Systems-based design of bi-ligand inhibitors of oxidoreductases: filling the chemical proteomic toolbox

Genomics-driven growth in the number of enzymes of unknown function has created a need for better strategies to characterize them. Since enzyme inhibitors have traditionally served this purpose, we present here an efficient systems-based inhibitor design strategy, enabled by bioinformatic and NMR structural developments. First, we parse the oxidoreductase gene family into structural subfamilies termed pharmacofamilies, which share pharmacophore features in their cofactor binding sites. Then we identify a ligand for this site and use NMR-based binding site mapping (NMR SOLVE) to determine where to extend a combinatorial library, such that diversity elements are directed into the adjacent substrate site. The cofactor mimic is reused in the library in a manner that parallels the reuse of cofactor domains in the oxidoreductase gene family. A library designed in this manner yielded specific inhibitors for multiple oxidoreductases.     

Desymmetrization by direct cross-metathesis producing hitherto unreachable P-stereogenic phosphine oxides

Desymmetrization of prochiral di- and trialkenyl phosphine oxides by cross-metathesis with various olefinic partners allowed direct access to novel racemic P-stereogenic products featuring two or three different alkenyl groups. The excellent control of product selectivity and E/Z selectivity allowed the preparation of desymmetrized products in good yields from readily available precursors. These are the first examples of desymmetrization of prochiral substrates by direct cross-metathesis.     

Galactose oxidase models: solution chemistry, and phenoxyl radical generation mediated by the copper status

Galactose oxidase (GO) is an enzyme that catalyzes two-electron oxidations. Its active site contains a copper atom coordinated to a tyrosyl radical, the biogenesis of which requires copper and dioxygen. We have recently studied the properties of electrochemically generated mononuclear Cu(II)-phenoxyl radical systems as model compounds of GO. We present here the solution chemistry of these ligands under various copper and dioxygen statuses: N(3)O ligands first chelate Cu(II), leading, in the presence of base, to [Cu(II)(ligand)(CH(3)CN)](+) complexes (ortho-tert-butylated ligands) or [(Cu(II))(2)(ligand)(2)](2+) complexes (ortho-methoxylated ligands). Excess copper(II) then oxidizes the complex to the corresponding mononuclear Cu(II)-phenoxyl radical species. N(2)O(2) tripodal ligands, in the presence of copper(II), afford directly a copper(II)-phenoxyl radical species. Addition of more than two molar equivalents of copper(II) affords a Cu(II)-bis(phenoxyl) diradical species. The donor set of the ligand directs the reaction towards comproportionation for ligands possessing an N(3)O donor set, while disproportionation is observed for ligands possessing an N(2)O(2) donor set. These results are discussed in the light of recent results concerning the self-processing of GO. A path involving copper(II) disproportionation is proposed for oxidation of the cross-linked tyrosinate of GO, supporting the fact that both copper(I) and copper(II) activate the enzyme.     

Effect of the pH, the concentration and the nature of the buffer on the adsorption mechanism of an ionic compound in reversed-phase liquid chromatography. II. Analytical and overloaded band profiles on Symmetry-C18 and Xterra-C18

In a previous report, the influence of the pH, the concentration, and the nature of the buffer on the retention and overloading behavior of propranolol (pKa = 9.45) was studied on Kromasil-C18 at 2.75 < pH < 6.75, using four buffers (phosphate, acetate, phthalate, and succinate), at three concentrations, 6, 20, and 60 mM. The results showed that the propranolol cation was eluted as an ion-pair with the buffer counter-anion. A similar study was carried out with Symmetry-C18 and Xterra-C18. Two additional buffers, formate and citrate, were also used. Propranolol elution band profiles were recorded for a small (less than 1 microg) and a large (375 microg) sample size. The results are similar to those obtained with Kromasil and confirm earlier conclusions. The buffer concentration, not its pH, controls the retention time of propranolol, in agreement with the chaotropic model. The retention factor depends also on the nature of the buffer, particularly on its valence, and on the hydrophobicity of the basic anion. With the monovalent anions HCOO- (pH 3.75), H2PO4- (pH 2.75), HOOC-Ph-COO- (pH 2.75), HOOC-CH2-CH2-COO- (pH 4.16), CH3COO- (pH 4.75) and HOOC-CHCOOH-COO- (pH 3.14), at moderate loadings, and for the two larger buffer concentrations, the band profiles are well accounted for by a simple bi-Langmuir isotherm model (no adsorbate-adsorbate interactions). By contrast, these profiles are accounted for by a bi-Moreau isotherm model (i.e., with significant adsorbate-adsorbate interactions) with the bivalent anions -OOC-Ph-COO- (pH 4.75), -OOC-CH2-CH2-COO- (pH 5.61), HPO4(2-) (pH 6.75), and HOOC-CHCOO(-)-COO- (pH 4.77) and with the trivalent anion -OOC-CHCOO(-)-COO- (pH 6.39). The best values of the isotherm parameters were determined using the inverse method. The saturation capacity and the equilibrium constant on the low-energy sites increase with increasing buffer concentration, a result consistent with the formation in the mobile phase of a hydrophobic complex between the propranolol cation and the buffer anion. With bivalent and trivalent anions, adsorbate-adsorbate interactions are strong on the low-energy sites but they remain negligible on the high-energy sites. The density of the high energy sites is lower and the equilibrium constant on the low-energy sites are both higher with the bivalent and the trivalent buffer anions than with the univalent buffer anions. These results are consistent with the formation of a 2:1 and a 3:1 propranolol-buffer complex with the bivalent and the trivalent anions, respectively.     

