Enzyme Design from the Bottom Up: An Active Nickel Electrocatalyst with a Structured Peptide Outer Coordination Sphere

Catalytic, peptide‐containing metal complexes with a well‐defined peptide structure have the potential to enhance molecular catalysts through an enzyme‐like outer coordination sphere. Here, we report the synthesis and characterization of an active, peptide‐based metal complex built upon the well‐characterized hydrogen production catalyst [Ni(P^Ph₂N^Ph)₂]²⁺ (P^Ph₂N^Ph=1,3,6‐triphenyl‐1‐aza‐3,6‐diphosphacycloheptane). The incorporated peptide maintains its β‐hairpin structure when appended to the metal core, and the electrocatalytic activity of the peptide‐based metal complex (≈100,000 s^?1) is enhanced compared to the parent complex ([Ni(P^Ph₂N^APPA)₂]²⁺; ≈50,500 s^‐1). The combination of an active molecular catalyst with a structured peptide provides a scaffold that permits the incorporation of features of an enzyme‐like outer‐coordination sphere necessary to create molecular electrocatalysts with enhanced functionality.     

Insights into the Decomposition of Olefin Metathesis Precatalysts

The decomposition of a series of benzylidene, methylidene, and 3‐phenylindenylidene complexes has been probed in alcohol solution in the presence of base. Tricyclohexylphosphane‐containing precatalysts are shown to yield [RuCl(H)(H₂)(PCy₃)₂] in isopropyl alcohol solutions, while 3‐phenylindenylidene complexes lead to η⁵‐(3‐phenyl)indenyl products. The potential‐energy surfaces for the formation of the latter species have been probed using density functional theory studies.     

Tetracyanoquinodimethane Reduction by Complexed Guanidinyl‐Functionalized Aromatic Compounds

In this work, we report on the reduction of tetracyanoquinodimethane (TCNQ) with dicationic complexes of guanidinyl‐functionalized aromatic (GFA) electron donors. In contrast to reduction with free GFAs, milder reduction conditions were achieved, and this led to semiconducting materials with extended TCNQ π stacking. The charge on the TCNQ units was estimated from the structural data obtained by single‐crystal X‐ray diffraction analysis and from IR spectroscopic data. The electrical conductivity was studied and the activation energy of the semiconducting materials was estimated from the temperature dependence of the conductivity.     

Click approaches in sol–gel chemistry

The combination of the copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction with sol–gel processing enables the versatile preparation of sol–gel materials under different shapes with targeted functionalities through a diversity-oriented approach. In this account, the development of the CuAAC reaction under anhydrous conditions for the synthesis of sol–gel precursors and for the assembling of magnetic nanoparticles on self-assembled monolayers is related, as well as the use of the classical CuAAC methodologies for the functionalization of mesoporous silica nanoparticles and microdots arrays. Coupling CuAAC and Sol–Gel will result in simplified preparations of multifunctional materials with controlled morphologies.     

Novel betulin derivatives inhibit IFN-γ and modulates COX-2 expression

Abstract

Betulin (BE) is a pentacyclic triterpenes, obtained from natural sources and with several biological activities described, such as anti-tumoral and anti-inflammatory activities. The BE esterification at hydroxyl group (C-3 and C-28) resulted in five new ester derivatives with different numbers of carbons or halogens (chlorine and fluorine). Among these BE derivatives, two (2a e 2c) were able to significantly decrease IFN-g (*p?=?0.0391; **p?=?0.0156) and 2c modulated the expression of COX-2 better than Dexamethasone (DEXA). Regarding to cytotoxic assay, the best results were obtained for BE without modifications, with emphasis on tumoral cell lines Raji and MCF-7. The derivatives 2a and 2c showed immunomodulation activity (for the cytokines IFN-g). The presence of chorine in BE seems to be important for the ability of modulate COX-2 expression, since the ester chloride derivative 2c at 100?μM is more powerful inhibitor of COX-2 than DEXA.     

