Equisetum arvense standardized dried extract hinders age-related osteosarcopenia.

Age-associated osteosarcopenia is an unresolved syndrome characterized by the concomitant loss of bone (osteopenia) and skeletal muscle (sarcopenia) tissues increasing falls, immobility, morbidity, and mortality. Unbalanced resorption of bone in the remodeling process and excessive protein breakdown, especially fast type II myosin heavy chain (MyHC-II) isoform and myofiber metabolic shift, are the leading causes of bone and muscle deterioration in the elderly, respectively. Equisetum arvense (EQ) is a plant traditionally recommended for many pathological conditions due to its anti-inflammatory properties. Thus, considering that a chronic low-grade inflammatory state predisposes to both osteoporosis and sarcopenia, we tested a standardized hydroalcoholic extract of EQ in in vitro models of muscle atrophy [C2C12 myotubes treated with proinflammatory cytokines (TNFα/IFNγ), excess glucocorticoids (dexamethasone), or the osteokine, receptor activator of nuclear factor kappa-B ligand (RANKL)] and osteoclastogenesis (RAW 264.7 cells treated with RANKL). We found that EQ counteracted myotube atrophy, blunting the activity of several pathways depending on the applied stimulus, and reduced osteoclast formation and activity. By in silico target fishing, IKKB-dependent nuclear factor kappa-B (NF-κB) inhibition emerges as a potential common mechanism underlying EQ's anti-atrophic effects. Consumption of EQ (500 mg/kg/day) by pre-geriatric C57BL/6 mice for 3 months translated into: i) maintenance of muscle mass and performance; ii) restrained myofiber oxidative shift; iii) slowed down age-related modifications in osteoporotic bone, significantly preserving trabecular connectivity density; iv) reduced muscle- and spleen-related inflammation. EQ can preserve muscle functionality and bone remodeling during aging, potentially valuable as a natural treatment for osteosarcopenia.

A novel black poplar propolis extract with promising health-promoting properties: focus on its chemical composition, antioxidant, anti-inflammatory, and anti-genotoxic activities.

Propolis is a resinous mixture produced by honeybees which has been used since ancient times for its useful properties. However, its chemical composition and bioactivity may vary, depending on the geographical area of origin and the type of tree bees use for collecting pollen. In this context, this research aimed to investigate the total phenolic content (using the Folin-Ciocalteu assay) and the total antioxidant capacity (using the FRAP, DPPH, and ABTS assays) of three black poplar (Populus nigra L.) propolis (BPP) solutions (S1, S2, and S3), as well as the chemical composition (HPLC-ESI-MSn) and biological activities (effect on cell viability, genotoxic/antigenotoxic properties, and anti-inflammatory activity, and effect on ROS production) of the one which showed the highest antioxidant activity (S1). The hydroalcoholic BPP solution S1 was a prototype of an innovative, research-type product by an Italian nutraceutical manufacturer. In contrast, hydroalcoholic BPP solutions S2 and S3 were conventional products purchased from local pharmacy stores. For the three extracts, 50 phenolic compounds, encompassing phenolic acids and flavonoids, were identified. In summary, the results showed an interesting chemical profile and the remarkable antioxidant, antigenotoxic, anti-inflammatory and ROS-modulating activities of the innovative BPP extract S1, paving the way for future research. In vivo investigations will be a possible line to take, which may help corroborate the hypothesis of the potential health benefits of this product, and even stimulate further ameliorations of the new prototype.

Optimization of Ultrasound-Assisted Extraction of Chlorogenic Acid from Potato Sprout Waste and Enhancement of the In Vitro Total Antioxidant Capacity.

