Synthesis of deuterium-labelled analogues of NLRP3 inflammasome inhibitor MCC950

This study describes the syntheses of di, tetra and hexa deuterated analogues of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950. In di and tetra deuterated analogues, deuteriums were incorporated into the 1,2,3,5,6,7-hexahydro-s-indacene moiety, whereas in the hexa deuterated MCC950 deuteriums were incorporated into the 2-(furan-3-yl)propan-2-ol moiety. The di deuterated MCC950 analogue was synthesised from 4-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one 5. Tetra deuterated analogues were synthesised in 10 chemical steps starting with 5-bromo-2,3-dihydro-1H-inden-1-one 9, whereas the hexa deuterated analogue was synthesised in four chemical steps starting with ethyl-3-furoate 24. All of the compounds exhibited similar activity to MCC950 (IC50 = 8 nM). These deuterated analogues are useful as internal standards in LC-MS analyses of biological samples from in vivo studies

Hydroxyapatite-intertwined hybrid nanofibres for the mineralization of osteoblasts

Advances in tissue engineering have enabled the development of bioactive composite materials to generate biomimetic nanofibrous scaffolds for bone replacement therapies. Polymeric biocomposite nanofibrous scaffolds architecturally mimic the native extracellular matrix (ECM), delivering tremendous regenerative potential for bone tissue engineering. In the present study, biocompatible poly(l-lactic acid)-co-poly(ε-caprolactone)-silk fibroin-hydroxyapatite-hyaluronic acid (PLACL-SF-HaP-HA) nanofibrous scaffolds were fabricated by electrospinning to mimic the native ECM. The developed nanofibrous scaffolds were characterized in terms of fibre morphology, functional group, hydrophilicity and mechanical strength, using SEM, FTIR, contact angle and tabletop tensile-tester, respectively. The nanofibrous scaffolds showed a higher level of pore size and increased porosity of up to 95% for the exchange of nutrients and metabolic wastes. The fibre diameters obtained were in the range of around 255 ± 13.4-789 ± 22.41 nm. Osteoblasts cultured on PLACL-SF-HaP-HA showed a significantly (p < 0.001) higher level of proliferation (53%) and increased osteogenic differentiation and mineralization (63%) for the inclusion of bioactive molecules SF-HA. Energy-dispersive X-ray analysis (EDX) data proved that the presence of calcium and phosphorous in PLACL-SF-HaP-HA nanofibrous scaffolds was greater than in the other nanofibrous scaffolds with cultured osteoblasts. The obtained results for functionalized PLACL-SF-HaP-HA nanofibrous scaffolds proved them to be a potential biocomposite for bone tissue engineering. Copyright © 2015 John Wiley & Sons, Ltd

Single Molecule Redox-targeting Reactions for a pH-neutral Aqueous Organic Redox Flow Battery

ANGEWANDTE CHEMIE-INTERNATIONAL EDITIONGerman

E-blood: High power aqueous redox flow cell for concurrent powering and cooling of electronic devices

10.1016/j.nanoen.2021.106864NANO ENERGY9

A Redox-Mediated Zinc–Air Fuel Cell

10.1021/acsenergylett.2c01347ACS Energy Letters2565-257

A redox-mediated zinc electrode for ultra-robust deep-cycle redox flow batteries

10.1039/d2ee02402kENERGY & ENVIRONMENTAL SCIENCE162438-44

Decoupled Redox Catalytic Hydrogen Production with a Robust Electrolyte-Borne Electron and Proton Carrier

10.1021/jacs.0c09510JOURNAL OF THE AMERICAN CHEMICAL SOCIETY1431223-23

Redox-Mediated Ambient Electrolytic Nitrogen Reduction for Hydrazine and Ammonia Generation

10.1002/anie.202105536ANGEWANDTE CHEMIE-INTERNATIONAL EDITION603418721-18727complete

Identification, synthesis, and biological evaluation of the major human metabolite of NLRP3 inflammasome inhibitor MCC950

MCC950 is an orally bioavailable small molecule inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that exhibits remarkable activity in multiple models of inflammatory disease. Incubation of MCC950 with human liver microsomes, and subsequent analysis by HPLC-MS/MS, revealed a major metabolite, where hydroxylation of MCC950 had occurred on the 1,2,3,5,6,7-hexahydro-s-indacene moiety. Three possible regioisomers were synthesized, and coelution using HPLC-MS/MS confirmed the structure of the metabolite. Further synthesis of individual enantiomers and coelution studies using a chiral column in HPLC-MS/MS showed the metabolite was R-(+)- N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoy1)-4-(2-hydroxypropan-2-y0furan-2-sulfonamide (2a). Incubation of MCC950 with a panel of cytochrome P450 enzymes showed P450s 2A6, 2C9, 2C18, 2C19, 2J2, and 3A4 catalyze the formation of the major metabolite 2a, with a lower level of activity shown by P450s 1A2 and 2B6. All of the synthesized compounds were tested for inhibition of NLRP3-induced production of the pro-inflammatory cytokine IL-1 beta from human monocyte derived macrophages. The identified metabolite 2a was 170-fold less potent than MCC950, while one regioisomer had nanomolar inhibitory activity. These findings also give first insight into the SAR of the hexahydroindacene moiety