Direct gem-Difluoroalkenylation of X−H Bonds with Trifluoromethyl Ketone N-Triftosylhydrazones for Synthesis of Tetrasubstituted Heteroatomic gem-Difluoroalkenes

The direct gem-difluoroalkenylation of X−H bonds represents the most straightforward approach to access heteroatomic gem-difluoroalkenes that, as the isostere of the carbonyl group, have great potency in drug discovery. However, the construction of tetrasubstituted heteroatomic gem-difluoroalkenes by this strategy is still an unsolved problem. Here, we report the first direct X−H bond gem-difluoroalkenylation of amines and alcohols with trifluoromethyl ketone N-triftosylhydrazones under silver (for (hetero)aryl hydrazones) or rhodium (for alkyl hydrazones), thereby providing a most powerful method for the synthesis of tetrasubstituted heteroatomic gem-difluoroalkenes. This method features a broad substrate scope, high product yield, excellent functional group tolerance, and operational simplicity (open air conditions). Moreover, the site-specific replacement of the carbonyl group with a gem-difluorovinyl ether bioisostere in drug Trimebutine and the post-modification of bioactive molecules demonstrates potential use in medicinal research. Finally, the reaction mechanism was investigated by combining experiments and DFT calculations, and disclosed that the key step of HF elimination occurred via five-membered ring transition state, and the difference in the electrophilicity of Ag- and Rh-carbenes as well as the multiple intermolecular interactions rendered the effectiveness of Rh catalyst selectively for alkyl hydrazones.     

ENERGY TRANSFER FROM ENZYME-GENERATED TRIPLET CARBONYLS TO THYLAKOID MEMBRANE FRACTIONS ENRICHED IN PHOTOSYSTEMS I and II

Abstract— Enzyme-generated triplet species transfer energy very efficiently to thylakoid membrane fractions enriched in either photosystem-I or photosystem-II. Independent of the nature of the triplet donor, the emission is always more intense with photosystem-I. Since the fluorescence quantum yield of chlorophyll in PS-I is lower and the rate of energy transfer usually smaller than to chlorophyll in PS-II, the yield of ¹S chlorophylls in PS-I is substantially higher. This is tentatively attributed to more favorable reverse intersystem crossing from an upper triplet state in PS-I.     

Peroxidase Activity May Play a Role in the Cytotoxic Effect of Indole Acetic Acid*

Peroxidase activity in neutrophils is higher than in thioglycollate macrophages, while in lymphocytes this enzyme activity is very low. Indole-3-acetic acid is oxidized by peroxidase and the role of this enzyme in the cytotoxic effect of the compound was evaluated by measuring oxygen consumption, light emission and cell death in neutrophils, macrophages and lymphocytes. The increase in light emission, oxygen consumption and rate of cell death in cells cultured in the presence of indole-3-acetic acid presented a direct correlation with the peroxidase activity of the cells as follows: neutrophils > thioglycollate macrophages > resident macrophages > lymphocytes. Indeed, in lymphocytes that possess very low peroxidase activity, indole-3-acetic acid did not result in an increase in light emission or oxygen consumption and it was not cytotoxic.     

Supramolecular adducts between macrocyclic Gd(iii) complexes and polyaromatic systems: a route to enhance the relaxivity through the formation of hydrophobic interactions

The set-up of reversible binding interactions between the hydrophobic region of macrocyclic GBCAs (Gadolinium Based Contrast Agents) and SO₃⁻/OH containing pyrene derivatives provides new insights for pursuing relaxivity enhancements of this class of MRI contrast agents. The strong binding affinity allows attaining relaxation enhancements up to 50% at pyrene/GBCA ratios of 3 : 1. High resolution NMR spectra of the Yb-HPDO3A/pyrene system fully support the formation of a supramolecular adduct based on the set-up of hydrophobic interactions. The relaxation enhancement may be accounted for in terms of the increase of the molecular reorientation time (τ_R) and the number of second sphere water molecules. This effect is maintained in blood serum and in vivo, as shown by the enhancement of contrast in T_1w-MR images obtained by simultaneous injection of GBCA and pyrene derivatives in mice.

The set-up of reversible binding interactions between the hydrophobic region of macrocyclic gadolinium based contrast agents and SO₃⁻/OH containing pyrene derivatives provides new insights for pursuing relaxivity enhancement of MRI contrast agents.     

Ambiphilic boryl groups in a neutral Ni(ii) complex: a new activation mode of H2

The concept of metal–ligand cooperation opens new avenues for the design of catalytic systems that may offer alternative reactivity patterns to the existing ones. Investigations of this concept with ligands bearing a boron center in their skeleton established mechanistic pathways for the activation of small molecules in which the boron atom usually performs as an electrophile. Here, we show how this electrophilic behavior can be modified by the ligand trans to the boron center, evincing its ambiphilic nature. Treatment of diphosphinoboryl (PBP) nickel–methyl complex 1 with bis(catecholato)diboron (B₂Cat₂) allows for the synthesis of nickel(ii) bis-boryl complex 3 that promotes the clean and reversible heterolytic cleavage of dihydrogen leading to the formation of dihydroborate nickel complex 4. Density functional theory analysis of this reaction revealed that the heterolytic activation of H₂ is facilitated by the cooperation of both boryl moieties and the metal atom in a concerted mechanism that involves a Ni(ii)/Ni(0)/Ni(ii) process. Contrary to 1, the boron atom from the PBP ligand in 3 behaves as a nucleophile, accepting a formally protic hydrogen, whereas the catecholboryl moiety acts as an electrophile, receiving the attack from the hydride-like fragment. This manifests the dramatic change in the electronic properties of a ligand by tuning the substituent trans to it and constitutes an unprecedented cooperative mechanism that involves two boryl ligands in the same molecule operating differently, one as a Lewis acid and the other one as a Lewis base, in cooperation with the metal. In addition, reactivity towards different nucleophiles such as amines or ammonia confirmed the electrophilic nature of the Bcat moiety, allowing the formation of aminoboranes.

