An unprecedented palladium-arsenic catalytic cycle for nitriles hydration

An unprecedented palladium/arsenic-based catalytic cycle for the hydration of nitriles to the corresponding amides is here described. It occurs in exceptionally mild conditions such as neutral pH and moderate temperature (60°C). The versatility of this new catalytic cycle was tested on various nitriles from aliphatic to aromatic. Also, the effect of ring substitution with electron withdrawing and electron donating groups was investigated in the cases of aromatic nitriles, as well as the effect of potentially interferent functional groups such as hydroxy group or pyridinic nitrogen. Furthermore, a pilot study on the potential suitability of this approach for its scale-up is presented, revealing that the catalytic cycle could be potentially and quickly scaled up

Metallo therapeutics for COVID-19. Exploiting metal-based compounds for the discovery of new antiviral drugs

Introduction: The COVID-19 pandemic poses an unprecedented challenge for the rapid discovery of drugs against this life-threatening disease. Owing to the peculiar features of the metal centers that are currently used in medicinal chemistry, metallodrugs might offer an excellent opportunity to achieve this goal. Areas covered: Two main strategies for developing metal-based drugs against the SARS-CoV-2 are herein illustrated. Firstly, a few clinically approved metallodrugs could be evaluated in patients according to a ‘drug repurposing’ approach. To this respect, the gold drug auranofin seems a promising candidate, but some other clinically established metal compounds are worthy of a careful evaluation as well. On the other hand, libraries of inorganic compounds, featuring a large chemical diversity, should be screened to identify the most effective molecules. This second strategy might be assisted by a pathway-driven discovery approach arising from a preliminary knowledge of the mode of action, exploitable to inhibit the functional activities of the key viral proteins. Also, attention must be paid to selectivity and toxicity issues. Expert opinion: The medicinal inorganic chemistry community may offer a valuable contribution against COVID-19. The screening of metallodrugs’ libraries can expand the explored ‘chemical space’ and increase the chance of finding effective anti-COVID agents

Reactions of medicinal gold(III) compounds with proteins and peptides explored by electrospray ionization mass spectrometry and complementary biophysical methods

Electrospray ionization mass spectrometry (ESI MS) is a powerful investigative tool to analyze the reactions of metallodrugs with proteins and peptides and characterize the resulting adducts. Here, we have applied this type of approach to four experimental anticancer gold(III) compounds for which extensive biological and mechanistic data had previously been gathered, namely, Auoxo6, Au2phen, AuL12, and Aubipyc. These gold(III) compounds were reacted with two representative proteins, i.e., human serum albumin (HSA) and human carbonic anhydrase I (hCA I), and with the C-terminal dodecapeptide of thioredoxin reductase. ESI MS analysis allowed us to elucidate the nature of the resulting metal–protein adducts from which the main features of the occurring metallodrug–protein reactions can be inferred. In selected cases, MS data were integrated and supported by independent 1HNMR and UV–Vis absorption measurements to gain an overall description of the occurring processes. From data analysis, it emerges that most of the investigated gold(III) complexes, endowed with an appreciable oxidizing character, undergo quite facile reduction to gold(I); the resulting gold(I) species tightly associate with the above proteins/peptides with a remarkable selectivity for free cysteine residues. In contrast, in the case of the less-oxidizing Aubipyc complex, the gold(III) oxidation state is conserved, and a gold(III) fragment still containing the original ligand is found to be associated with the target proteins. It is notable that the C-terminal dodecapeptide of thioredoxin reductase containing the characteristic –Gly–Cys–Sec–Gly metal-binding motif is able in all cases to trigger gold(III)-to-gold(I) reduction. Our investigation allowed us to identify in detail the nature of the gold fragments that ultimately bind the protein targets and determine the exact binding stoichiometry; some insight on the reaction kinetics was also gained. Notably, a few clear correlations could be established between the structure of the metal complexes and the nature of the resulting protein adducts. The mechanistic implications of these findings are analyzed and thoroughly discussed. Overall, the present results set the stage to better understand the real target biomolecules of these gold compounds and elucidate at the atomic level their interaction modes with proteins and peptides

Aging and diet alter the protein ubiquitylation landscape in the mouse brain.

