashO interaction as a moiety that reproduces electrostatic properties of the transition state of peptidolysis. Consequently, we prepared a series of compounds with an unusual hydrazino-urea core. In polar protic media, these adopt solely a cyclic constitution displaying the interaction on one side of the molecule while offering a urea moiety on the opposite side meant to hydrogen-bond with the enzyme flaps. Each inhibitor candidate was obtained via a key series of three synthetic steps employing carbonyl-di-imidazole (CDI). It was thus possible to efficiently fuse two independent building blocks, a hydrazine and a protected aminoaldehyde in a convergent manner. NMR and UV analysis proved that all compounds, when dissolved in polar protic media, existed exclusively in the cyclic constitution exhibiting the N→Cdouble bond; length as m-dashO interaction. In total, five inhibitor candidates were tested with HIV PR for their potency. The one carrying the least bulk in peripheral substituents showed the highest activity. Its very low molecular weight (365 g/mol) holds great promise for future improvements in affinity without violating Lipinski’s rule of remaining within the limit of 500 g/mol

Selective Capture of Thallium and Cesium by a Cryptophane Soluble at Neutral pH

International audienceWe report in this article the synthesis of a asymmetrical cryptophane derivative (possessing only C3-symmetry) bearing three phenol groups and three other carboxylic acid functions, each of these groups on the aromatic rings. Thanks to isothermal titration calorimetry experiments, we show that this compound binds large monovalent cations, such as Cs+ and Tl+ with a binding constant significantly lower than its congeners bearing a larger number of phenol groups grafted on the benzene rings. However, higher selectivity for Cs+ and Tl+ was observed with this compound since it does not show any affinity for other alkali cations. More importantly, due to the greater solubility of this derivative in pure water, we show for the first time that effective thallium(I) complexation takes place at neutral pH. This result demonstrates that cryptophane derivatives decorated with a higher number of phenol groups are promising host molecules for removing traces of thallium(I) from aqueous phases at neutral pH or above

Specific detection of cysteine sulphenic acid by coupling Mass Spectrometry with Laser Induced Dissociation

International audienceOverview Improvement of oxidative stress induced modification of cysteine residues detection. Protein cysteine residues are oxidized into sulphenic acid (SOH), derivatized with a specific chromophore and specificaly detected and identified thanks to Laser Induced Dissociation (LID) in the visible range Chromophore derivatization of cysteine sulphenic aci

Specific detection of cysteine sulphenic acid by coupling Mass Spectrometry with Laser Induced Dissociation

International audienceImprovement of oxidative stress induced modification of cysteine residues detection. Protein cysteine residues are oxidized into sulphenic acid (SOH), derivatized with a specific chromophore and specificaly detected and identified thanks to Laser Induced Dissociation (LID) in the visible range. In a context of population aging, discovery and validation of novel oxidative stress biomarkers for screening of neurodegenerative diseases is a key issue. One of the modification induced by reactive oxygen species (ROS) is the oxidation of protein cysteine (Cys) residues . As this oxidative process is minor, the detection of these oxidized proteins at low concentrations is problematic due to the complexity and dynamic concentration range of the samples to be analyzed. In order to improve the detection specificity for oxidized proteins, we use an experimental setup coupling mass spectrometry and laser induced dissociation (LID) in the visible range (473 nm) to add a stringent optical specificity to the mass selectivity

Specific detection of cysteine sulphenic acid by coupling Mass Spectrometry with Laser Induced Dissociation

International audienceImprovement of oxidative stress induced modification of cysteine residues detection. Protein cysteine residues are oxidized into sulphenic acid (SOH), derivatized with a specific chromophore and specificaly detected and identified thanks to Laser Induced Dissociation (LID) in the visible range. In a context of population aging, discovery and validation of novel oxidative stress biomarkers for screening of neurodegenerative diseases is a key issue. One of the modification induced by reactive oxygen species (ROS) is the oxidation of protein cysteine (Cys) residues . As this oxidative process is minor, the detection of these oxidized proteins at low concentrations is problematic due to the complexity and dynamic concentration range of the samples to be analyzed. In order to improve the detection specificity for oxidized proteins, we use an experimental setup coupling mass spectrometry and laser induced dissociation (LID) in the visible range (473 nm) to add a stringent optical specificity to the mass selectivity

Relative quantification of sulfenic acids in plasma proteins using differential labelling and mass spectrometry coupled with 473 nm photo-dissociation analysis: a multiplexed approach applied to an Alzheimer's disease cohort

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Unbiased Detection of Cysteine Sulfenic Acid by 473 nm Photodissociation Mass Spectrometry: Toward Facile In Vivo Oxidative Status of Plasma Proteins

International audienceCysteine (Cys) is prone to diverse post-translational modifications in proteins, including oxidation into sulfenic acid (Cys-SOH) by reactive oxygen species generated under oxidative stress. Detection of low concentrated and metastable Cys-SOH within complex biological matrices is challenging due to the dynamic concentration range of proteins in the samples. Herein, visible laser-induced dissociation (LID) implemented in a mass spectrometer was used for streamlining the detection of Cys oxidized proteins thanks to proper derivatization of Cys-SOH with a chromophore tag functionalized with a cyclohexanedione group. Once grafted, peptides undergo a high fragmentation yield under LID, leading concomitantly to informative backbone ions and to a chromophore reporter ion. 79 % of the Cys-containing tryptic peptides deriving from human serum albumin and serotransferrin tracked by Parallel Reaction Monitoring (PRM) were detected as targets subjected to oxidation. These candidates, as well as Cys-containing peptides predicted by in silico trypsin digestion of 5 other human plasma proteins, were then tracked in real plasma samples to pinpoint the endogenous Cys-SOH subpopulation. Most of the targeted peptides were detected in all plasma samples by LID-PRM, with significant differences in their relative amounts. By eliminating the signal of interfering co-eluted compounds, LID-PRM surpasses conventional HCD-PRM in detecting grafted Cys-SOH containing peptides and allows now to foresee clinical applications in large human cohorts