Potato sprouts, an underutilized by-product of potato processing, could be exploited for the recovery of caffeoyl-quinic acids (CQAs), a family of polyphenols with well-recognized biological activities. In this work, the predominant compound of this class, 5-CQA, was extracted by Ultrasound-Assisted Extraction (UAE) under conditions optimized by an Experimental Design. The investigated variables solid/solvent ratio (1:10-1:50 g/mL), water content in ethanol (30-100% v/v) and UAE time (5-20 min) highlighted a critical influence of the last two factors on the extraction efficiency: extracts richer in 5-CQA were obtained with lower water content (30%) and time (5 min). The addition of ascorbic acid (1.7 mM) as anti-browning agent to the extraction solvent improved the extraction efficiency of 5-CQA compared to acetic and citric acids (3158.71 µg/mL, 1766.71 µg/mL, 1468.20 µg/mL, respectively). A parallel trend for the three acids and an increase in 5-CQA recovery was obtained with the use of freeze-dried sprouts (4980.05 µg/mL, 4795.62, 4211.25 µg/mL, respectively). Total antioxidant capacity (TAC) in vitro demonstrated UAE being a more valuable technique than conventional maceration. Furthermore, three-times-higher values of TPC (7.89 mg GAE/g) and TAC (FRAP: 24.01 mg TE/g; DPPH: 26.20 mg TE/g; ABTS 26.72 mg TE/g) were measured for the optimized extract compared to the initial one. An HPLC-DAD method was applied to monitor 5-CQA recovery, while an LC-HRMS/MS investigation allowed us to perform analyte identity confirmation along with detection of the glycoalkaloids α-solanine and α-chaconine. This evidence underlines the necessity to develop purification strategies in order to maximize the potential of potato sprout waste as a source of 5-CQA.

Effect of Cocoa Roasting on Chocolate Polyphenols Evolution.

Cocoa and chocolate antioxidants might contribute to human health through, for instance, blood flow improvement or blood pressure and glycemia reduction, as well as cognitive function improvement. Unfortunately, polyphenol content is reduced during cocoa fermentation, drying, roasting and all the other phases involved in the chocolate production. Here, we investigated the evolution of the polyphenol content during all the different steps of chocolate production, with a special emphasis on roasting (3 different roasting cycles with 80, 100, and 130 °C as maximum temperature). Samples were followed throughout all processes by evaluating the total polyphenols content, the antioxidant power, the epicatechin content, and epicatechin mean degree of polymerization (phloroglucinol adducts method). Results showed a similar trend for total polyphenol content and antioxidant power with an unexpected bell-shaped curve: an increase followed by a decrease for the three different roasting temperatures. At the intermediate temperature (100 °C), the higher polyphenol content was found just after roasting. The epicatechin content had a trend similar to that of total polyphenol content but, interestingly, the mean degree of polymerization data had the opposite behavior with some deviation in the case of the highest temperature, probably due to epicatechin degradation. It seems likely that roasting can free epicatechin from oligomers, as a consequence of oligomers remodeling.

Microsampling and enantioselective liquid chromatography coupled to mass spectrometry for chiral bioanalysis of novel psychoactive substances.

In this paper, the development of efficient enantioselective HPLC methods for the analysis of five benzofuran-substituted phenethylamines, two substituted tryptamines, and three substituted cathinones is described. For the first time, reversed-phase (eluents made up with acidic water-methanol solutions) and polar-ionic (eluent made up with an acetonitrile-methanol solution incorporating both an acidic and a basic additive) conditions fully compatible with mass spectrometry (MS) detectors were applied with a chiral stationary phase (CSP) incorporating the (+)-(18-crown-6)-tetracarboxylic acid chiral selector. Enantioresolution was achieved for nine compounds with α and RS factors up to 1.32 and 5.12, respectively. Circular dichroism (CD) detection, CD spectroscopy in stopped-flow mode and quantum mechanical (QM) calculations were successfully employed to investigate the absolute stereochemistry of mephedrone, methylone and butylone and allowed to establish a (R)<(S) enantiomeric elution order for these compounds on the chosen CSP. Whole blood miniaturized samples collected by means of volumetric absorptive microsampling (VAMS) technology and fortified with the target analytes were extracted following an optimized protocol and effectively analysed by means of an ultra-high performance liquid chromatography-MS system. By this way a proof-of-concept procedure was applied, demonstrating the suitability of the method for quali-quantitative enantioselective assessment of the selected psychoactive substances in advanced biological microsamples. VAMS microsamplers including a polypropylene handle topped with a small tip of a polymeric porous material were used and allowed to volumetrically collect small aliquots of whole blood (10 µL) independently from its density. Highly appreciable volumetric accuracy (bias, in the -8.7-8.1% range) and precision (% CV, in the 2.8-5.9% range) turned out.

