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What is known and objective Trimethylaminuria is a metabolic disorder characterized by excessive excretion of trimethylamine in body fluids following FMO3 gene mutations. Secondary forms of the disease may be due to consumption of trimethylamine precursor-rich foods or metabolism of some xenobiotics. Case summary A HIV patient developed secondary trimethylaminuria following antiretroviral treatment. Riboflavin supplementation ameliorated his phenotype. 1 H-NMR confirmed increased urine level of TMA. Several genes involved in choline catabolism harboured missense mutations. Riboflavin supplement improved enzymatic activity of mutated enzymes promoting TMA clearance. What is new and conclusion Antiretrovirals may increase the concentration of TMA precursors. The present study reports antiretroviral treatment as risk factor for such secondary trimethylaminuria. Riboflavin is an effective treatment.

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.

The reactivity of 2-alkynylbenzoic acids toward Lawesson's reagent (LR) under microwave irradiation (300 W, 100 °C, CH2 Cl2 ) was assessed. It was found that, depending on reaction conditions, either a dithionation- or a monothionation-cycloisomerization process takes place with formation of important sulfurated heterocycles. In particular, using 1 equivalent of LR for 1 h, dithionation occurred, with formation of benzo[c]thiophene-1(3H)-thiones or 1H-isothiochromene-1-thiones, while with 0.5 equiv. of LR for 10-30 min, monothionated products were selectively obtained (benzo[c]thiophen-1(3H)-ones or 1H-isothiochromen-1-ones). The regiochemical output of the process strongly depended on the substitution pattern of the starting 2-alkynylbenzoic acid derivatives. These compounds were also assayed as potential herbicides by assessing their phytotoxic activity on seedling growth and development of the model species Arabidopsis thaliana. All compounds, to different extents, influenced the morpho-physiological parameters that were monitored; in particular, the fresh weight (FW) was significantly affected, with ED50 values ranging from 4.81-63.7 μM.

The click cycloaddition reaction of azides and alkynes affording 1,2,3-triazoles is a widely used and effective chemical transformation, applied to obtain relevant products in medicine, biology and materials science. In this work, a set of Natural Deep Eutectic Solvents (NADESs) as green and “active” reaction media, has been investigated in the copper-catalysed azide–alkyne cycloaddition reactions (CuAAc). The use of these innovative solvents has shown to improve the reaction effectiveness, giving excellent yields. NADESs proved to be “active” in these transformations for the absence of added bases in all the performed reactions and in several cases, for their reducing capabilities. The reactions outcomes were rationalized by DFT calculations which demonstrated the involvement of H-bonds between DESs and alkynes as well as a stabilization of copper catalytic intermediates. The green experimental conditions, namely the absence of a base, the low temperatures, the lowering of reagents and the possibility of recycling of the green solvents, outline the great potential of NADESs for CuAAc and in general, for green organic synthesis.

A series of azastilbene derivatives, characterized by the presence of the 1,2,4-oxadiazole-5-one system as a linker of the two aromatic rings of stilbenes, have been prepared as novel potential inhibitors of p38 MAPK. Biological assays indicated that some of the synthesized compounds are endowed with good inhibitory activity towards the kinase. Molecular modeling data support the biological results showing that the designed compounds possess a reasonable binding mode in the ATP binding pocket of p38α kinase with a good binding affinity.

The spread of SARS-CoV-2, along with the lack of targeted medicaments, encouraged research of existing drugs for repurposing. The rapid response to SARS-CoV-2 infection comprises a complex interaction of cytokine storm, endothelial dysfunction, inflammation, and pathologic coagulation. Thus, active molecules targeting multiple steps in SARS-CoV-2 lifecycle are highly wanted. Herein we explored the in silico capability of silibinin from Silybum marianum to interact with the SARS-CoV-2 main target proteins, and the in vitro effects against cytokine-induced-inflammation and dysfunction in human umbilical vein endothelial cells (HUVECs). Computational analysis revealed that silibinin forms a stable complex with SARS-CoV-2 spike protein RBD, has good negative binding affinity with Mpro, and interacts with many residues on the active site of Mpro, thus supporting its potentiality in inhibiting viral entry and replication. Moreover, HUVECs pretreatment with silibinin reduced TNF-α-induced gene expression of the proinflammatory genes IL-6 and MCP-1, as well as of PAI-1, a critical factor in coagulopathy and thrombosis, and of ET-1, a peptide involved in hemostatic vasoconstriction. Then, due to endothelium antiinflammatory and anticoagulant properties of silibinin and its capability to interact with SARS-CoV-2 main target proteins demonstrated herein, silibinin could be a strong candidate for COVID-19 management from a multitarget perspective.

