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Carlos Gavín,1 Francisco J Blanco,2 José L Pablos,3 Miguel A Caracuel,4 José Rosas,5 Enrique Gómez-Barrena,6 Francisco Navarro,7 María Pilar Coronel,8 Mercedes Gimeno8 1Hospital Universitario Fundación Alcorcón, Madrid, Spain; 2Complejo Hospitalario Universitario aCoruña, La Coruña, Spain; 3Hospital Universitario 12 de Octubre, Madrid, Spain; 4Hospital Universitario Reina Sofía, Córdoba, Spain; 5Hospital Marina Baixa, Villajoyosa, Alicante, Spain; 6Hospital Universitario La Paz, Madrid, Spain; 7Hospital General Universitario de Elche, Alicante, Spain; 8Meiji Pharma Spain, Alcalá de Henares, Madrid, SpainCorrespondence: Mercedes GimenoClinical Development Department, Meiji Pharma Spain, Av Madrid 28802, Alcalá de Henares, Madrid, SpainTel +34 918 870 980Email m.gimeno@meiji.esPurpose: To assess the efficacy and safety of a single injection of a new formulation of hyaluronic acid (MPS-HA2%) in patients with symptomatic knee osteoarthritis after 12 months’ follow-up.Patients and Methods: Prospective, single-arm, multicentre, open-label, 12-month follow-up study. Patients with Kellgren–Lawrence (KL) 2– 3 and visual analogue scale (VAS) pain scores of ≥ 40–< 80 mm received a single injection of MPS-HA2%. The primary outcome was the reduction in VAS pain scores from baseline, and the secondary outcomes were the Western Ontario and McMaster (WOMAC) Universities Osteoarthritis Index, the minimum clinically important improvement (MCII), and patient and investigator global assessments (PGA, IGA) measured on 5-point Likert scale. Adverse events were recorded throughout the study for safety purposes.Results: A total of 101 patients (mean age: 68 years; 74% female; and 78% overweight) were included. The mean reduction in pain at 12 months was 37.7%; the total WOMAC score improved by 36.5% and the pain, stiffness and physical function subscores returned improvements of 32.1%, 34.1% and 32.7%, respectively (p=0.0001 with respect to baseline). At 12 months, a statistically significant 62.2% of patients obtained an improvement equal to or greater than the MCII. The mean PGA score at baseline was 2.44 and 1.46 at 12 months (p< 0.05), and the mean IGA scores at equivalent timepoints were 2.29 and 1.48 (p< 0.05). Fourteen patients received a second injection at the 6-month follow-up visit. Eight patients reported a total of 12 treatment-related adverse events that were local, non-serious and of mild-to-moderate intensity.Conclusion: With just a single intra-articular injection, this not controlled trial suggests that MPS-HA2% is effective 12 months after the procedure in most cases. Patient tolerability and safety were both optimal (NCT03852914).Keywords: osteoarthritis, pain, hyaluronic acid, viscosupplementation

J Lasierra-Cirujeda,1 P Coronel,2 MJ Aza,3 M Gimeno2 1CM Hematológico SC, Logroño, La Rioja, Spain; 2Tedec-Meiji Farma, SA, Alcalá de Henares, Madrid, Spain; 3Pharmaceutical Act, Ministry of Health, Regional Government, La Rioja, Spain Abstract: In this review, we hypothesized the importance of the interaction between the brain glutathione (GSH) system, the proteolytic tissue plasminogen activator (t-PA)/plasminogen/plasmin system, regulated by plasminogen activator inhibitor (PAI-1), and neuroserpin in the pathogenesis of Alzheimer's disease. The histopathological characteristic hallmark that gives personality to the diagnosis of Alzheimer's disease is the accumulation of neurofibroid tangles located intracellularly in the brain, such as the protein tau and extracellular senile plaques made primarily of amyloidal substance. These formations of complex etiology are intimately related to GSH, brain protective antioxidants, and the proteolytic system, in which t-PA plays a key role. There is scientific evidence that suggests a relationship between aging, a number of neurodegenerative disorders, and the excessive production of reactive oxygen species and accompanying decreased brain proteolysis. The plasminogen system in the brain is an essential proteolytic mechanism that effectively degrades amyloid peptides ("beta-amyloidolysis") through action of the plasmin, and this physiologic process may be considered to be a means of prevention of neurodegenerative disorders. In parallel to the decrease in GSH levels seen in aging, there is also a decrease in plasmin brain activity and a progressive decrease of t-PA activity, caused by a decrease in the expression of the t-PA together with an increase of the PAI-1 levels, which rise to an increment in the production of amyloid peptides and a lesser clearance of them. Better knowledge of the GSH mechanism and cerebral proteolysis will allow us to hypothesize about therapeutic practices. Keywords: glutathione, Alzheimer's disease, t-PA, PAI-1, plasminogen