In-depth characterization of phenolic profiling of Moraiolo extra-virgin olive oil extract and initial investigation of the inhibitory effect on Indoleamine-2,3-Dioxygenase (IDO1) enzyme.

In this research, the phenolic extract from Moraiolo extra-virgin olive oil (EVOO) was thoroughly characterized. A reversed-phase HPLC method with a photodiode detector allowed to measure a total phenol content higher than 500 mg/kg EVOO, with elevated amounts of oleocanthal, oleacein, and oleouropein aglycone (131.2, 213.5, and 158.4 mg/kg EVOO, respectively). Appreciable amounts of (+)-pinoresinol and (+)- 1-acetoxy-pinoresinol, 3.2 and 12.5 mg/kg EVOO respectively, were measured. High-resolution mass spectrometry with Orbitrap mass analyzer technology was used to confirm the identity of the analytes. Afterwards, the extract was tested, for the first time, for its activity on Indoleamine-2,3-Dioxygenase (IDO1). This enzyme appears as a promising target for the modulation of the neuroinflammatory-oxidative processes relying on the pathogenesis of several neurodegenerative diseases. The extract showed an inhibitory effect on the catalytic activity of both human and murine IDO1, with a good safety at the concentrations of 15 and 30 µg/mL.

Separation and determination of cysteine enantiomers in plasma after derivatization with 4-fluoro-7-nitrobenzofurazan.

The importance of D-amino acids in mammals associated with enantio-dependent biological functions has been increasingly highlighted. In addition to naturally occurring, D-amino acid supplementation could have a positive biological impact, including cytoprotective implications. In this context, supplementation with D-cysteine has revealed beneficial effects. Quantification of cysteine enantiomers in rodent plasma has been achieved by using 4-fluoro-7-nitrobenzofurazan derivatization of the target analytes. Cystine, the main form of cysteine in the plasma, was initially reduced to cysteine using DL-dithiothreitol. Baseline enantioseparation was then achieved in less than 3 min using a (R,R)-Whelk-O 1 stationary phase and isocratic elution using CH3OH-H2O 90:10 (v/v) with 15 mM ammonium formate (apparent pH 6.0) at 0.5 mL/min. The derivatives were then detected using negative ESI-MS in SRM mode. An external calibration was employed for D-cysteine, while L-cysteine quantification, as an endogenous analyte, was addressed using a background subtraction strategy. The method was validated. Response functions were obtained from 0 to 300 µM and from 0 to 125 µM for D-cysteine and L-cysteine, respectively. The trueness ranged from 96% to 105% for both enantiomers with repeatability and intermediate precision lower than 8% and 15% for the D-form and the endogenous L-form, respectively. The method was successfully applied for determining D- and L-cysteine in mouse plasma after D-cysteine administration.

Antioxidant Power on Dermal Cells by Textiles Dyed with an Onion (Allium cepa L.) Skin Extract.