The outbreak of COVID-19 disease caused by SARS-CoV-2, along with the lack of targeted medicaments, forced the scientific world to search for new antiviral formulations. In the current emergent situation, drug repurposing of well-known traditional and/or approved drugs could be the most effective strategy. Herein, through computational approaches, we aimed to screen 14 natural compounds from limonoids and terpenoids class for their ability to inhibit the key therapeutic target proteins of SARS-CoV-2. Among these, some limonoids, namely deacetylnomilin, ichangin and nomilin, and the terpenoid β-amyrin provided good interaction energies with SARS-CoV-2 3CL hydrolase (Mpro) in molecular dynamic simulation. Interestingly, deacetylnomilin and ichangin showed direct interaction with the catalytic dyad of the enzyme so supporting their potential role in preventing SARS-CoV-2 replication and growth. On the contrary, despite the good affinity with the spike protein RBD site, all the selected phytochemicals lose contact with the amino acid residues over the course of 120ns-long molecular dynamics simulations therefore suggesting they scarcely can interfere in SARS-CoV-2 binding to the ACE2 receptor. The in silico analyses of docking score and binding energies, along with predicted pharmacokinetic profiles, indicate that these triterpenoids might have potential as inhibitors of SARS-CoV-2 Mpro, recommending further in vitro and in vivo investigations for a complete understanding and confirmation of their inhibitory potential.

Due to their outstanding physicochemical properties, the next generation of the graphene family&mdash, graphene quantum dots (GQDs)&mdash, are at the cutting edge of nanotechnology development. GQDs generally possess many hydrophilic functionalities which allow their dispersibility in water but, on the other hand, could interfere with reactions that are mainly performed in organic solvents, as for cycloaddition reactions. We investigated the 1,3-dipolar cycloaddition (1,3-DCA) reactions of the C-ethoxycarbonyl N-methyl nitrone 1a and the newly synthesized C-diethoxyphosphorylpropilidene N-benzyl nitrone 1b with the surface of GQDs, affording the isoxazolidine cycloadducts isox-GQDs 2a and isox-GQDs 2b. Reactions were performed in mild and eco-friendly conditions, through the use of a natural deep eutectic solvent (NADES), free of chloride or any metal ions in its composition, and formed by the zwitterionic trimethylglycine as the -bond acceptor, and glycolic acid as the hydrogen-bond donor. The results reported in this study have for the first time proved the possibility of performing cycloaddition reactions directly to the p-cloud of the GQDs surface. The use of DES for the cycloaddition reactions on GQDs, other than to improve the solubility of reactants, has been shown to bring additional advantages because of the great affinity of these green solvents with aromatic systems.

In this paper, a new formulation of biodegradable and bioresorbable chitosan-based hydrogel for controlled drug release was investigated. A chitosan&ndash, dendrimer&ndash, hydroxyapatite hydrogel, obtained by covalently grafting chitosan powder with an hyperbranched PAMAM dendrimer followed by in-situ precipitation of hydroxyapatite and gelification, was synthesized and characterized by FTIR, NMR, TGA, XRD and rheological studies. The hydrogels have been also doped with an anti-inflammatory drug (ketoprofen) in order to investigate their drug release properties. Chemical and chemical-physical characterizations confirmed the successful covalent functionalization of chitosan with PAMAM and the synthesis of nanostructured hydroxyapatite. The developed hydrogel made it possible to obtain an innovative system with tunable rheological and drug-releasing properties relative to the well-known formulation containing chitosan and hydroxyapatite powder. The developed hydrogel showed different rheological and drug-releasing properties of chitosan matrix mixed with hydroxyapatite as a function of dendrimer molecular weight, therefore, the chitosan&ndash, hydroxyapatite hydrogel can couple the well-known osteoconductive properties of hydroxyapatite with the drug-release behavior and good processability of chitosan&ndash, dendrimer hydrogels, opening new approaches in the field of tissue engineering based on biopolymeric scaffolds.

