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Glioblastoma (GBM) is one of the most aggressive cancers, characterized by a decrease in antioxidant levels. Evidence has demonstrated that ferulic acid (FA), a natural antioxidant particularly abundant in vegetables and fruits, could be a promising candidate for GBM treatment. Since FA shows a high instability that compromises its therapeutic application, it has been encapsulated into Nanostructured Lipid Carriers (NLCs) to improve its bioavailability in the brain. It has been demonstrated that tissue transglutaminase (TG2) is a multi-functional protein implicated in many physiological and pathological processes, including cancer. TG2 is also involved in GBM correlated with metastasis formation and drug resistance. Therefore, the evaluation of TG2 expression levels and its cellular localization are important to assess the anti-cancer effect of FA against GBM cancer. Our results have demonstrated that treatment with free FA and FA-NLCs in the U87-MG cancer cell line differently modified TG2 localization and expression levels. In the cells treated with free FA, TG2 appeared expressed both in the cytosol and in the nucleus, while the treatment with FA-NLCs showed that the protein is exclusively localized in the cytosol, exerting its pro-apoptotic effect. Therefore, our data suggest that FA loaded in NLCs could represent a promising natural agent for supplementing the current anti-cancer drugs used for the treatment of GBM.

Schiff bases (SBs) are important ligands in coordination chemistry due to their unique structural properties. Their ability to form complexes with metal ions has been exploited for the environmental detection of emerging water contaminants. In this work, we evaluated the complexation ability of three newly proposed SBs, 1-3, by complete conformational analysis, using a combination of Molecular Dynamics and Density Functional Theory studies, to understand their ability to coordinate toxic heavy metal (HMs) ions. From this study, it emerges that all the ligands present geometries that make them suitable to complex HMs through the N-imino moieties or, in the case of 3, with the support of the oxygen atoms of the ethylene diether chain. In particular, this ligand shows the most promising coordination behavior, particularly with Pb2+.

In recent decades, the world has gained experience of the dangerous effects of pandemic events caused by emerging respiratory viruses. In particular, annual epidemics of influenza are responsible for severe illness and deaths. Even if conventional influenza vaccines represent the most effective tool for preventing virus infections, they are not completely effective in patients with severe chronic disease and immunocompromised and new small molecules have emerged to prevent and control the influenza viruses. Thus, the attention of chemists is continuously focused on the synthesis of new antiviral drugs able to interact with the different molecular targets involved in the virus replication cycle. To date, different classes of influenza viruses inhibitors able to target neuraminidase enzyme, hemagglutinin protein, Matrix-2 (M2) protein ion channel, nucleoprotein or RNA-dependent RNA polymerase have been synthesized using several synthetic strategies comprising the chemical modification of currently used drugs. The best results, in terms of inhibitory activity, are in the nanomolar range and have been obtained from the chemical modification of clinically used drugs such as Peramivir, Zanamivir, Oseltamir, Rimantadine, as well as sialylated molecules, and hydroxypyridinone derivatives. The aim of this review is to report, covering the period 2016-2022, the most recent routes related to the synthesis of effective influenza virus inhibitors.

The present review contains a representative sampling of mechanistic studies, which have appeared in the literature in the last 5 years, on 1,3-dipolar cycloaddition reactions, using DFT calculations. Attention is focused on the mechanistic insights into 1,3-dipoles of propargyl/allenyl type and allyl type such as aza-ylides, nitrile oxides and azomethyne ylides and nitrones, respectively. The important role played by various metal–chiral–ligand complexes and the use of chiral eductors in promoting the site-, regio-, diastereo- and enatioselectivity of the reaction are also outlined.

Aldaric acids are becoming valuable platform chemicals in bioeconomy and circular economy approaches. Among them, mucic acid (meso-galactaric acid) is gaining industrial attention as a bio-based precursor of adipic acid found in polyamides, and of 2,5-furan dicarboxylic acid, a valuable substitute for terephthalic acid in polyesters. A combination of detailed experimental protocols and conditions with DFT computational calculations for the synthesis of mucic acid from galactose are herein described. The product is obtained by reaction with diluted aqueous nitric acid as the oxidizing agent and the reaction medium. Optimized reaction conditions require 5 M nitric acid, 95 °C, galactose/HNO3 molar ratio 1 : 9, 100 g/L galactose concentration in the reaction medium. Computational calculations suggest that the oxidation mechanism may involve a contextual oxygen protonation and nitrate nucleophilic attack, leading to the oxidized product. The proposed mechanism requires a stoichiometry of 6 moles of nitric acid per galactose mole, albeit both experimental and computational data evidence that proton excess may be necessary to start the reaction. The reported study gives useful insights for the production of galactaric acid.