In this study, the phenol loading and antioxidant activity of wool yarn prepared with the aqueous extract of onion (Allium cepa L.) skin was enhanced by implementing the dyeing process with the use of alum as a mordant. Spectrophotometric and chromatographic methods were applied for the characterization of polyphenolic substances loaded on the wool yarn. The antioxidant/anti-inflammatory properties were evaluated by determining the level of intra- and extra-cellular reactive oxygen species (ROS) production in keratinocytes and dermal fibroblasts pre-treated with lipopolysaccharide put in contact with artificial sweat. An elevated dye uptake on wool was observed for the pre-mordanted sample, as demonstrated by high absorbance values in the UV-Visible spectral range. Chromatographic results showed that protocatechuic acid and its glucoside were the main phenolic acid released in artificial sweat by the wool yarns, while quercetin-4'-glucoside and its aglycone quercetin were more retained. The extract released from the textile immersed in artificial sweat showed a significant reducing effect on the intra-and extracellular ROS levels in the two cell lines considered. Cytofluorimetric analyses demonstrated that the selected mordant was safe at the concentration used in the dyeing procedure. Therefore, alum pre-mordanted textiles dyed with onion-skin extracts may represent an interesting tool against skin diseases.

Exploiting Food-Grade Mesoporous Silica to Preserve the Antioxidant Properties of Fresh Olive Mill Wastewaters Phenolic Extracts.

Fresh olive mill wastewaters phenolic extracts are of great interest as preservatives or fortifying ingredients but are characterized by limited stability. The purpose of this study was to use mesoporous silica to enhance their stability and preserve their antioxidant properties. The phenolic extracts were characterized for their composition by HPLC-DAD and included in a mesoporous matrix with or without a lipid coating. The inclusion complexes were characterized in terms of total phenolic content, radical scavenging capacity and in vitro antioxidative activity and cell compatibility. Besides, inclusion complex stability under different storage conditions (22 and 37 °C, 75% relative humidity, 1 month) was evaluated. The inclusion process was nearly quantitative and modified neither the total phenolic content nor the total antioxidant capacity. None of the inclusion complex concentrations assayed on the HT29 cell line showed toxicity. Moreover, HT29 cells treated with the inclusion complex exhibited a significant antioxidant effect, while the lipid coating impaired the antioxidant activity. The complexes without lipid were stable under all the investigated conditions, while the lipid-coated products were less stable under the more drastic conditions. Overall, inclusion complexes in mesoporous silica have suitable characteristics to be used for different applications, including food supplementation.

3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine.

Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-L-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1ß, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance.

Quantitative analysis of cucurbitane-type triterpenes in Ibervillea sonorae extracts: Relationship study with their antiproliferative activity.

Ibervillea sonorae (Cucurbitaceae) is a Mexican plant commonly used by local population for its hypoglycaemic activity. Root extracts showed also other different biological activities, including antimicrobial, antifungal, antioxidant and anti-inflammatory activity. Main components of this plant are cucurbitacins, steroid-like triterpenes that possess, among others, antiproliferative activity. In previous studies, kinoin A and cucurbitacin IIb extracted from I. sonorae showed antiproliferative and apoptotic effects against different cancer cell lines. Based on all the above, a RP-HPLC method was developed and validated for the quantitative analysis of these two compounds in I. sonorae root extracts obtained with different extraction conditions. In the present study, the quantitative analysis of kinoin B diglycoside in all the extracts was performed as well. As a result, no direct correlation was found between the antiproliferative activity (IC50) against human cervical cancer cell line (HeLa) and the composition of the above three compounds. Only a slight statically significant negative correlation was observed between IC50s and the content of kinoin A (r = 0.29, p = 0.12), meaning that, at least in part, this is the main compound among the three, contributing to the antiproliferative activity on the real samples. Accordingly, a synergistic effect by the phytocomplex components can account for the observed antiproliferative activity of the methanolic extracts towards HeLa cells.

Chromatograpic resolution of phenylethanolic-azole racemic compounds highlighted stereoselective inhibition of heme oxygenase-1 by (R)-enantiomers.