Development of new high‐performance visible light photoinitiators based on carbazole scaffold and their applications in 3d printing and photocomposite synthesis

In this article, new compounds based on the carbazole scaffold (DMs = DM1 and DM2, constituted by a carbazole unit connected on positions 3 and 6 to a two 4,4′‐dimethoxydiphenylamine groups and differing by the substituent present on the nitrogen heteroatom of the carbazole core) were synthesized and proposed as high‐performance visible light photoinitiators/photosensitizers for both the free‐radical polymerization of methacrylates and the cationic polymerization of epoxides upon visible light exposure using LED@405 nm. Remarkably, DM2 leads to higher final conversions than DM1. In order to study the photophysical and photochemical properties of the carbazole derivatives, different parameters were taken into account such as the light absorption, the steady‐state photolysis, and the fluorescence spectroscopy. Using different techniques such as fluorescence quenching, redox behavior, and cyclic voltammetry, we are able to discuss the photosensitization/photoinitiation reactions providing a full coherent picture of the involved chemical mechanisms. The photosensitization of the carbazole derivatives occurred predominantly via singlet excited states at the rate of the diffusion limit. Upon exposure to laser diode at 405 nm, DMs show high performance in initiating systems for 3D resins. Remarkably, DM2 can also be used in photocomposite synthesis using light‐emitting diode conveyor. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 2081–2092     

Discovering patterns in time-varying graphs: a triclustering approach

This paper introduces a novel technique to track structures in time varying graphs. The method uses a maximum a posteriori approach for adjusting a three-dimensional co-clustering of the source vertices, the destination vertices and the time, to the data under study, in a way that does not require any hyper-parameter tuning. The three dimensions are simultaneously segmented in order to build clusters of source vertices, destination vertices and time segments where the edge distributions across clusters of vertices follow the same evolution over the time segments. The main novelty of this approach lies in that the time segments are directly inferred from the evolution of the edge distribution between the vertices, thus not requiring the user to make any a priori quantization. Experiments conducted on artificial data illustrate the good behavior of the technique, and a study of a real-life data set shows the potential of the proposed approach for exploratory data analysis.     

Solvato Modulation of the Magnetic Memory in Isotopically Enriched Erbium Polyoxometalate

Single-Molecule Magnet (SMM) property is by essence molecular, while commonly measured in solid crystalline state. Solvent crystallization molecules are usually neglected in the analysis and interpretation of solid-state properties. The solvation/desolvation process in the polyoxometalate(POM)-based Na₉[Er(W₅O₁₈)₂] ⋅ 35 H₂O SMM demonstrates that the dehydrated form relaxes more than 1000 times faster than the initial state, while the rehydration process allows the quasi complete recovering of the initial magnetic behaviour. This dehydration process is monitored by thermogravimetric analysis (TGA) and temperature-dependent X-ray powder diffraction, and rationalized by periodic quantum chemical calculations evidencing the tremendous role of the labile water molecules in the stability of the edifice. Ab-initio calculations highlight that sodium ions localization in the structure drive the magnetic responses. Isotopic enrichment with nuclear spin free (¹⁶⁶Er, I=0) Er^III ions shows that the relaxation dynamics in the quantum regime depends on the nuclear spin.     

Characterization of polyoxometalate/polymer photo-composites: A toolbox for the photodegradation of organic pollutants

Different inorganic/organic photocomposites based on polyoxometalate (POM) nanoparticles have been developed for photocatalytic applications. Currently, polyoxometalate nanoparticles have been successfully in-situ embedded into an acrylate polymer network by photopolymerization upon mild visible light irradiation at 405 nm. The proposed POM/polymer photocomposites have been characterized using complementary techniques for a better understanding of their photocatalytic activity. Interestingly, the obtained photocomposites exhibit high rigidity, excellent thermal stability, a non-negligible porosity and new functionalities such as light reactivity and redox properties. Moreover, developed composites showed efficient catalytic activity for the color removal of aqueous solutions of erythrosine and rose Bengal under Light Emitting Diodes LED@375 nm irradiation reaching 80 and 90% as a final color removal, respectively.     

Rapid Discrimination of Crystal Handedness by X-ray Natural Circular Dichroism (XNCD) Mapping

An original method for determining the handedness of individual non-centrosymmetric crystals in a mixture using a tightly-focused, circularly polarized X-ray beam is presented. The X-ray natural circular dichroism (XNCD) spectra recorded at the metal K-edge on selected crystals of [Δ-M(en)₃](NO₃)₂ and [Λ-M(en)₃](NO₃)₂ (M=Co^II, Ni^II) show extrema at the metal pre-edge (7712 eV for Co, 8335 eV for Ni). A mapping of a collection of some 220 crystals was performed at the respective energies by using left and right circular polarizations. The difference in absorption for the two polarizations, being either negative or positive, directly yielded the handedness of the crystal volume probed by the beam. By using this technique, it was found that the addition of l -ascorbic acid during the synthesis of [Co(en)₃](NO₃)₂ resulted in an enantiomeric enrichment of the Λ-isomer of 67±13 %, whereas the Ni analogue was similarly, but conversely, enriched in the Δ-isomer (65±22 %).