This study introduces a sustainable and pioneering cascade synthesis of 1,3‐thiazolidine derivatives under eco‐friendly conditions. The methodology transcends traditional approaches yielding complex novel compounds with unique N,S‐heterocyclic structures. By operating at room temperature, utilizing green solvents, and minimizing excess of reactants, this procedure offers an innovative pathway for sustainable chemical development. Notably, this method not only prioritizes sustainability but also delivers high‐purity products with exceptional yields. The simplicity of the process, requiring only a simple filtration and featuring short reaction times, underscores its efficiency and utility. [ABSTRACT FROM AUTHOR]

Five heterobimetallic ReI/AuI and a tri‐metallic ReI/AuI/ReI species following the formulas fac‐[ReCl (CO)3(N^N^CAuR)]0/+ and [(fac‐[ReCl (CO)3(N^N^C)])2Au]+, where R is an iodide (1), phenylacetylene (2), dodecanethiol (3), 2,3,4,6‐tetra‐O‐acetyl‐1‐thio‐β‐D‐glucopyranose (4) and JohnPhos (5) and N^N^C is the fused imidazo[4,5‐f]‐1,10‐phenanthroline heterotopic ligand, were synthesised and fully characterised by a variety of spectroscopic and analytical techniques. The resultant complexes are luminescent in the orange region, revealing classical metal‐to‐ligand charge transfer (3MLCT) ((Re (dπ) → (N^N^C)(π*)) emission in aerated DMSO solution. The red shifted emission observed on going from 3 to 4 suggests that the electronic properties of the gold ancillary ligand are implicated in the emissive properties. Antiproliferative activity in tumour cell lines, lung (A549) and cervix (HeLa) cells revealed that only complex 4 containing a 2,3,4,6‐tetra‐O‐acetyl‐1‐thio‐β‐D‐glucopyranose as gold ancillary ligand possesses certain cytotoxicity in both cell lines. [ABSTRACT FROM AUTHOR]

Another class of gold(I) redox‐switchable catalysts, incorporating ferrocenyl phosphane‐imines, enriches the existing library of gold(I) complexes. Our catalyst proves efficacy in gold(I)‐catalyzed cyclizations of furans and benzamides, exhibiting reversible "on‐off" switching. Furthermore, we explored the unconventional role of "Magic Blue", commonly used as an oxidizing agent in various organic transformations, as a potential activator of the Au−Cl bond, initiating conventional gold(I) catalysis. [ABSTRACT FROM AUTHOR]

Gold catalysis has emerged as a groundbreaking field in synthetic chemistry, revolutionizing numerous organic transformations. Despite the significant achieved advancements, the mechanistic understanding behind many gold‐catalyzed reactions remains elusive. This Concept article covers the so‐called "self‐activating" Au(I) complexes, sorting out their pivotal role in gold catalysis. We comment on how Au(I) complexes can undergo self‐activation, triggering diverse catalytic transformations without the need for external additives. The most important examples reported so far that underlie the catalytic activity of these species are discussed. This intrinsic reactivity represents a paradigm shift in gold catalysis, offering new avenues for the design of efficient and sustainable catalytic systems. Furthermore, we explore the factors influencing the stability, reactivity, and selectivity of these Au(I) complexes, providing insights into their synthetic utility and potential applications. This area of research not only advances our fundamental understanding of gold catalysis but also paves the way for the development of novel catalytic strategies with broad implications in organic synthesis and the chemical industry. [ABSTRACT FROM AUTHOR]