Heme oxygenase-1 (HO-1) has been recognized as extensively involved in the development and aggravation of cancer, cell propagation and at in the mechanism of chemoresistance development. Low micromolar HO-1 inhibitors selective towards HO-2 has been recently reported, wherein the azole core and the hydrophobic residues are linked through a phenylethanolic spacer bearing a chiral center. Since less information are known about the stereoselective requirements for HO-1 inhibition, here we report the enantiomeric resolution of 1-(biphenyl-3-yl)-2-(1H-imidazol-1-yl)ethanol (1) and 1-[4-[(4-bromobenzyl)oxy]phenyl]-2-(1H-imidazol-1-yl)ethanol (2), two among the most potent and selective HO-1 inhibitors known thus far when tested as racemates. The absolute configuration was established for 1 by a combination of experimental and in silico derived electronic circular dichroism spectra, while docking approaches were useful in the case of compound 2. Biological evaluation of pure enantiomers highlighted higher HO-1 inhibitory activity of (R)-enantiomers. Docking studies demonstrated the importance of hydrogen bond interaction, more pronounced for the (R)-enantiomers, with a consensus water molecule within the binding pocket. The present study demonstrates that differences in three-dimensional structure amongst compounds 1 and 2 enantiomers affect significantly the selectivity of these HO-1 inhibitors.

Optimized one-pot derivatization and enantioseparation of cysteine: Application to the study of a dietary supplement.

Cysteine is a sulfur-containing amino acid which plays an outstanding role in many biological pathways in mammals. The analysis and quantification of native cysteine remains a critical issue due to its highly reactive thiol group evolving to the disulfide cystine derivative through oxidation reaction. Aimed at improving the derivative stability, cysteine was labelled with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), which reacts with both amino and thiol groups. The derivatization was optimized and the chemical identity of the reaction product was assessed via high-resolution mass spectrometry. The NBD-cysteine derivative resulted stable for 10 days. This derivative was enantioresolved (α and RS equal to 1.25 and 2.70, respectively) thanks to a (R,R)-Whelk-O1 phase with the following chromatographic setting: eluent, MeOH/water-90/10 (v/v) with 15 mM ammonium formate (pwsH 6.0); column temperature, 35 °C; flow rate, 1.0 mL/min. The developed method was validated following the ICH guidelines and applied for the quality control of a L-cysteine containing dietary supplement.

Development and validation of a chiral UHPLC-MS method for the analysis of cysteine enantiomers in biological samples.

For years, d-amino acids were thought to have a minor function in biological processes compared to that of l-enantiomers. Recently, many studies have shown that d-amino acids are present in high concentrations in microorganisms, plants, mammals and humans and execute specific biological functions. One relevant example is that of d-cysteine, whose hydrogen sulfide-producing properties have been found to protect neurons against oxidative stress and to promote dendritic development. Herein, we introduce a chiral LCMS method for the rapid determination of cysteine enantiomers under polar ionic elution conditions (MeOH/MeCN/H2O 49/49/2 v/v/v, containing 50 mM formic acid and 50 mM ammonium formate) developed on a Chiralpak® ZWIX(+) chiral stationary phase. Cysteine enantiomers were analysed in biological samples after efficient reduction of the disulfide bond in cystine; the latter was achieved with the use of 1,4-dithio-dl-threitol as a reducing agent. A baseline resolution (RS = 2.7) was obtained, and the d-enantiomer eluted before the l-enantiomer. For the enantioselective analysis, cysteine was labelled with AccQ-Tag reagent, resulting in improved chromatographic behaviour and MS detection sensitivity. The method was validated according to the Food and Drug Administration guidelines. Good linearity was determined in the ranges of 0.05-0.50 mg/L for d-cysteine and 0.11-0.56 mg/L for l-cysteine. The repeatability and intermediate precision were found to be lower than 4.0%, with trueness ranging from 95.6 to 100.2% for both enantiomers. The LOD and LOQ values were 0.02 and 0.05 mg/L for d-cysteine and 0.04 and 0.11 mg/L for l-cysteine, respectively. The method was successfully applied to cell culture samples treated with d-cysteine.

