Cyclic carbamates based on (R)-(+)-limonene oxide for ring-opening polymerization.

A novel synthetic pathway for synthesizing isocyanate-free polyurethanes is reported here. ß-Amino alcohols were efficiently synthesized from the aminolysis of the epoxide ring of (R)-(+)-limonene oxide with different primary amines as nucleophiles and hot water as catalysts. The regio- and diastereoselectivities of the reactions were investigated and supported by computational studies. DFT calculations were performed to understand the experimental results more deeply. It confirmed the crucial roles of water molecules and the nature of the nucleophile in forming the products. The formation of the product is entirely driven by the free energy of activation that affects the reaction rate. Cyclic carbamates were prepared from ß-amino alcohols using the dialkyl carbonate (DAC) chemistry. An oligourethane was obtained from Anionic Ring-Opening Polymerization (AROP) of a cyclic carbamate derived from (R)-(+)-limonene-oxide. All the products were characterized by employing 1H and 13C NMR spectroscopies. The assignments of the signals in 1H and 13C NMR spectra were also supported by 2D NMR spectroscopy.

Developing Advanced Antibacterial Alginic Acid Biomaterials through Dual Functionalization.

This paper delves into the intersection of biomaterials and antibacterial agents, highlighting the importance of alginic acid-based biomaterials. We investigate enhancing antibacterial properties by functionalizing alginic acid with an ionic liquid and a potent chelating agent, tris(hydroxypyridinone) (THP). Initial functionalization with the ionic liquid markedly improves the material's antibacterial efficacy. Subsequent functionalization with THP further enhances this activity, reducing the minimum inhibitory concentration from 6 to 3 mg/mL. Notably, the newly developed dual-functionalized materials exhibit no cytotoxic effects at the concentrations tested, underscoring their potential for safe and effective antibacterial applications. These findings highlight the promising role of dual-functionalized alginic acid biomaterials in developing advanced antibacterial treatments.

Nature-inspired innovation: Alginic-kojic acid material for sustainable antibacterial and carbon dioxide fixation.

The current environmental consciousness of the world's population encourages researchers to work on new materials that are environmentally benign and able to display the appropriate features for the needed application. To develop high-performing, inexpensive eco-materials, scientists have frequently turned to nature, attempting to mimic its processes' excellent performance at a reasonable price. In this regard, we decided to focus on alginic acid (AA), a polysaccharide widely found in brown algae, and kojic acid (KA), a chelating agent fungi produces. This study proposes rapidly synthesizing a sustainable, biocompatible material (AK) based on AA and KA, employing chlorokojic acid (CKA). The material has a dual function: antibacterial activity on both Gram-positive and Gram-negative bacteria, without any cytotoxic action on human cells in vitro, and catalytic ability to convert CO2 into cyclic carbonates at atmospheric pressure, without solvents, with high yields, and without the use of metals. Furthermore, the material's insolubility in organic solvents allows it to be easily separated from the reaction product and reused for other catalytic cycles. Both applications have a key role in the medical and environmental fields, combating the outbreak of infections and providing an innovative methodology to fix the CO2 on specific substrates.

THP as a sensor for the electrochemical detection of H2O2.

Hydrogen peroxide (H2O2) detection is paramount in biological and clinical domains due to its pivotal role in various physiological and pathological processes. This molecule is a crucial metabolite and effector in cellular redox mechanisms, influencing diverse cellular signaling pathways and bolstering the body's defense mechanisms against infection and oxidative stress. Organic molecule-based electrodes present unique advantages such as operational versatility and scalability, rendering them attractive candidates for sensor development across diverse fields encompassing food safety, healthcare, and environmental monitoring. This study explores the electrochemical properties of a tris(3-hydroxypyridin-4-one) THP, which has been unexplored in electrochemical sensing. Leveraging THP's chelating properties, we aimed to develop an electrochemical probe for hydrogen peroxide detection. Our investigations reveal promising results, with the developed sensor exhibiting a low limit of detection (LOD) of 144 nM, underscoring its potential utility in sensitive and selective H2O2 detection applications. In addition, the new sensor was also tested on fetal bovine serum (FBS) to emphasize future applications on biological matrices. This research signifies a significant stride in advancing electrochemical sensor technologies for hydrogen peroxide detection with several novelties related to the usage of THP, such as high sensitivity and selectivity, performance in biological matrices, repeatability, stability, and reproducibility, economical and practical advantages. This research opens new avenues for enhanced biomedical diagnostics and therapeutic interventions.

Tetrazine-trans-cyclooctene ligation: Unveiling the chemistry and applications within the human body.