Boron containing compounds (BCCs) aroused increasing interest in the scientific community due to their wide application as drugs in various fields. In order to design new compounds hopefully endowed with pharmacological activity and also investigate their conformational behavior, the support of computational studies is crucial. Nevertheless, the suitable molecular mechanics parameterization and the force fields needed to perform these simulations are not completely available for this class of molecules. In this paper, Amber force field parameters for phenyl-, benzyl-, benzylamino-, and methylamino-boronates, a group of boron-containing compounds involved in different branches of the medicinal chemistry, were created. The robustness of the obtained data was confirmed through molecular dynamics simulations on ligand/-lactamases covalent complexes. The ligand torsional angles, populated over the trajectory frames, were confirmed by values found in the ligand geometries, located through optimizations at the DFT/B3LYP/6-31g(d) level, using water as a solvent. In summary, this study successfully provided a library of parameters, opening the possibility to perform molecular dynamics simulations of this class of boron-containing compounds.

The direct oxidation reaction of isoxazolidines plays an important role in organic chemistry, leading to the synthesis of biologically active compounds. In this paper, we report a computational mechanistic study of RuO4-catalyzed oxidation of differently N-substituted isoxazolidines 1a–c. Attention was focused on the endo/exo oxidation selectivity. For all the investigated compounds, the exo attack is preferred to the endo one, showing exo percentages growing in parallel with the stability order of transient carbocations found along the reaction pathway. The study has been supported by experimental data that nicely confirm the modeling results.

In this paper, we report a mechanistic study of RuO4-catalyzed oxidation on the 2-methylisoxazolidine through computational methods. The investigation was performed taken into consideration that the oxidation could take place on different sites of the substrate. This reaction occurs in two steps, involving a double H-transfer. In particular, the rate-determining one implies a [3 + 2] one-step, but asynchronous mechanism. In the first step, when methyl propanoate is used as solvent, the formation of an ion pair, which affords to the product, is involved. Furthermore, the study highlights that all carbon atoms of the isoxazolidine system, near to the heteroatoms, can undergo the oxidation process. The detected selectivity is correlated to the stability of the corresponding carbocations, leading to the N-methylisoxazolidin-3-one as preferred product.

Hybrid hydrogels composed of chitosan (CS) have shown great potential in bone tissue engineering and regeneration. The introduction of polyhedral oligomeric silsesquioxanes (POSS) in the biopolymeric matrix has been demonstrated to improve the rheological and biological properties of the hybrid composites. In this work, we have integrated the favourable features of chitosan (CS) and POSS nanoparticles to design new nanocomposites for bone tissue regeneration, focusing our attention on the effect of POSS concentration within the CS matrix (0.5, 1, and 1.5 equivalents in weight of POSS with respect to CS) on the chemical, physical, rheological, and in vitro biological properties of the final composites. The drug release ability of the synthesized hydrogel scaffolds were also investigated using, as the model drug, ketoprofen, that was included in the scaffold during the gelling procedure, showing a more controlled release for the hybrids with respect to CS (86–91% of drug released after two weeks). The results of the in vitro biological tests performed on human fetal osteoblastic cells (hFOB 1.19) culture demonstrated the great biocompatibility of the hybrid materials. The hybrids, at the different POSS concentrations, showed values of cell mortality superimposable with control cells (11.1 vs. 9.8%), thus revealing the CS/POSS hydrogels as possible candidates for bone tissue engineering applications.

Herein, we assess the gene expression changes activated in thyroid tumors through a computational approach, using the MapReduce algorithm. Through this predictive analysis, we identified the TfR1 gene as a critical mediator of thyroid tumor progression. Then, we investigated the effect of TfR1 gene silencing through small interfering RNA (siRNA) in the expression of extracellular signal-regulated kinase 1/2 (Erk1/2) pathway and c-Myc in human differentiated follicular and undifferentiated anaplastic thyroid cancer. The expression levels of cyclin D1, p53, and p27, proteins involved in cell cycle progression, were also evaluated. The effect of TfR1 gene silencing through siRNA on the apoptotic pathway activation was also tested. Computational prediction and in vitro studies demonstrate that TfR1 plays a key role in thyroid cancer and that its downregulation was able to inhibit the ERK pathway, reducing also c-Myc expression, which blocks the cell cycle and activates the apoptotic pathway. We demonstrate that TfR1 plays a crucial role for a rapid and transient activation of the ERK signaling pathway, which induces a deregulation of genes involved in the aberrant accumulation of intracellular free iron and in drug resistance. We also suggest that TfR1 might represent an important target for thyroid cancer therapy.

