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1. Triple-stimuli responsive polymers with fine tuneable magnetic responses

Author

I. Chikh Alard, Gilles Berger, J. Goole, Karim Amighi, S. Spassov, Michel Gelbcke, Franck Meyer, and Jalal Soubhye

Subjects
chemistry.chemical_classification, Polymers and Plastics, Ion exchange, Chemistry, Organic Chemistry, Bioengineering, 02 engineering and technology, Polymer, equipment and supplies, 010402 general chemistry, 021001 nanoscience & nanotechnology, Metathesis, Methacrylate, 01 natural sciences, Biochemistry, Magnetic susceptibility, 0104 chemical sciences, Polymer chemistry, Copolymer, 0210 nano-technology, Ternary operation, human activities, Alkyl
Abstract

The formation of multi-stimuli responsive polymers exhibiting magnetic, pH and light sensitivity is reported. After quaternization of tertiary amines along poly(2-(N,N-dimethylamino) ethyl methacrylate) (PDMAEMA) with varied alkyl and benzyl halides, a series of tetrahalogenoferrate(III) salts were obtained by anion metathesis, conferring tailored and high magnetic responses. Experimental and theoretical Raman analyses allowed one to distinguish between the different magnetic anions present in the materials. This strategy was then implemented to the formation of multi-responsive compounds, by using random copolymers that incorporate various amounts of DMAEMA (∼40, 65 and 80%) and diazobenzene units. Partial or total quaternization of the dimethylamino end groups (10, 50 and 100%) followed by magnetic anion exchange afforded the magnetic-responsive copolymers, as evidenced by their magnetic susceptibility. Free ternary amino groups and diazobenzene moieties further brought pH and light sensitivity, giving rise to triple-stimuli responsive materials. This simple and rapid procedure offers the opportunity to fine tune the magnetic properties of remotely controlled smart devices.

Published
2017
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2. Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure.

Author

Soubhye J, Chikh Alard I, Aldib I, Prévost M, Gelbcke M, De Carvalho A, Furtmüller PG, Obinger C, Flemmig J, Tadrent S, Meyer F, Rousseau A, Nève J, Mathieu V, Zouaoui Boudjeltia K, Dufrasne F, and Van Antwerpen P

Subjects
Benzimidazoles chemical synthesis, Benzimidazoles toxicity, Cell Line, Databases, Chemical, Drug Design, Drug Evaluation, Preclinical, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors toxicity, Glutamic Acid chemistry, Glutamine chemistry, Guanidines chemical synthesis, Guanidines toxicity, Humans, Hydrogen Peroxide chemistry, Kinetics, Lactoperoxidase antagonists & inhibitors, Lipoproteins, LDL chemistry, Models, Chemical, Molecular Docking Simulation, Neutrophils drug effects, Neutrophils metabolism, Oxidation-Reduction, Quinazolines chemical synthesis, Quinazolines toxicity, Stereoisomerism, Benzimidazoles pharmacology, Enzyme Inhibitors pharmacology, Guanidines pharmacology, Peroxidase antagonists & inhibitors, Quinazolines pharmacology
Abstract

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC 50 less than 5 μM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC 50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.

Published
2017
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