Simple Summary Nanotherapeutics are useful tools to improve the deliverability of drugs, especially anti-cancer drugs that need to target specific cells. Several approaches have been studied for multiple myeloma, considering that immune cells are not easy to target with the available drugs. These pharmacological agents are administered in various combinations using Thalidomide (or Lenalidomide, Pomalidomide), corticosteroids (Dexamethasone), proteasome inhibitors (Bortezomib, Carfilzomib, Ixazomib), deacetylase inhibitors (Panobinostat), and monoclonal antibodies (Elotuzumab, Daratumumab). As all drugs these agents might have serious side effects and in addition, the reliance on stochastic events to deliver drugs to tumors reduces their effectiveness either through rapid clearance from blood or inadequate concentration in cancer cells. To address these issues liposomes, micelles, polymeric nanoparticles, inorganic nanoparticles, and carbon-based nanomaterials have been successfully tested in vivo and can be considered as useful tools to improve delivery of active pharmaceuticals that show poor bioavailability or poor internalization into myeloma cells. Abstract Anticancer therapies cannot be included in a one-size-fits-all scenario; it is imperative to adapt therapies to the tumor molecular profile and most importantly to develop target-specific therapeutics. Nanotherapeutics can combine molecular imaging with molecular therapy in order to provide the maximum benefit to patients in terms of disease prevention, identification, and treatment. Nanotechnology applied to therapy provides numerous advantages in diagnostics and in drug delivery, especially for those malignant cells that are difficult to target or for drugs with poor bioavailability, such as those used for multiple myeloma (MM). This review summarizes the recent advances in the development of nanoparticle-based systems for the treatment of MM, taking into account the methods used for their functionalization, biocompatibility, and anticancer activity.

Aldose reductase (ALR2) is a key enzyme involved in diabetic complications and the search for new aldose reductase inhibitors (ARIs) is currently very important. The synthetic ARIs are often associated with deleterious side effects and medicinal and edible plants, containing compounds with aldose reductase inhibitory activity, could be useful for prevention and therapy of diabetic complications. Non-psychotropic phytocannabinoids exert multiple pharmacological effects with therapeutic potential in many diseases such as inflammation, cancer, diabetes. Here, we have investigated the inhibitory effects of extracts and their fractions from two Cannabis sativa L. chemotypes with high content of cannabidiol (CBD)/cannabidiolic acid (CBDA) and cannabigerol (CBG)/cannabigerolic acid (CBGA), respectively, on human recombinant and pig kidney aldose reductase activity in vitro. A molecular docking study was performed to evaluate the interaction of these cannabinoids with the active site of ALR2 compared to known ARIs. The extracts showed significant dose-dependent aldose reductase inhibitory activity (>70%) and higher than fractions. The inhibitory activity of the fractions was greater for acidic cannabinoid-rich fractions. Comparative molecular docking results have shown a higher stability of the ALR2-cannabinoid acids complex than the other inhibitors. The extracts of Cannabis with high content of non-psychotropic cannabinoids CBD/CBDA or CBG/CBGA significantly inhibit aldose reductase activity. These results may have some relevance for the possible use of C. sativa chemotypes based preparations as aldose reductase inhibitors.

A novel carbonylative approach to the synthesis of functionalized 1H-benzo[d]imidazo[1,2-a]imidazoles is presented. The method consists of the oxidative aminocarbonylation of N-substituted-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-2-amines, carried out in the presence of secondary nucleophilic amines, to give the corresponding alkynylamide intermediates, followed by in situ conjugated addition and double-bond isomerization, to give 2-(1-alkyl-1H-benzo[d]imidazo[1,2-a]imidazol-2-yl)acetamides. Products were obtained in good to excellent yields (64–96%) and high turnover numbers (192–288 mol of product per mol of catalyst) under relatively mild conditions (100 °C under 20 atm of a 4:1 mixture of CO–air), using a simple catalytic system, consisting of PdI2 (0.33 mol %) in conjunction with KI (0.33 equiv).