Alpine areas represent one of the richest biodiversity hotspots of Europe. They are threatened by the combining effect of climate change and land-use modifications. In this study, we used visual encounter surveys along transects to investigate occupancy and detection probability of Rana temporaria in Paneveggio-Pale di San Martino Nature Park, Trentino (IT). Multi-season occupancy models revealed that the species occurrence depended on environmental characteristics, namely distance from water and ground vegetation height, while extinction/colonization rates were determined by a combination of weather and microhabitat conditions. Moreover, occupancy and detectability values abruptly collapsed over the study period, indicating a possible population decline issue. Since no main landscape modifications or pathogens have been observed, we hypothesized that the main cause of this decline could be due to the climate. In particular, the reduction affected the juvenile subfraction of the population and we argue that, even if these drops could be considered as stochastic fluctuations, they pose a serious threat to the viability of the population.

The synthesis and reactivity in an [4+2] inverse electron demand hetero Diels-Alder reaction (ihDA) of an original class of electron-poor heterodienes, the N-substituted-1H-benzo[c][1,2]thiazin-4-one-2,2-dioxides, are described. These are highly reactive electrophiles that allow easy access to unprecedented benzo-thiazine glyco-fused derivatives in a remarkably selective way, even when using acetylated glycals, previously unexplored within this version of ihDA. DFT calculations support the experimental data, and moreover show that acetylated dienophiles can easily react making cycloadditions feasible.

Azepane–based compounds are saturated seven-membered carbocycles where one carbon atom is replaced with a nitrogen atom. The azepane structure is also found in fused-ring derivatives endowed of a wide range of pharmacological activities. The azepane motif is in the top 100 most frequently used ring systems for small molecule drugs. Several synthetic methods toward the preparation of new azepane-based compounds scaffolds have gained significant interest and represent a continuous challenge for synthetic organic chemists. The synthesis of the azepane ring is based on different synthetic approaches such as: ring-closing reactions; ring-expansion reactions of cyclic compounds; and multistep sequences. The azepane based compounds continue to play great synthetic relevance because of their different biological activities such as anti-cancer, antimicrobial, anti-Alzheimer's disease and anticonvulsant activity. New synthetic methods for the construction of azepane derivatives endowed of relevant biological activity and good pharmacological profiles is expected in near future.

Pyridine and pyrimidine derivatives have received great interest in recent pharmacological research, being effective in the treatment of various malignancies, such as myeloid leukemia, breast cancer and idiopathic pulmonary fibrosis. Most of the FDA approved drugs show a pyridine or pyrimidine core bearing different substituents. The aim of this review is to describe the most recent reports in this field, with reference to the newly discovered pyridineor pyrimidine-based drugs, to their synthesis and to the evaluation of the most biologically active derivatives. The corresponding benzo-fused heterocyclic compounds, i.e. quinolines and quinazolines, are also reported.

Heterocyclic compounds represent a significant target for anti-cancer research and drug discovery, due to their structural and chemical diversity. Oxazoles, with oxygen and nitrogen atoms present in the core structure, enable various types of interactions with different enzymes and receptors, favoring the discovery of new drugs. Aim of this review is to describe the most recent reports on the use of oxazole-based compounds in anticancer research, with reference to the newly discovered iso/oxazole-based drugs, to their synthesis and to the evaluation of the most biologically active derivatives. The corresponding dehydrogenated derivatives, i.e. iso/oxazolines and iso/oxazolidines, are also reported.

An isoxazolidine is a pentatomic heterocycle, containing adjacent nitrogen and oxygen atoms. This ring is present in many compounds, showing significant biological activity, and plays a very significant role in the preparation of nucleotide and nucleoside analogs, which are used as anticancer and antiviral agents in medicinal chemistry. This chapter summarizes the last five years of the literature on the synthesis of isoxazolidines using conventional and modern methods, with reference to the structures of the products (i.e. substituted isoxazolidines, fused isoxazolidines, spiro-isoxazolidines, nucleoside and nucleotide analogs) obtained by cycloaddition reactions. Organocatalysts have been much used in the synthesis of substituted isoxazolidines in recent years. In particular, the employment of chiral metal complexes plays an important role in improving the reactivity and providing better control of the selectivity of cycloaddition reactions. The fused isoxazolidine presents a second ring fused to the isoxazolidine moiety, making the structure rigid and conformationally restricted.

