Towards Green Reductions in Bio-Derived Solvents

The hydrogenation processes, and all the reactions that formally add two hydrogen atoms to an unsaturated bond, are among the most used transformations in the manufacture of bulk and fine chemicals. Although their potential as powerful tool for the sustainable synthesis of organic compounds, hydrogenations, and more generally the reductions, have been typically carried out in volatile organic solvents deriving from petroleum; indeed, all studies and fascinating advances related to the catalysts’ activity or the reducing agents’ reactivity have been limited to such volatile and often toxic reaction media. In this review, recent advances in the reducing methodologies with an improved degree of sustainability have been described. In particular, a series of examples have been reported to highlight the chance to reduce an organic compound by using a benign solvent deriving from renewable sources, without waiving to the process efficiency and selectivity. Some important key points of green chemistry, such as the easiness of catalyst recovery or the simplicity of product isolation, have been considered in the choice of the described studies

Pd-catalyzed Reductions in Deep Eutectic Solvents by Using Aluminum and Water as Hydrogen Source

The reduction of organic functional groups, using metal-catalyzed hydrogenations, is one of the most employed strategy in organic chemistry for the synthesis of both fine and bulk chemicals.[1] Hydrogen is an explosive gas and its production needs extensive energy and generates a considerable amount of carbon dioxide. Therefore, the development of cost-effective reduction methods that use safe reagents, environmentally-friendly solvents and prevent or minimize waste formation represents a challenge of great interest in sustainable chemistry. As part of our ongoing efforts in the discovery of sustainable synthetic methodologies,[2] an alternative and safe palladium-catalyzed hydrogenation reaction in Deep Eutectic Solvents (DESs) is here described.[3] The use of aluminum powder in combination with water and a base in DESs, results in an environmentally-responsible system for the controlled in-situ generation of hydrogen. Our optimized protocol is effective for the reduction of a wide range of functional groups, containing C–C, C–N, C–O, N–O multiple bonds as well as for the dearomatization of (hetero)aromatic compounds, and leads to the desired products in yield up-to 99%. The simplicity, cost, tunability, scalability and the environmentally benign character of both catalytic system and DESs, offer numerous advantages over the currently available methods that employ external and dangerous H2 source and harsh, volatile organic solvents

A Glycerol-Based Deep Eutectic Solvent as Natural Medium and Organic Reductant for Homocoupling of (Hetero)Aryl Chlorides: a Green Route to 2,2’-Bipyridine and Biaryl Scaffolds

A glycerol-based Deep Eutectic Solvent (DES) enables the Pd-catalyzed activation of (hetero)arylchlorides and promotes the formation of 2,2’-bipiyridines and biaryls through an Ullmann-type homocoupling in smooth experimental conditions (80 °C) with Ca(OH)2 as a green base and Pd/C as heterogeneous catalyst. Noteworthy, the coupling does not need the addition of external reducing agents, like metals, since the glycerol present in the DES acts as a safe and green organic reductant. The heterogeneous catalytic system (DES-Pd/C) showed to be easily recyclable and has been applied to the sustainable synthesis of the Abametapir drug

Gas-Free Amino- and Alkoxycarbonylation of Aryl Iodides in a Bioinspired Deep Eutectic Solvent with Mo(CO)6 as a Safe CO Source

The Pd-catalyzed amino- and alkoxycarbonylation of aryl iodides has been exploited, for the first time, in a bioinspired Deep Eutectic Solvent and under gas-free conditions, by using Mo(CO)6 as the CO source. The method allows for the preparation of carboxylic amides and esters in high yields (up to 99%), short reaction time (2 h) and under mild reaction conditions (80 °C), with a low catalyst loading (2.5 mol%). Noteworthy, in the case of N-hexylbenzamide, it has been demonstrated that both the catalyst and DES can be used for four consecutive runs, with a moderate decrease of catalytic efficiency. The methodology has been also applied to the preparation of an Active Pharmaceutical Ingredient used for the treatment of human scabies and lice

Design, stereoselective synthesis, configurational stability and biological activity of 7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide

Chiral 5-arylbenzothiadiazine derivatives have recently attracted particular attention because they exhibit an interesting pharmacological activity as AMPA receptor (AMPAr) positive modulators. However, investigations on their configurational stability suggest a rapid enantiomerization in physiological conditions. In order to enhance configurational stability, preserving AMPAr activity, we have designed the novel compound (R,S)-7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide bearing a pyrrolo moiety coupled with the 5-(furan-3-yl) substituent on benzothiadiazine core. A stereoselective synthesis was projected to obtain single enantiomer of the latter compound. Absolute configuration was assigned by X-ray crystal structure. Patch clamp experiments evaluating the activity of single enantiomers as AMPAr positive allosteric modulator showed that R stereoisomer is the active component. Molecular modeling studies were performed to explain biological results. An on-column stopped-flow bidimensional recycling HPLC procedure was applied to obtain on a large scale the active enantiomer with enantiomeric enrichment starting from the racemic mixture of the compound

Cardiovascular risk factors, anxiety symptoms and inflammation markers: Evidence of association from a cross-sectional study

Introduction Anxiety disorders and Cardiovascular (CV) diseases, among the most common disorders in Western World, are often comorbid. A chronic systemic inflammatory state might be a shared underlining pathophysiological mechanism. Aims To investigate the association between anxiety symptoms, CV risks factors and inflammatory markers in an outpatient sample. Methods Cross-sectional study. Inclusion criteria: outpatients aged ≥40 years, attending colonoscopy after positive faecal occult blood test, negative medical history for cancer. Collected data: blood pressure, glycaemia, lipid profile, waist circumference, BMI, PCR (C Reactive Protein), LPS (bacterial Lipopolysaccharide). Psychometric tests: HADS, TCI, IMSA, SF36. Statistical analysis performed with STATA13. Results Fifty four patients enrolled (27 males, 27 females). Sixteen patients (30.19%) were positive for anxiety symptoms. Thirty-three patients (61.11%) had hypertension, 14 (25.93%) hyperglycaemia and 64.81% were overweight, with frank obesity (BMI≥ 30) in 11 subjects (20.37%). Anxiety symptoms were associated with low hematic HDL values (OR = 0.01; P = 0.01) and high concentration of triglycerides (OR = 0.023; P = 0.02) at the multiple regression model. At the univariate logistic analysis, anxiety was associated with LPS (OR = 1.06; P = 0.04). Conclusions Further evidence over the epidemiological link between common mental disorders and CV diseases was collected, with possible hints on pathophysiology and causative mechanisms related to inflammation. The importance of screening for anxiety and depression in medical populations is confirmed. Suggestions on future availability of screening tools based on inflammatory-related indicators should be the focus of future research

A functional gene expression analysis in epithelial sinonasal cancer: Biology and clinical relevance behind three histological subtypes

Epithelial sinonasal cancers (SNCs) are rare diseases with overlapping morphological features and a dismal prognosis. We aimed to investigate the expression differences among the histological subtypes for discerning their molecular characteristics. We selected 47 SNCs: (i) 21 nonkeratinizing squamous cell carcinomas (NKSCCs), (ii) 13 sinonasal neuroendocrine cancers (SNECs), and (iii) 13 sinonasal undifferentiated cancers (SNUCs). Gene expression profiling was performed by DASL (cDNA-mediated annealing, selection, extension, and ligation) microarray analysis with internal validation by quantitative RT-PCR (RT-qPCR). Relevant molecular patterns were uncovered by sparse partial-least squares discriminant analysis (sPLS-DA), microenvironment cell type (xCell), CIBERSORT, and gene set enrichment (GSEA) analyses. The first two sPLS-DA components stratified samples by histological subtypes. xCell highlighted increased expression of immune components (CD8 + effector memory cells, in SNUC) and \u201cother cells\u201d: keratinocytes and neurons in NKSCC and SNEC, respectively. Pathway enrichment was observed in NKSCC (six gene sets, proliferation related), SNEC (one gene set, pancreatic \u3b2-cells), and SNUC (twenty gene sets, some of them immune-system related). Major neuroendocrine involvement was observed in all the SNEC samples. Our high-throughput analysis revealed a good diagnostic ability to differentiate NKSCC, SNEC, and SNUC, but indicated that the neuroendocrine pathway, typical and pathognomonic of SNEC is also present at lower expression levels in the other two histological subtypes. The different and specific profiles may be exploited for elucidating their biology and could help to identify prognostic and therapeutic opportunities

Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer-V-shoRT-R3 (Valproic acid--short Radiotherapy--rectum 3rd trial).

BACKGROUND: Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target. METHODS/DESIGN: Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power.Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT. DISCUSSION: This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.EudraCT Number: 2012-002831-28. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01898104