This work presents the synthesis and characterization of mono‐ (1) and di‐nuclear (2) imidazolium salts stabilized by [AuPPh3]+ fragments. The presence of the gold moiety induces a significant decrease in the carbenic proton's acidic character (high pKa). This high stability is consistent with the pronounced instability of the conjugate bases obtained through deprotonation using strong bases. The formation of carbene species is accompanied by the identification of a 1,2‐rearrangement process in which a preference for the C‐bound species over the N‐bound species is observed. Experimental techniques such as NMR, single‐crystal X‐ray diffraction analysis, mass spectrometry, and computational calculations are employed to investigate the reactivity exhibited by the imidazolium salts. Additionally, the electrochemical properties of the two imidazolium salts were also investigated. This study reveals that both species 1 and 2 display two cathodic peaks which are related to two electro‐chemical irreversible reduction events. The results obtained from both experimental and theoretical studies of this system reveal a strong tendency of the [AuPPh3]+ fragment to stabilize imidazolium salts. Additionally, they demonstrate the preference of this fragment for C‐bound species over N‐bound ones, with the former proving to be highly unstable even under severe conditions of air and moisture exclusion. [ABSTRACT FROM AUTHOR]

The combination of the ferrocene moiety with gold(I) catalysis remains a relatively unexplored field. In this article, we delve into the synthesis, characterization, and potential catalytic activity of four complexes utilizing both monodentate and bidentate ferrocenyl diphenylphosphane ligands (ppf and dppf), coordinated with two gold(I) metal centers, linked by either chloride or pentafluorophenylthiolate bridging ligands. This leads to the formation of cationic "self‐activated" precatalysts capable of initiating the catalytic cycle without the need for external additives. The catalytic activity of these complexes was assessed through a model reaction in gold(I) catalysis, specifically the cyclization of a N‐propargylbenzamide to produce an oxazole. In addition, we studied and compared the influence exerted by both the phosphane and the bridging ligand on the performance of these catalysts. [ABSTRACT FROM AUTHOR]

Twelve (N^N^N)platinum pyridyl complexes, (N^N^N)Pt(pyF), were synthesised and investigated for their singlet oxygen generation and potential biological activities. They exhibited 1IL and 1MLCT absorption transitions at approximately 325 and 360 nm, identified through TD-DFT calculations. Luminescence was observed only in the L1-derived compounds in solution, with a dual emission with the main contribution of phosphorescence under deaerated conditions. Room temperature phosphorescence was detected in all solid-state cases. Electron-withdrawing substituents at specific positions (R1 and X) and the number of fluorine atoms in R2 were found to enhance the photosensitizing capabilities of these compounds. Biological assessments, including cytotoxicity and photocytotoxicity, were conducted to evaluate their potential as chemotherapeutic agents and photosensitizers. Complexes with chloro substitution in the N^N^N tridentate ligand of the central pyridine ring exhibited promising chemotherapeutic properties. Ancillary pyridine ring substitution became significant under irradiation conditions, with fluoromethylated substituents enhancing cytotoxicity. Complex 2-CF3 was the most efficient singlet oxygen producer and a highly effective photosensitizer. CHF2-substituted complexes also showed improved photosensitizing activity. DNA binding studies indicated moderate interactions with DNA, offering insights into potential biological applications. [ABSTRACT FROM AUTHOR]

Gold(II) complexes, unlike their gold(I) and gold(III) counterparts, have been sparsely employed in the field of catalysis. This is primarily due to the challenges associated with isolating and characterising these open-shell species. However, these complexes offer a wide range of possibilities. On one hand, this intermediate oxidation state has proven to be more easily accessible through reduction and oxidation processes compared to the gold(I)/gold(III) redox couple, thereby facilitating potential homo-coupling and cross-coupling reactions. On the other hand, gold(II) exhibits Lewis acid behaviour, bridging the characteristics of the soft acid gold(I) and the hard acid gold(III). In this review, we focus on mono- and dinuclear gold(II) complexes, whether they are isolated and well-studied or proposed as intermediates in cross-coupling reactions induced by the action of oxidants or light. We delve into the unique reactivity and potential applications of these gold(II) species, shedding light on their role in this field. This comprehensive exploration aims to underscore the latent promise of gold(II) complexes in catalysis, offering insights into their structural and mechanistic aspects while highlighting their relevance in contemporary chemical transformations. [ABSTRACT FROM AUTHOR]