The first example of supramolecular recognition of phosphocholine by a cavitand receptor has been reported here. The chemical structure of the receptor has been optimized by DFT calculations. The recognition mechanism is based on a "multi-topic approach", which leads to highly efficient (K value up to 107 M-1), selective and sensitive (ppb level) sensing of phosphocholine. The recognition mechanism proposed here is similar to those exploited by Nature, and paves the way for the realization of new sensors with important applications in medicine and security fields.

Functionalized polyhedral oligosilsesquioxanes (POSS) containing an isoxazolidine nucleus have been synthesized by microwave assisted 1,3-dipolar cycloaddition of N-methyl-C-alkoxycarbonyl nitrone 1 with POSS containing olefin moieties. The results of cycloaddition processes were rationalized by computational studies at the DFT level. The covalent conjugation of chitosan with the cycloadduct 3a leads to composite material CS-POSS 7 which was gelified using genipin as cross linking agent. The suitability of the system for bone tissue engineering purposes was evaluated by in vitro drug release studies using ketoprofen as a model drug and cytotoxicity assays performed on human fetal osteoblastic cells. The preliminary biological tests showed the lack of cytotoxicity of the hybrid material and suggest its potential role in bone tissue engineering applications.

The ruthenium tetroxide-mediated oxidation of cyclopentane, tetrahydrofuran, tetrahydrothiophene and N-substituted pyrrolidines has been studied computationally by DFT and topological (analysis of the electron localization function, ELF) methods. In agreement with experimental observations and previous DFT calculations, the rate-limiting step of the reaction takes place through a highly asynchronous (3 + 2) concerted cycloaddition through a single transition structure (one kinetic step). The ELF analysis identifies the reaction as a typical one-step-two-stages process and corroborates the existence of a transient carbocation. In the case of pyrrolidines, the carbocation is completely stabilized as an energy minimum in the form of an iminium ion and the reaction takes place in two steps.

The thionation reaction of carbonyl compounds with Lawesson's reagent (LR) has been studied using density functional theory methods and topological analyses. After dissociation of LR, the reaction takes place through a two-step mechanism involving (i) a concerted cycloaddition between one monomer and the carbonyl compound to form a four-membered intermediate and (ii) a cycloreversion leading to the thiocarbonyl derivative and phenyl(thioxo)phosphine oxide. Topological analyses confirmed the concertedness and asynchronicity of the process. The second step is the rate-limiting one, and the whole process resembles the currently accepted mechanism for the lithium salt-free Wittig reaction. No zwitterionic intermediates are formed during the reaction, although stabilizing electrostatic interactions are present in initial stages. Phenyl(thioxo)phosphine oxide formed in the thionation reaction is capable of performing a second thionation, although with energy barriers higher than the first one. The driving force of the thionation reactions is the formation of trimers from the resulting monomers. In agreement with experimental observations, the amides are the most reactive when compared with esters, aldehydes, and ketones and the reaction is slightly influenced by the polarity of the solvent. Whereas for amides and esters substituents have little effect, aldehydes and ketones are influenced by both steric and electronic effects.

Carbohydrate mimics have been studied for a long time as useful sugar substitutes, both in the investigation of biological events and in the treatment of sugar-related diseases. Here we report further evaluation of the capabilities of inositols as carbohydrate substitutes. The conformational features of an inositol-model of a simplified repeating unit corresponding to the capsular polysaccharide of Streptococcus pneumoniae 19F has been evaluated by computational analysis, and compared to the native repeating unit. The inositol mimic was synthesized, and its experimental spectroscopic data allowed for verification of the theoretical results.

The mechanism of the thionation of alcohols with Lawesson's reagent was explored through quantum chemical DFT methods. Evidence that carbocations are involved was found. The mechanism is completely different to that established recently for the thionation of carbonyls. The presence of a phenyl ring at the alcoholic carbon atom exerts a pivotal role in the stability of the carbocation and enables a S-pi interaction, which is crucial for favoring thionation instead of undesired elimination. The influence of the solvent was also studied, and elimination is preferred in toluene, whereas substitution leading to thionation is favored in acetonitrile. A clear correlation between solvent polarity and elimination was observed. The study is in complete agreement with the different behavior observed experimentally for primary, secondary, and tertiary alcohols (bearing a phenyl ring or not), and the best conditions for minimizing undesired elimination can be predicted.