Onion (Allium cepa L.) Skin: A Rich Resource of Biomolecules for the Sustainable Production of Colored Biofunctional Textiles.

The aqueous extract of dry onion skin waste from the 'Dorata di Parma' cultivar was tested as a new source of biomolecules for the production of colored and biofunctional wool yarns, through environmentally friendly dyeing procedures. Specific attention was paid to the antioxidant and UV protection properties of the resulting textiles. On the basis of spectrophotometric and mass spectrometry analyses, the obtained deep red-brown color was assigned to quercetin and its glycoside derivatives. The Folin⁻Ciocalteu method revealed good phenol uptakes on the wool fiber (higher than 27% for the textile after the first dyeing cycle), with respect to the original total content estimated in the water extract (78.50 ± 2.49 mg equivalent gallic acid/g onion skin). The manufactured materials showed remarkable antioxidant activity and ability to protect human skin against lipid peroxidation following UV radiation: 7.65 ± 1.43 (FRAP assay) and 13.60 (ORAC assay) mg equivalent trolox/g textile; lipid peroxidation inhibition up to 89.37%. This photoprotective and antioxidant activity were therefore ascribed to the polyphenol pool contained in the outer dried gold skins of onion. It is worth noting that citofluorimetric analysis demonstrated that the aqueous extract does not have a significative influence on cell viability, neither is capable of inducing a proapoptotic effect.

Last ten years (2008-2018) of chiral ligand-exchange chromatography in HPLC: An updated review.

Chiral ligand-exchange chromatography is one of the elective strategies for the direct enantioresolution of small chelating compounds: amino acids, diamines, amino alcohols, diols, small peptides, etc. Unlike other methods, the interaction between chiral selector and analyte enantiomers is mediated by a cation, thus producing diastereomeric ternary complexes. Two main approaches are conventionally applied in chiral ligand-exchange chromatography. The first relies upon chiral stationary phases where the chiral selector is either covalently immobilized or physically adsorbed onto suitable packing materials (coated phases). In the second approach, chiral molecules are added to the eluent, thus generating chiral eluent systems. Among the advantages of chiral ligand-exchange chromatography, the generation of UV/vis-active metal complexes, and the use of commercially available or easy-to-synthesize chiral selectors, in combination to rather inexpensive achiral columns for coated phases and chiral eluents, are noteworthy. Besides amino acids and amino alcohols, other species have proven suitable for chiral ligand-exchange chromatography applications. Recently, the use of either chiral ionic liquids or micellar liquid chromatography systems as well as the successful off-column formation of diastereomeric complexes have expanded the selectivity profiles and application fields. All of these issues are touched in the review, shedding light to the contributions appeared in the last decade.

Hydrophilic interaction liquid chromatography of aminoglycoside antibiotics with a diol-type stationary phase.

Owing to their pronounced polarity, hydrophilic interaction liquid chromatography (HILIC) can be considered as the elective choice for the LC analysis of aminoglycoside (AG) antibiotics. In the present work, a gradient program was optimized for the first time with a diol-type stationary phase and an evaporative light scattering detector (ELSD), thus allowing the almost complete separation of the nine analysed AGs: spectinomycin, dihydrostreptomycin, streptomycin A, gentamicin C1, amikacin, kanamycin A, paromomycin, apramycin and neomycin. In the optimized analysis conditions, analyte retention was found to be governed by a multimodal mechanism encompassing electrostatic, partitioning and hydrophilic interactions. However, the gradient mode of elution complicated a deep understanding of the influence of each contribution on the retention behaviour. The developed HILIC-ELSD method was applied for the analysis of commercial tablets containing neomycin co-formulated with the polypeptide antibiotic bacitracin. The method was fully validated according to the guidelines enshrined in the International Conference on Harmonization (ICH). The use of the diol-type stationary phase was well suited for implementing a successful 2D-HPLC system. Indeed, in order to cope with the absence of chemoselectivity for the couples amikacin/kanamycin and paromomycin/apramycin, a successful 2D-HPLC method was implemented with the "heart-cut" approach and the use of either heptafluorobutyric (for the former) or perfluorooctanoic acid (for the latter) as the ion-pair reagent in the second RP-LC dimension.