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

There is a need for new, cost-effective drugs to treat leishmaniasis. A strategy based on traditional medicine practiced in Bolivia led to the discovery of the 2-substituted quinoline series as a source of molecules with antileishmanial activity and low toxicity. This review documents the development of the series from the first isolated natural compounds through several hundred synthetized molecules to an optimized compound exhibiting an in vitro IC₅₀ value of 0.2 µM against Leishmania donovani, and a selectivity index value of 187, together with in vivo activity on the L. donovani/hamster model. Attempts to establish structure–activity relationships are described, as well as studies that have attempted to determine the mechanism of action. For the latter, it appears that molecules of this series act on multiple targets, possibly including the immune system, which could explain the observed lack of drug resistance after in vitro drug pressure. We also show how nanotechnology strategies could valorize these drugs through adapted formulations and how a mechanistic targeting approach could generate new compounds with increased activity.     

Sensing the Anti-Epileptic Drug Perampanel with Paper-Based Spinning SERS Substrates

The applications of SERS in therapeutic drug monitoring, or other fields of analytical chemistry, require the availability of sensitive sensors and experimental approaches that can be implemented in affordable ways. In this contribution, we show the production of cost-effective SERS sensors obtained by depositing Lee-Meisel Ag colloids on filter paper either by natural sedimentation or centrifugation. We have characterized the morphological and plasmonic features of the sensors by optical microscopy, SEM, and UV-Vis spectroscopy. Such sensors can be used to quantify by SERS the anti-epileptic drug Perampanel (in the concentration range 1 × 10⁻⁴–5 × 10⁻⁶ M) by spinning them during the micro-Raman measurements on the top of a custom device obtained from spare part hard disk drives. This approach minimizes laser-induced heating effects and allows averaging over the spatial non-uniformity of the sensor.     

A Probabilistic Re-Intepretation of Confidence Scores in Multi-Exit Models

In this paper, we propose a new approach to train a deep neural network with multiple intermediate auxiliary classifiers, branching from it. These ‘multi-exits’ models can be used to reduce the inference time by performing early exit on the intermediate branches, if the confidence of the prediction is higher than a threshold. They rely on the assumption that not all the samples require the same amount of processing to yield a good prediction. In this paper, we propose a way to train jointly all the branches of a multi-exit model without hyper-parameters, by weighting the predictions from each branch with a trained confidence score. Each confidence score is an approximation of the real one produced by the branch, and it is calculated and regularized while training the rest of the model. We evaluate our proposal on a set of image classification benchmarks, using different neural models and early-exit stopping criteria.     

Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection

Like other organs, brain functions diminish with age. Furthermore, for a variety of neurological disorders—including Alzheimer’s disease—age is one of the higher-risk factors. Since in many Western countries the average age is increasing, determining approaches for decreasing the effects of aging on brain function is taking on a new urgency. Neuroinflammation and oxidative stress are two convoluted key factors in brain aging and chronic neurodegenerative diseases. The diverseness of factors, causing an age-related decrease in brain functions, requires identifying small molecules that have multiple biological activities that can affect all these factors. One great source of these small molecules is related to polyphenolic flavonoids. Recently, 3,3′,4′,7-tetrahydroxyflavone (fisetin) has been reported as a potent senotherapeutic capable of extending lifespan by reducing peroxidation levels and enhancing antioxidant cell responses. The neuroprotective effects of fisetin have been shown in several in vitro and in vivo models of neurological disorders due to its actions on multiple pathways associated with different neurological disorders. The present work aims to collect the most recent achievements related to the antioxidant and neuroprotective effects of fisetin. Moreover, in silico pharmacokinetics, pharmacodynamics, and toxicity of fisetin are also comprehensively described along with emerging novel drug delivery strategies for the amelioration of this flavonol bioavailability and chemical stability.