Bioorthogonal reactions have revolutionized chemical biology by enabling selective chemical transformations within living organisms and cells. This review comprehensively explores bioorthogonal chemistry, emphasizing inverse-electron-demand Diels-Alder (IEDDA) reactions between tetrazines and strained dienophiles and their crucial role in chemical biology and various applications within the human body. This highly reactive and selective reaction finds diverse applications, including cleaving antibody-drug conjugates, prodrugs, proteins, peptide antigens, and enzyme substrates. The versatility extends to hydrogel chemistry, which is crucial for biomedical applications, yet it faces challenges in achieving precise cellularization. In situ activation of cytotoxic compounds from injectable biopolymer belongs to the click-activated protodrugs against cancer (CAPAC) platform, an innovative approach to tumor-targeted prodrug delivery and activation. The CAPAC platform, relying on click chemistry between trans-cyclooctene (TCO) and tetrazine-modified biopolymers, exhibits modularity across diverse tumor characteristics, presenting a promising approach in anticancer therapeutics. The review highlights the importance of bioorthogonal reactions in developing radiopharmaceuticals for positron emission tomography (PET) imaging and theranostics, offering a promising avenue for diverse therapeutic applications.

CYP7B1 as a Biomarker for Prostate Cancer Risk and Progression: Metabolic and Oncogenic Signatures (Diagnostic Immunohistochemistry Analysis by Tissue Microarray in Prostate Cancer Patients-Diamond Study).

We aimed to analyze the association between CYP7B1 and prostate cancer, along with its association with proteins involved in cancer and metabolic processes. A retrospective analysis was performed on 390 patients with prostate cancer (PC) or benign prostatic hyperplasia (BPH). We investigated the interactions between CYP7B1 expression and proteins associated with PC and metabolic processes, followed by an analysis of the risk of biochemical recurrence based on CYP7B1 expression. Of the 139 patients with elevated CYP7B1 expression, 92.8% had prostate cancer. Overall, no increased risk of biochemical recurrence was associated with CYP7B1 expression. However, in a non-diabetic subgroup analysis, higher CYP7B1 expression indicated a higher risk of biochemical recurrence, with an HR of 1.78 (CI: 1.0-3.2, p = 0.05). PC is associated with elevated CYP7B1 expression. In a subgroup analysis of non-diabetic patients, elevated CYP7B1 expression was associated with an increased risk of biochemical recurrence, suggesting increased cancer aggressiveness.

Synthesis, Characterisation, and In Vitro Evaluation of Biocompatibility, Antibacterial and Antitumor Activity of Imidazolium Ionic Liquids.

In recent decades, ionic liquids (ILs) have garnered research interest for their noteworthy properties, such as thermal stability, low or no flammability, and negligible vapour pressure. Moreover, their tunability offers limitless opportunities to design ILs with properties suitable for applications in many industrial fields. This study aims to synthetise two series of methylimidazolium ILs bearing long alkyl chain in their cations (C9, C10, C12, C14, C16, C18, C20) and with tetrafluoroborate (BF4) and the 1,3-dimethyl-5-sulfoisophthalate (DMSIP) as counter ions. The ILs were characterised using 1H-NMR and MALDI-TOF, and their thermal behaviour was investigated through DSC and TGA. Additionally, the antimicrobial, anticancer, and cytotoxic activities of the ILs were analysed. Moreover, the most promising ILs were incorporated at different concentrations (0.5, 1, 5 wt%) into polyvinyl chloride (PVC) by solvent casting to obtain antimicrobial blend films. The thermal properties and stability of the resulting PVC/IL films, along with their hydrophobicity/hydrophilicity, IL surface distribution, and release, were studied using DSC and TGA, contact angle (CA), SEM, and UV-vis spectrometry, respectively. Furthermore, the antimicrobial and cytotoxic properties of blends were analysed. The in vitro results demonstrated that the antimicrobial and antitumor activities of pure ILs against t Listeria monocytogenes, Escherichia coli, Pseudomonas fluorescens strains, and the breast cancer cell line (MCF7), respectively, were mainly dependent on their structure. These activities were higher in the series containing the BF4 anion and increased with the increase in the methylimidazolium cation alkyl chain length. However, the elongation of the alkyl chain beyond C16 induced a decrease in antimicrobial activity, indicating a cut-off effect. A similar trend was also observed in terms of in vitro biocompatibility. The loading of both the series of ILs into the PVC matrix did not affect the thermal stability of PVC blend films. However, their Tonset decreased with increased IL concentration and alkyl chain length. Similarly, both the series of PVC/IL films became more hydrophilic with increasing IL concentration and alkyl chain. The loading of ILs at 5% concentration led to considerable IL accumulation on the blend film surfaces (as observed in SEM images) and, subsequently, their higher release. The biocompatibility assessment with healthy human dermal fibroblast (HDF) cells and the investigation of antitumoral properties unveiled promising pharmacological characteristics. These findings provide strong support for the potential utilisation of ILs in biomedical applications, especially in the context of cancer therapy and as antibacterial agents to address the challenge of antibiotic resistance. Furthermore, the unique properties of the PVC/IL films make them versatile materials for advancing healthcare technologies, from drug delivery to tissue engineering and antimicrobial coatings to diagnostic devices.