A biocompatible and cell traceable drug delivery system Graphene Quantum Dots (GQD) based, for the targeted delivery of the DNA intercalating drug doxorubicin (DOX) to cancer cells, is here reported. Highly dispersible and water soluble GQD, synthesized by acidic oxidation and exfoliation of multi-walled carbon nanotubes (MWCNT), were covalently linked to the tumor targeting module biotin (BTN), able to efficiently recognize biotin receptors over-expressed on cancer cells and loaded with DOX. Biological test performed on A549 cells reported a very low toxicity of the synthesized carrier (GQD and GQD-BTN). In GQD-BTN-DOX treated cancer cells, the cytotoxicity was strongly dependent from cell uptake which was greater and delayed after treatment with GQD-BTN-DOX system with respect to what observed for cells treated with the same system lacking of the targeting module BTN (GQD-DOX) or with the free drug alone. A delayed nuclear internalization of the drug is reported, due to the drug detachment from the nanosystem, triggered by the acidic environment of cancer cells.

The cycloisomerization of readily available 2-alkynylbenzamides has been conveniently carried out with CuCl2 as catalyst under basic conditions in 1-ethyl-3-methylimidazolium ethyl sulfate (EmimEtSO4) as an unconventional solvent. The process leads to (Z)-3-alkylideneisoindolin-1-ones in a chemo-, regio-, and stereoselective manner. The catalyst/solvent/base system could be recycled several times without appreciable loss of activity. The structures of representative products, that are, (Z)-3-benzylidene-2-phenylisoindolin-1-one and (Z)-3-pentylidene-2-phenylisoindolin-1-one, have been confirmed by X-ray diffraction analysis, and DFT (density functional theory) calculations have been carried out to clarify the roles exerted by the base and CuCl2 in favoring the reaction course leading to (Z)-3-alkylideneisoindolinones.

Graphene quantum dots (GQD), the new generation members of graphene-family, have shown promising applications in anticancer therapy. In this study, we report the synthesis of a fluorescent and biocompatible nanovector, based on GQD, for the targeted delivery of an anticancer drug with benzofuran structure (BFG) and bearing the targeting ligand riboflavin (RF, vitamin B2). The highly water-dispersible nanoparticles, synthesized from multi-walled carbon nanotubes (MWCNT) by prolonged acidic treatment, were linked covalently to the drug by means of a cleavable PEG linker while the targeting ligand RF was conjugated to the GQD by π–π interaction using a pyrene linker. The cytotoxic effect of the synthesized drug delivery system (DDS) GQD-PEG-BFG@Pyr-RF was tested on three cancer cell lines and this effect was compared with that exerted by the same nanovector lacking the RF ligand (GQD-PEG-BFG) or the anticancer drug (GQD@Pyr-RF). The results of biological tests underlined the low cytotoxicity of the GQD sample and the cytotoxic activity of the DDS against the investigated cancer cell lines with a higher or similar potency to that exerted by the BFG alone, thus opening new possibilities for the use of this drug or other anticancer agents endowed of cytotoxicity and serious side effects.

A series of 2,3,4-triaryl-substituted 1,2,4-oxadiazole-5-ones have been prepared as fixed-ring analogues of tamoxifen (TAM), a drug inhibitor of Estradiol Receptor (ER) used in breast cancer therapy, by an efficient synthetic protocol based on a 1,3-dipolar cycloaddition of nitrones to isocyanates. Some of the newly synthesized compounds (14d-f, 14h and 14k) show a significant cytotoxic effect in a human breast cancer cell line (MCF-7) possessing IC50 values between 15.63 and 31.82 μM. In addition, compounds 14d-f, 14h and 14k are able to increase the p53 expression levels, activating also the apoptotic pathway. Molecular modeling studies of novel compounds performed on the crystal structure of ER reveal the presence of strong hydrophobic interactions with the aromatic rings of the ligands similar to TAM. These data suggest that 1,2,4-oxadiazole-5-ones can be considered analogues of TAM, and that their anticancer activity might be partially due to ER inhibition.