A bis(boryl)nickel complex promotes the facile and reversible activation of H₂ through a cooperative mechanism that involves the metal and both boryl moieties in a concerted five-center process.     

ParaHydrogen Polarized Ethyl-[1-13C]pyruvate in Water,a Key Substrate for Fostering the PHIP-SAH Approach to Metabolic Imaging

An efficient synthesis of vinyl-[1-¹³C]pyruvate has been reported, from which ¹³C hyperpolarized (HP) ethyl-[1-¹³C]pyruvate has been obtained by means of ParaHydrogen Induced Polarization (PHIP). Due to the intrinsic lability of pyruvate, which leads quickly to degradation of the reaction mixture even under mild reaction conditions, the vinyl-ester has been synthesized through the intermediacy of a more stable ketal derivative. ¹³C and ¹H hyperpolarizations of ethyl-[1-¹³C]pyruvate, hydrogenated using ParaHydrogen, have been compared to those observed on the more widely used allyl-derivative. It has been demonstrated that the spin order transfer from ParaHydrogen protons to ¹³C, is more efficient on the ethyl than on the allyl-esterdue to the larger J-couplings involved. The main requirements needed for the biological application of this HP product have been met, i. e. an aqueous solution of the product at high concentration (40 mM) with a good ¹³C polarization level (4.8 %) has been obtained. The in vitro metabolic transformation of the HP ethyl-[1-¹³C]pyruvate, catalyzed by an esterase, has been observed. This substrate appears to be a good candidate for in vivo metabolic investigations using PHIP hyperpolarized probes.     

Development of a Novel Microwave Distillation Technique for the Isolation of Cannabis sativa L. Essential Oil and Gas Chromatography Analyses for the Comprehensive Characterization of Terpenes and Terpenoids,Including Their Enantio-Distribution

A microwave distillation method was optimized for the extraction and isolation of cannabis essential oil from fresh and dried hemp inflorescences. The developed method enabled us to obtain a distilled product rich in terpenes and terpenoid compounds, responsible of the typical and unique smell of the cannabis plant. The distillate from different hemp cultivars, including Kompolti, Futura 75, Carmagnola, Felina 32 and Finola were characterized by using a gas chromatograph equipped with both mass spectrometer and flame ionization detectors. In a single chromatographic run, the identity and absolute amounts of distilled compounds were determined. Peak assignment was established using a reliable approach based on the usage of two identification parameters, named reverse match, and linear retention index filter. Absolute quantification (mg g⁻¹) of the analytes was performed using an internal standard method applying the flame ionization detector (FID) response factors according to each chemical family. An enantio-GC-MS method was also developed in order to evaluate the enantiomeric distribution of chiral compounds, an analytical approach commonly utilized for establishing the authenticity of suspicious samples.     

Impact of Matrix Metalloproteinase-9 during Periodontitis and Cardiovascular Diseases

Matrix metalloproteinase-9 (MMP-9) has been shown to play a key role in endothelial function and perhaps pivotal in the correlation between periodontal disease and cardiovascular disease (CVD). For the study, the impact of MMP-9 of periodontitis and CVD on serum and saliva concentrations was analyzed. For the study patients with periodontitis (n = 31), CVD (n = 31), periodontitis + CVD (n = 31), and healthy patients (n = 31) were enrolled. Clinical and demographic characteristics as well as serum and salivary MMP-9 were evaluated. MMP-9 concentrations in serum and saliva were statistically elevated in patients with CVD (p < 0.01) and in patients with periodontitis plus CVD (p < 0.001) compared to patients with periodontitis and healthy subjects. Multivariate regression analysis showed that c-reactive protein (hs-CRP) was the only significant predictor for MMP-9 serum (p < 0.001), whereas hs-CRP (p < 0.001) and total cholesterol (p = 0.029) were the statistically significant salivary MMP-9 predictors. This study evidenced that patients with CVD and periodontitis + CVD presented elevated MMP-9 concentrations in serum and saliva compared to patients with periodontitis and healthy subjects. Furthermore, hs-CRP was a negative predictor of serum and salivary MMP-9.     

Prebiotic Route to Thymine from Formamide—A Combined Experimental–Theoretical Study

Synthesis of RNA nucleobases from formamide is one of the recurring topics of prebiotic chemistry research. Earlier reports suggest that thymine, the substitute for uracil in DNA, may also be synthesized from formamide in the presence of catalysts enabling conversion of formamide to formaldehyde. In the current paper, we show that to a lesser extent conversion of uracil to thymine may occur even in the absence of catalysts. This is enabled by the presence of formic acid in the reaction mixture that forms as the hydrolysis product of formamide. Under the reaction conditions of our study, the disproportionation of formic acid may produce formaldehyde that hydroxymethylates uracil in the first step of the conversion process. The experiments are supplemented by quantum chemical modeling of the reaction pathway, supporting the plausibility of the mechanism suggested by Saladino and coworkers.     

Agile Detection of Chemical Warfare Agents by Machine Vision: a Supramolecular Approach

The supramolecular detection by image analysis of a simulant chemical warfare agent on a solid device containing a selective molecular sensor based on a BODIPY scaffold is reported. The recognition properties were investigated in solution, demonstrating high affinity (log K 6.60) and sensitivity (LOD 10 ppt). A test strip also confirmed the sensing properties in gas phase. Image analysis of the solid device allows quantitative information about the simulant to be obtained, recovering the sensor almost 5 times and thus confirming the goal of the supramolecular approach.