Targeting Viral and Cellular Cysteine Proteases for Treatment of New Variants of SARS-CoV-2.

The continuous emergence of SARS-CoV-2 variants caused the persistence of the COVID-19 epidemic and challenged the effectiveness of the existing vaccines. The viral proteases are the most attractive targets for developing antiviral drugs. In this scenario, our study explores the use of HIV-1 protease inhibitors against SARS-CoV-2. An in silico screening of a library of HIV-1 proteases identified four anti-HIV compounds able to interact with the 3CLpro of SARS-CoV-2. Thus, in vitro studies were designed to evaluate their potential antiviral effectiveness against SARS-CoV-2. We employed pseudovirus technology to simulate, in a highly safe manner, the adsorption of the alpha (α-SARS-CoV-2) and omicron (ο-SARS-CoV-2) variants of SARS-CoV-2 and study the inhibitory mechanism of the selected compounds for cell-virus interaction. The results reported a mild activity against the viral proteases 3CLpro and PLpro, but efficient inhibitory effects on the internalization of both variants mediated by cathepsin B/L. Our findings provide insights into the feasibility of using drugs exhibiting antiviral effects for other viruses against the viral and host SARS-CoV-2 proteases required for entry.

Rutin/Sulfobutylether-ß-Cyclodextrin as a Promising Therapeutic Formulation for Ocular Infection.

Ocular pathologies present significant challenges to achieving effective therapeutic results due to various anatomical and physiological barriers. Natural products such as flavonoids, alone or in association with allopathic drugs, present many therapeutic actions including anticancer, anti-inflammatory, and antibacterial action. However, their clinical employment is challenging for scientists due to their low water solubility. In this study, we designed a liquid formulation based on rutin/sulfobutylether-ß-cyclodextrin (RTN/SBE-ß-CD) inclusion complex for treating ocular infections. The correct stoichiometry and the accurate binding constant were determined by employing SupraFit software (2.5.120) in the UV-vis titration experiment. A deep physical-chemical characterization of the RTN/SBE-ß-CD inclusion complex was also performed; it confirmed the predominant formation of a stable complex (Kc, 9660 M-1) in a 1:1 molar ratio, with high water solubility that was 20 times (2.5 mg/mL) higher than the free molecule (0.125 mg/mL), permitting the dissolution of the solid complex within 30 min. NMR studies revealed the involvement of the bicyclic flavonoid moiety in the complexation, which was also confirmed by molecular modeling studies. In vitro, the antibacterial and antibiofilm activity of the formulation was assayed against Staphylococcus aureus and Pseudomonas aeruginosa strains. The results demonstrated a significant activity of the formulation than that of the free molecules.

TiO2/Loofah-Halloysite Bio-Hybrid Composites as Efficient Systems for VOCs Removal.

Volatile organic compounds (VOCs), recognized as hazardous air contaminants, prompt the exploration of sustainable air purification methods. Solar photocatalytic oxidation emerges as a promising solution, utilizing semiconductor photocatalysts like titanium dioxide (TiO2). However, the raw material crisis necessitates reduced TiO2 usage, leading to investigations into TiO2 modification techniques. The study introduces a novel approach by employing natural fibers, specifically loofah sponge, as a TiO2 support. This method aims to maintain photocatalytic activity while minimizing TiO2 content. The article explores using halloysite, a natural clay mineral, as a supportive material, enhancing mechanical strength and adsorption properties. The resulting TiO2/loofah-halloysite composites are evaluated for their efficacy in gas-phase photocatalytic oxidation of toluene and ethanol, chosen as representative VOCs. The conversion of toluene and ethanol on the composite was 88 % and 39 %, respectively, with high selectivity toward CO2. In addition to its high performance, the bio-composite was stable for several conversion cycles, keeping the conversion activity unchanged. The study contributes to developing green hybrid materials for VOC removal, showcasing potential applications across industries.

γ-Cyclodextrins as Supramolecular Reactors for the Three-component Aza-Darzens Reaction in Water.

