Silver-Nanoparticle-Embedded Porous Silicon Disks Enabled SERS Signal Amplification for Selective Glutathione Detection

As the major redox couple and nonprotein thiol source in human tissues, the level of glutathione (GSH) has been a concern for its relation with many diseases. However, the similar physical and chemical properties of interference molecules such as cysteine (Cys) and homocysteine (Hcy) make discriminative detection of GSH in complex biological fluids challenging. Here we report a novel surface-enhanced Raman scattering (SERS) platform, based on silver-nanoparticle-embedded porous silicon disks (PSDs/Ag) substrates for highly sensitive and selective detection of GSH in biofluids. Silver nanoparticles (AgNPs) were reductively synthesized and aggregated directly into pores of PSDs, achieving a SERS enhancement factor (EF) up to 2.59 × 10⁷. Ellman’s reagent 5,5′-ditho-bis (2-nitrobenzoic acid) (DTNB) was selected as the Raman reactive reporting agent, and the GSH quantification was determined using enzymatic recycling method, and allowed the detection limit of GSH to be down to 74.9 nM using a portable Raman spectrometer. Moreover, the significantly overwhelmed enhancement ratio of GSH over other substances enables the discrimination of GSH detection in complex biofluids

Discovery of ((<i>S</i>)-5-(Methoxymethyl)-7-(1-methyl-1<i>H</i>-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-<i>a</i>]pyrimidin-6-yl)((<i>S</i>)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone As a Potent and Selective I_Kur Inhibitor

Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I_Kur current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent I_Kur inhibitors, with selectivity over <i>h</i>ERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((<i>S</i>)-5-(methoxymethyl)-7-(1-methyl-1<i>H</i>-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo­[1,5-<i>a</i>]­pyrimidin-6-yl)­((<i>S</i>)-2-(3-methylisoxazol-5-yl)­pyrrolidin-1-yl)­methanone (<b>13j</b>), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model