A convenient approach to the synthesis of alkyl esters of aspirin (ASA-OR) has been developed. The synthesis of ASA-OR has been realized in two steps: (1) direct esterification of salicylic acid with alcohols in the presence of dicyclohexylcarbodiimide to give alkyl salicylates (SAL-OR); (2) acetylation of SAL-OR with acetyl chloride to yield ASA-OR. Molecular mechanics simulations, performed to calculate the kinetic radii of several ASA-OR, indicated that the pentyl and hexyl acetylsalicylates possess the best properties to cross cell membranes. The in vitro biological tests demonstrate their anti-inflammatory activity, superimposable to that of aspirin. The results of our study suggest that ASA-OR may be used as anti-inflammatory drugs for topical application.

The first example of a tandem thionation/S-cyclization process leading to benzo[c]thiophene-1(3H)-thione and 1H-isothiochromene-1-thione derivatives, starting from 2-alkynylbenzoic acids, is reported. The reaction is carried out in CH2Cl2 using 1 equiv. of Lawesson's reagent under MW irradiation at 100 °C and 300 W for 1 h. Depending on the nature of the substituent at the distal β carbon of the triple bond, either benzothiophenethiones or isothiochromenethiones were obtained selectively, in high to excellent yields. The structure of the representative compounds has been confirmed by X-ray diffraction analysis.

A direct on-line method based on the coupling of supercritical fluid extraction and supercritical fluid chromatography with triple quadrupole mass spectrometry detection (SFE-SFC-QqQ/MS) for selected carotenoids determination and apocarotenoids detection in intact human blood was developed for the first time. Carotenoids and apocarotenoids were identified by using the available standard together with full scan, selected ion monitoring (SIM), and multiple reaction monitoring (MRM) experiments. Moreover, β-Cryptoxanthin, Zeaxanthin, β-Carotene and Capsanthin were directly quantified by the developed methodology, using a multiple reaction monitoring (MRM) approach; the determined average content of β-carotene was 123.8 nmol L−1 (range 18.7–485.1 nmol L−1), of β-cryptoxanthin was 385.3 nmol L−1 (range 72.5–1920.3 nmol L−1), of zeaxanthin was 396.9 nmol L−1 (range

A total of 205 bluefin and yellowfin tuna samples were examined for mercury detection in order to verify possible differences and have a detailed risk assessment of the two tuna species. The results showed significant higher mercury concentration in muscle tissue of bluefin tuna respect yellowfin tuna (p&nbsp

Pyrimidine-1,3-oxazolidin-2-arylimino hybrids have been synthesized as a new class of antibacterial agents. The synthetic approach exploits a Cu(II)-catalyzed intramolecular halkoxyhalogenation of alkynyl ureas, followed by a Suzuki coupling reaction with 2,4-dimethoxypyrimidin-5-boronic acid. Biological screenings revealed that most of the compounds showed moderate to good activity against two Gram-positive (B. subtilis, S. aureus) and three Gram-negative (P. aeruginosa, S. typhi, K. pneumonia) pathogenic strains. A molecular docking study, performed in the crystal structure of 50S ribosomal unit of Haloarcula marismortui, indicated that pyrimidine-oxazolidin-2-arylimino hybrids 8c and 8h exhibited a high binding affinity (&minus, 9.65 and &minus, 10.74 kcal/mol), which was in agreement with their good antibacterial activity. The obtained results suggest that the combination of pyrimidine and oxazolidone moieties can be considered as a valid basis to develop new further modifications towards more efficacious antibacterial compounds.

Coumarin is a natural compound well known for its phytotoxic potential. In the search for new herbicidal compounds to manage weeds, three synthetic derivatives bearing the coumarin scaffold (1–3), synthesized by a carbonylative organometallic approach, were in vitro assayed on germination and root growth of two noxious weeds, Amaranthus retroflexus and Echinochloa crus-galli. Moreover, the synthetic coumarins 1–3 were also in vitro assayed on seedlings growth of the model species Arabidopsis thaliana to identify the possible physiological targets. All molecules strongly affected seed germination and root growth of both weeds. Interestingly, the effects of synthetic coumarins on weed germination were higher than template natural coumarin, pointing out ED50 values ranging from 50–115 µM. Moreover, all synthetic coumarins showed a strong phytotoxic potential on both Arabidopsis shoot and root growth, causing a strong reduction in shoot fresh weight (ED50 values ≤ 60 µM), accompanied by leaf development and a decrease in pigment content. Furthermore, they caused a strong alteration in root growth (ED50 values ≤ 170 µM) and morphology with evident alterations in root tip anatomy. Taken together, our results highlight the promising potential herbicidal activity of these compounds.