In recent decades, many efforts have been devoted to studying reactions catalyzed in nanoconfined spaces. The most impressive aspect of catalysis in nanoconfined spaces is that the reactivity of the molecules can be smartly driven to disobey classical behavior. A green and efficient three-component aza-Darzens (TCAD) reaction using a catalytic amount of γ-cyclodextrins (CDs) in water has been developed to synthesize N-phenylaziridines. CDs effectively performed this reaction in an environmentally friendly setting, achieving good yields. The same reaction was then performed using polymeric γ-CD such as a γ-cyclodextrin polymer crosslinked (GCDPC) with epichlorohydrin, a sponge-like macroporous γ-cyclodextrin-based cryogel (GCDC), and a γ-cyclodextrin-based hydrogel (GCDH). The homogeneous and heterogeneous catalyst recovery was then studied, and it was proved to be easily recycled several times without relevant activity loss. Water, as a unique and eco-friendly reaction medium, has been utilized for the first time, to the best of our knowledge, in this reaction. The inclusion of the reagents in CDs has been studied and rationalized by NMR spectroscopy experiments and molecular modeling calculations. The credit of the presented protocol includes good yields and catalyst reusability and precludes the use of organic solvents.

Discovery of first novel sigma/HDACi dual-ligands with a potent in vitro antiproliferative activity.

Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simultaneous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands σR/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (Kiσ1R = 38 ± 3.7; Kiσ2R = 2917 ± 769 and HDACs IC50 = 0.59 µM) is the most promising candidate as an antiproliferative agent with an IC50 of 0.9 µM on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over σ1R and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets.

Insights into the Friedel-Crafts Benzoylation of N-Methylpyrrole inside the Confined Space of the Self-Assembled Resorcinarene Capsule.

Friedel-Crafts benzoylation of N-methylpyrrole 2 can run inside the confined space of the hexameric resorcinarene capsule C. The bridged water molecules at the corner of C act as H-bonding donor groups to polarize the C-Cl bond of benzoyl chlorides 3a-f. Confinement effects on the regiochemistry of the FC benzoylation of N-methylpyrrole are observed. The nature of the para-substituents of 3a-f and their ability to establish H-bonds with the water molecules of C work synergistically with the steric constrictions imposed by the capsule to drive the regiochemistry of products 4a-f. QM investigations indicate that inside the cavity of C, the FC benzoylation of 2 has a bimolecular concerted SN2 mechanism, appropriately, above-plane nucleophilic vinylic substitution (SNVπ)─supported by H-bonding interactions between water molecules and both the leaving Cl atom and the carbonyl group.

Total Bio-Based Material for Drug Delivery and Iron Chelation to Fight Cancer through Antimicrobial Activity.

Bacterial involvement in cancer's development, along with their impact on therapeutic interventions, has been increasingly recognized. This has prompted the development of novel strategies to disrupt essential biological processes in microbial cells. Among these approaches, metal-chelating agents have gained attention for their ability to hinder microbial metal metabolism and impede critical reactions. Nanotechnology has also contributed to the antibacterial field by offering various nanomaterials, including antimicrobial nanoparticles with potential therapeutic and drug-delivery applications. Halloysite nanotubes (HNTs) are naturally occurring tubular clay nanomaterials composed of aluminosilicate kaolin sheets rolled multiple times. The aluminum and siloxane groups on the surface of HNTs enable hydrogen bonding with biomaterials, making them versatile in various domains, such as environmental sciences, wastewater treatment, nanoelectronics, catalytic studies, and cosmetics. This study aimed to create an antibacterial material by combining the unique properties of halloysite nanotubes with the iron-chelating capability of kojic acid. A nucleophilic substitution reaction involving the hydroxyl groups on the nanotubes' surface was employed to functionalize the material using kojic acid. The resulting material was characterized using infrared spectroscopy (IR), thermogravimetric analysis (TGA), energy-dispersive X-ray spectroscopy (EDX), and scanning electron microscopy (SEM), and its iron-chelating ability was assessed. Furthermore, the potential for drug loading-specifically, with resveratrol and curcumin-was evaluated through ultraviolet (UV) analysis. The antibacterial assay was evaluated following CLSI guidelines. The results suggested that the HNTs-kojic acid formulation had great antibacterial activity against all tested pathogens. The outcome of this work yielded a novel bio-based material with dual functionality as a drug carrier and an antimicrobial agent. This innovative approach holds promise for addressing challenges related to bacterial infections, antibiotic resistance, and the development of advanced therapeutic interventions.

Progress of the "Molecular Informatics" Section in 2022.

This is the first Editorial of the "Molecular Informatics" Section (MIS) of the International Journal of Molecular Sciences (IJMS), which was created towards the end of 2018 (the first article was submitted on 27 September 2018) and has experienced significant growth from 2018 to now [...].