A 2‐year‐old Standardbred gelding was referred for a mass on the palmaromedial right front pastern which was accompanied by progressively worsening lameness. The mass was firm to palpation and covered by normal skin. Ultrasonographically, a smooth encapsulated mass was present, medial to the flexor tendons and palmar to the neurovascular bundle. Because of a poor prognosis for future athletic performance without surgical or chemotherapeutic intervention and economic constraints preventing further diagnostics and treatment, the horse was euthanised. Post‐mortem magnetic resonance imaging, histopathology and immunohistochemistry revealed the mass to be a perivascular wall tumour, the first record of such a neoplasia in the horse. [ABSTRACT FROM AUTHOR]

The potential of phosphites as nucleophiles for the asymmetric synthesis of chiral chromene derivatives has been overlooked in the literature. Herein, we report a promising approach via asymmetric organocatalyzed phospha‐Michael addition to iminochromenes, using a bifunctional squaramide, which gives access to chromenylphosphonates, an interesting family of bioactive compounds. Our optimized protocol provides very good reactivity, affording yields of up to 95% and with chiral products exhibiting an enantiomeric excess of up to 98%. [ABSTRACT FROM AUTHOR]

A novel approach for the allylic alkylation of anilines, hydrazides, indole derivatives and additional interesting nucleophiles is described, which involves the direct use of a variety of allylic alcohols under very mild conditions, such as room temperature, and the use of sustainable deep eutectic solvents (DESs). The search for the optimum DES to be used in the reaction revealed that a simple mixture of choline chloride (ChCl) and lactic acid provides excellent results for a wide range of substrates with high isolated yields. This methodology represents a significant improvement compared to other procedures described in the literature, for which high temperatures, stronger reaction conditions or metal catalysts are usually required. In some cases, this protocol provides the first examples of trapping allylic carbocations with indole derivatives. In addition, challenging nucleophiles such as amides, carbamates, azides or sulfonamides, among others, have also been successfully used. All these features render this procedure an appealing and green alternative compared to other examples reported in the literature on the alkylation of amines by allylic alcohols. Preliminary mechanistic studies using unsymmetrically substituted alcohols support that the reaction could proceed via an SN1 pathway. [ABSTRACT FROM AUTHOR]

Objective: Oropharyngeal dysphagia is caused by difficulty in bolus preparation and transport from the mouth to the oesophagus; this may result in malnutrition and aspiration pneumonia. It has a high prevalence in head and neck cancer patients. The objective of this study is to reduce these complications using a new protocol of diagnosis and evaluation of oropharyngeal dysphagia. Method: This is a prospective study developed in a secondary hospital. All patients diagnosed with head and neck cancer in 2021 and 2022 are subjected to this protocol: an oropharyngeal dysphagia screening test, a swallowing-related quality of life questionnaire and a flexible endoscopic evaluation of swallow. Results: A total of 72 evaluations are reported using this protocol, before and after cancer treatment, and only 1 presents with aspiration pneumonia. Conclusion: Using this protocol, the incidence of aspiration pneumonia can be reduced, and diet recommendations can be given earlier in order to maintain a patient's nutritional requirements. [ABSTRACT FROM AUTHOR]