Post-translational modifications (PTMs) regulate protein homeostasis, but how aging impacts PTMs remains unclear. Here, we used mass spectrometry to reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the mouse aging brain. We show that aging has a major impact on protein ubiquitylation. 29% of the quantified ubiquitylation sites were affected independently of protein abundance, indicating altered PTM stoichiometry. Using iPSC-derived neurons, we estimated that 35% of ubiquitylation changes observed in the aged brain can be attributed to reduced proteasome activity. Finally, we tested whether protein ubiquitylation in the brain can be influenced by dietary intervention. We found that one cycle of dietary restriction and re-feeding modifies the brain ubiquitylome, rescuing some but exacerbating other ubiquitylation changes observed in old brains. Our findings reveal an age-dependent ubiquitylation signature modifiable by dietary intervention, providing insights into mechanisms of protein homeostasis impairment and highlighting potential biomarkers of brain aging

Advanced Technologies for Oral Controlled Release: Cyclodextrins for oral controlled release

Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug-drug or drug-additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g. as osmotic pumps) and/ or hydrophobic CDs. New controlled delivery systems based on nanotechonology carriers (nanoparticles and conjugates) have also been reviewed

On the Different Mode of Action of Au(I)/Ag(I)-NHC Bis-Anthracenyl Complexes Towards Selected Target Biomolecules

Gold and silver N-heterocyclic carbenes (NHCs) are emerging for therapeutic applications. Multiple techniques are here used to unveil the mechanistic details of the binding to different biosubstrates of bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) silver chloride [Ag(EIA)2]Cl and bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) gold chloride [Au(EIA)2]Cl. As the biosubstrates, we tested natural double-stranded DNA, synthetic RNA polynucleotides (single-poly(A), double-poly(A)poly(U) and triple-stranded poly(A)2poly(U)), DNA G-quadruplex structures (G4s), and bovine serum albumin (BSA) protein. Absorbance and fluorescence titrations, mass spectrometry together with melting and viscometry tests show significant differences in the binding features between silver and gold compounds. [Au(EIA)2]Cl covalently binds BSA. It is here evidenced that the selectivity is high: low affinity and external binding for all polynucleotides and G4s are found. Conversely, in the case of [Ag(EIA)2]Cl, the binding to BSA is weak and relies on electrostatic interactions. [Ag(EIA)2]Cl strongly/selectively interacts only with double strands by a mechanism where intercalation plays the major role, but groove binding is also operative. The absence of an interaction with triplexes indicates the major role played by the geometrical constraints to drive the binding mode

Tissue hyaluronan expression, as reflected in the sputum of lung cancer patients, is an indicator of malignancy

Hyaluronan (HA) shows promise for detecting cancerous change in pleural effusion and urine. However, there is uncertainty about the localization of HA in tumor tissue and its relationship with different histological types and other components of the extracellular matrix, such as angiogenesis. We evaluated the association between HA and degree of malignancy through expression in lung tumor tissue and sputum. Tumoral tissue had significantly increased HA compared to normal tissue. Strong HA staining intensity associated with cancer cells was significant in squamous cell carcinoma compared to adenocarcinoma and large cell carcinoma. A significant direct association was found between tumors with a high percentage of HA and MVD (microvessel density) in tumoral stroma. Similarly significant was the direct association between N1 tumors and high levels of HA in cancer cells. Cox multivariate analysis showed significant association between better survival and low HA. HA increased in sputum from lung cancer patients compared to cancer-free and healthy volunteers and a significant correlation was found between HA in sputum and HA in cancer tissue. Localization of HA in tumor tissue was related to malignancy and reflected in sputum, making this an emerging factor for an important diagnostic procedure in patients suspected to have lung cancer. Further study in additional patients in a randomized prospective trial is required to finalize these results and to validate our quantitative assessment of HA, as well as to couple it to gold standard sputum cytology.Research supported by FAPESP (2010/11005-5 and 2010/04462) and CNPq (#471939/2010-2 and 483005/2012-6

Late histological findings in symptomatic COVID-19 patients: A case report

RATIONALE: Although there have been several studies describing clinical and radiographic features about the novel coronavirus (COVID-19) infection, there is a lack of pathologic data conducted on biopsies or autopsies. PATIENT CONCERNS: A 56-year-old and a 70-year-old men with fever, cough, and respiratory fatigue were admitted to the intensive care unit and intubated for respiratory distress. DIAGNOSIS: The nasopharyngeal swab was positive for COVID-19 and the chest Computed Tomography (CT) scan showed the presence of peripheral and bilateral ground-glass opacities. INTERVENTIONS: Both patients developed pneumothoraces after intubation and was managed with chest tube. Due to persistent air leak, thoracoscopies with blebs resection and pleurectomies were performed on 23rd and 16th days from symptoms onset. OUTCOMES: The procedures were successful with no evidence of postoperative air-leak, with respiratory improvement. Pathological specimens were analyzed with evidence of diffuse alveolar septum disruption, interstitium thickness, and infiltration of inflammatory cells with diffuse endothelial dysfunction and hemorrhagic thrombosis. LESSONS: Despite well-known pulmonary damages induced by the COVID-19, the late-phase histological changes include diffused peripheral vessels endothelial hyperplasia, in toto muscular wall thickening, and intravascular hemorrhagic thrombosis