Selective noncovalent proteasome inhibiting activity of trifluoromethyl-containing gem-quaternary aziridines.

The ubiquitin-proteasome pathway (UPP) represents the principal proteolytic apparatus in the cytosol and nucleus of all eukaryotic cells. Nowadays, proteasome inhibitors (PIs) are well-known as anticancer agents. However, although three of them have been approved by the US Food and Drug Administration (FDA) for treating multiple myeloma and mantel cell lymphoma, they present several side effects and develop resistance. For these reasons, the development of new PIs with better pharmacological characteristics is needed. Recently, noncovalent inhibitors have gained much attention since they are less toxic as compared with covalent ones, providing an alternative mechanism for solid tumors. Herein, we describe a new class of bis-homologated chloromethyl(trifluoromethyl)aziridines as selective noncovalent PIs. In silico and in vitro studies were conducted to elucidate the mechanism of action of such compounds. Human gastrointestinal absorption (HIA) and blood-brain barrier (BBB) penetration were also considered together with absorption, distribution, metabolism, and excretion (ADMET) predictions.

Computer-Assisted Design of Peptide-Based Radiotracers.

In medical imaging, techniques such as magnetic resonance imaging, contrast-enhanced computerized tomography, positron emission tomography (PET), and single-photon emission computed tomography (SPECT) are extensively available and routinely used for disease diagnosis. PET probes with peptide-based targeting are typically composed of small peptides especially developed to have high affinity and specificity for a range of cellular and tissue targets. These probes' key benefits include being less expensive than traditional antibody-based PET tracers and having an effective chemical modification process that allows them to be radiolabeled with almost any radionuclide, making them highly appealing for clinical usage. Currently, as with every pharmaceutical design, the use of in silico strategies is steadily growing in this field, even though it is not part of the standard toolkit used during radiopharmaceutical design. This review describes the recent applications of computational design approaches in the design of novel peptide-based radiopharmaceuticals.

Soluble peptidoglycan fragments produced by Limosilactobacillus fermentum with antiproliferative activity are suitable for potential therapeutic development: A preliminary report.

Currently, the use of probiotic strains and their products represents a promising innovative approach as an antagonist treatment against many human diseases. Previous studies showed that a strain of Limosilactobacillus fermentum (LAC92), previously defined as Lactobacillus fermentum, exhibited a suitable amensalistic property. The present study aimed to purify the active components from LAC92 to evaluate the biological properties of soluble peptidoglycan fragments (SPFs). The cell-free supernatant (CFS) and bacterial cells were separated after 48 h of growth in MRS medium broth and treated for isolation of SPFs. Antimicrobial activity and proliferation analysis on the human cell line HTC116 were performed using technologies such as xCELLigence, count and viability, and clonogenic analysis. MALDI-MS investigation and docking analysis were performed to determine the molecular structure and hypothetical mode of action, respectively. Our results showed that the antimicrobial activity was mainly due to SPFs. Moreover, the results obtained when investigating the SPF effect on the cell line HCT116 showed substantial preliminary evidence, suggesting their significant cytostatic and quite antiproliferative properties. Although MALDI was unable to identify the molecular structure, it was subsequently revealed by analysis of the bacterial genome. The amino acid structure is called peptide 92. Furthermore, we confirmed by molecular docking studies the interaction of peptide 92 with MDM2 protein, the negative regulator of p53. This study showed that SPFs from the LAC92 strain exerted anticancer effects on the human colon cancer HCT116 cell line via antiproliferation and inducing apoptosis. These findings indicated that this probiotic strain might be a potential candidate for applications in functional products in the future. Further examination is needed to understand the specific advantages of this probiotic strain and improve its functional features to confirm these data. Moreover, deeper research on peptide 92 could increase our knowledge and help us understand if it will be possible to apply to specific diseases such as CRC.

Steered Molecular Dynamics Simulations Study on FABP4 Inhibitors.

Ordinary small molecule de novo drug design is time-consuming and expensive. Recently, computational tools were employed and proved their efficacy in accelerating the overall drug design process. Molecular dynamics (MD) simulations and a derivative of MD, steered molecular dynamics (SMD), turned out to be promising rational drug design tools. In this paper, we report the first application of SMD to evaluate the binding properties of small molecules toward FABP4, considering our recent interest in inhibiting fatty acid binding protein 4 (FABP4). FABP4 inhibitors (FABP4is) are small molecules of therapeutic interest, and ongoing clinical studies indicate that they are promising for treating cancer and other diseases such as metabolic syndrome and diabetes.