An enantioselective C−P bond formation has been developed through a C(sp3)−H activation in an oxidation step followed by an organocatalyzed hydrophosphonylation protocol. The asymmetric organocatalytic Pudovik reaction has been achieved following a one‐pot strategy, starting from different benzylic and allylic alcohols and dibenzyl phosphite, using MnO2 as the oxidant and a chiral squaramide as organocatalyst. The scope of the reaction provides enantiomerically enriched α‐hydroxy phosphonates with yields from 40% to >95% and enantioselectivities from 64% to >99%. Furthermore, the use of this methodology has been demonstrated to form a tetrasubstituted carbon stereocenter, generating an acetophenone derivative in situ, using diphenyl phosphite. Therefore, this approach represents an asymmetric strategy for constructing chiral C−P bonds, which are of interest to the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Silver complexes bearing substituted terpyridine or tetra‐2‐pyridinylpyrazine ligands have been prepared and structurally characterised. The study of the anticancer properties of silver complexes with this type of ligands is scarce, despite the possibilities of combining the properties of the metal and the ability of the ligands for DNA binding. Here, the antiproliferative activity, stability, CT‐DNA binding, and mechanism of cell death of these types of derivatives are studied. High cytotoxicity against different tumour cells was observed, and, more important, a great selectivity index has been detected between tumour cells and healthy lymphocytes T for some of these compounds. The CT‐DNA interaction study has shown that these derivatives are able to interact with CT‐DNA by moderate intercalation. Furthermore, cell death studies indicate that these derivatives promote the apoptosis by a mitochondrial pathway. [ABSTRACT FROM AUTHOR]

The reaction of propargylamines with isothiocyanates results in the selective formation of iminothiazolidines, aminothiazolines or mixed thiazolidine–thiourea compounds under mild conditions. It has been observed that secondary propargylamines lead to the selective formation of cyclic 2-amino-2-thiazoline derivatives, while primary propargylamines form iminothiazoline species. In addition, these cyclic thiazoline derivatives can further react with an excess of isothiocyanate to give rise to thiazolidine–thiourea compounds. These species can also be achieved by reaction of propargylamines with isothiocynates in a molar ratio of 1 : 2. Coordination studies of these heterocyclic species towards silver and gold with different stoichiometries have been carried out and complexes of the type [ML(PPh3)]OTf, [ML2]OTf (M = Ag, Au) or [Au(C6F5)L] have been synthesised. Preliminary studies of the cytotoxic activity in lung cancer cells have also been performed in both ligands and complexes, showing that although the ligands do not exhibit anticancer activity, their coordination to metals, especially silver, greatly enhances the cytotoxic activity. [ABSTRACT FROM AUTHOR]

A series of neutral acridine-based gold(III)-NHC complexes containing the pentafluorophenyl (–C6F5) group were synthesized. All of the complexes were fully characterized by analytical techniques. The square planar geometry around the gold center was confirmed by X-ray diffraction analysis for complexes 1 (Trichloro [1-methyl-3-(9-acridine)imidazol-2-ylidene]gold(III)) and 2 (Chloro-bis(pentafluorophenyl)[1-methyl-3-(9-acridine)imidazol-2-ylidene]gold(III)). In both cases, the acridine rings play a key role in the crystal packing of the solid structures by mean of π–π stacking interactions, with centroid–centroid and interplanar distances being similar to those found in other previously reported acridine-based Au(I)-NHC complexes. A different reactivity when using a bulkier N-heterocyclic carbene ligand such as 1,3-bis-(2,6-diisopropylphenyl)-2-imidazolidinylidene (SIPr) was observed. While the use of the acridine-based NHC ligand led to the expected organometallic gold(III) species, the steric hindrance of the bulky SIPr ligand led to the formation of the corresponding imidazolinium cation stabilized by the tetrakis(pentafluorophenyl)aurate(III) [Au(C6F5)4]− anion. Computational experiments were carried out in order to figure out the ground state electronic structure and the binding formation energy of the complexes and, therefore, to explain the observed reactivity. [ABSTRACT FROM AUTHOR]

The front cover of the journal "Advanced Synthesis & Catalysis" features an illustration of the "Magic Blue" molecule and its role in gold(I) redox switchable catalysis. The image depicts a wizard in a forest, conjuring two gold complexes in a cauldron filled with "Magic Blue". The compounds react differently depending on the catalyst used, either through chloride abstraction or one-electron oxidation. The illustration showcases the dynamic nature of the "Magic Blue" oxidant. For more information, refer to the research article by Pérez‐Sánchez, Herrera, and Gimeno in the same journal. [Extracted from the article]