Targeting Wnt-driven cancers: Discovery of novel tankyrase inhibitors.

Recent years have seen substantially heightened interest in the discovery of tankyrase inhibitors (TNKSi) as new promising anticancer agents. In this framework, the aim of this review article is focused on the description of potent TNKSi also endowed with disruptor activity toward the Wnt/ß-catenin signaling pathway. Beginning with an overview of the most characterized TNKSi deriving from several drug design approaches and classifying them on the basis of the molecular interactions with the target, we discuss only those ones acting against Wnt cancer cell lines. In addition, comprehensive structure property relationships (SPR) emerging from the hit evolution processes and preclinical results are provided. We then review the most promising TNKSi hitherto reported in literature, acting in vivo models of Wnt-driven cancers. Some outlooks on current issues and future directions in this field are also discussed.

N-Decyl-S-trityl-(R)-cysteine, a new chiral selector for "green" ligand-exchange chromatography applications.

In search for new enantioselectivity profiles, the N-decyl-S-trityl-(R)-cysteine [C10-(R)-STC] was synthesized through a one-step procedure and then hydrophobically adsorbed onto an octadecylsilica surface to generate a stable chiral stationary phase for ligand-exchange chromatography (CLEC-CSP) applications. The CLEC analysis was carried out on underivatized amino acids, by using a Cu(II) sulphate (1.0mM) containing aqueous eluent system. Most of the analysed compounds (34 out of 45) were enantiodiscriminated by the C10-(R)-STC-based CSP, with resolution factor (RS) values up to 8.86. Conformationally rigid and hydrophobic ligands often experienced the largest enantioselectivity effects. A high loadability emerged from the analysis of rac-NorVal (selected as prototype test compound): up to 20mg/mL were efficiently enantioseparated with the CLEC-CSP. Two in-line hand-made cartridges filled with a strong cation-exchange resin allowed the effective catching of Cu(II) ions after the semi-preparative enantioseparation. The quantitative recovery of the rac-NorVal enantiomers was made possible by flowing through the cartridge a 5% (v) ammonia solution. The CLEC phase proved successful in the enantioselective analysis of a commercially available (S)-Leu containing tablet. Furthermore, in order to understand the molecular basis for a successful use of the C10-(R)-STC-based CLEC system, a descriptive structure-separation relationship study was performed. As a result, all compounds with a MEAN-QPlogS (a hydrophilicity descriptor) value lower than 0.373 can be most likely enantioseparated with the CLEC system under investigation. In the work, the numerous aspects complying with the principles of green chromatography are highlighted and discussed.

Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry.

Indoleamine 2,3-dioxygenase 1 (IDO1) mediates multiple immunoregulatory processes including the induction of regulatory T cell differentiation and activation, suppression of T cell immune responses and inhibition of dendritic cell function, which impair immune recognition of cancer cells and promote tumor growth. On this basis, this enzyme is widely recognized as a valuable drug target for the development of immunotherapeutic small molecules in oncology. Although medicinal chemistry has made a substantial contribution to the discovery of numerous chemical classes of potent IDO1 inhibitors in the past 20 years, only very few compounds have progressed in clinical trials. In this review, we provide an overview of the current understanding of structure-function relationships of the enzyme, and discuss structure-activity relationships of selected classes of inhibitors that have shaped the hitherto few successes of IDO1 medicinal chemistry. An outlook opinion is also given on trends in the design of next generation inhibitors of the enzyme.