Several natural antioxidants, including anthocyanins, have been reported to have chemotherapeutic activity in vivo and in vitro. The aim of the present study was to delineate the anti-proliferative activity and the cytodifferentiation properties mediated by cyanidin-3-O-β-glucopyranoside (C3G) treatment in the DU145 and LnCap human prostatic cancer cell lines. C3G produced anti-proliferative effects through activation of caspase-3 and induction of p21 protein expression. The reduced cell viability was associated with a clear increase of DNA fragmentation in both cell lines after C3G treatment. Since LnCap and DU145 exhibited differences in sensitivity to C3G treatment, the redox state of these cells was further investigated by estimating the levels of ROS and GSH. C3G antioxidant activity was confirmed only in DU145 cell line. Treatment with C3G increased the levels of tumor suppressor P75NGFR, indicating a possible role of C3G in the acquisition of a normal-like cell phenotype. Results reported in the present study demonstrate that C3G, the most abundant anthocyanin in diet, may represent a new approach and highly effective strategy in reducing carcinogenesis. C3G may be considered a new therapeutic agent with both anti-proliferative and pro-differentiation properties.

Aloe vera L., is a plant used worldwide as folk remedy for the treatment of various ailments, including skin disorders. Its gel is present in cosmetics, medicinal products and food supplements. Psoriasis, an immune-mediated chronic inflammatory disease, involving mainly the skin, affects about the 2-3% of general population. Conventional pharmacological treatments for psoriasis can have limited effectiveness and can cause adverse reactions. For this reason often psoriatic patients look for alternative treatments based on natural products containing Aloe vera. We conducted a systematic review of clinical trials assessing effectiveness and safety of aloe for the treatment of psoriasis. Clinical studies published in English were considered; a total of four clinical trials met inclusion criteria. Studies were also evaluated by using the Jadad scale and Consort Statement in Reporting Clinical trials of Herbal Medicine Intervention. Quality and methodological accuracy of considered studies varied considerably, and some crucial information to reproduce clinical results was missing. We conclude that administration of aloe as cutaneous treatment is generally well tolerated, as no serious side effects were reported. Results on the effectiveness of Aloe vera are contradictory; our analysis reveals the presence of methodological gaps preventing to reach final conclusions.

Background The first reports of the natural enediyne anticancer antibiotics date back to the late 1980s; since then, a great deal of interest has been devoted to the chemistry, biology and potential medical applications of this family of compounds. The biological activity of enediynes is linked to the presence of a highly unsaturated hex-1-ene-1,5-diyne system. The thermally induced transformation of this unit into a benzene σ-σ diradical (the Bergman cycloaromatization) is the key step of the antitumor properties of such compounds: 1,4-diaryl radicals are able to abstract H-atoms from the deoxyribose backbone of DNA, thus leading to DNA strand cleavage and ultimately cell death. Methods We undertook a structured search of bibliographic databases for peer-reviewed research literature using focused and high quality papers. Research efforts addressed at understanding and mimicking the various processes involved in the targeting, activation and DNA cleavage associated with these products are described. The potential of a great number of non natural enediynes in the treatment of many infectious diseases, apart their role in anticancer drugs, such as antibacterial activity, protein degradation activity, has been reported Results: Due to the interesting mode of action of this class of compounds, the unique molecular architecture of enediynes has been exploited towards the synthesis of many non natural compounds in order to study and enhance their biological properties. Seventy-six papers were included in this review. It is divided in paragraphs that include: Carbo- oxygen-nitrogen- and sulfur- enediynes, polymers and macrocycles. The synthetic approaches to the different classes of compounds are discussed in detail together with the biological implications of the synthesized compounds Conclusion: The review summarizes the most recent advances in the synthesis and reactivity of non natural enediynes by focusing the attention particularly to the biological properties of the most interesting members of the family of carbo- and hetero- enediynes. The findings of this review confirm the importance of non natural enediynes as potential drugs in the treatment of cancer and many infectious diseases.

The antioxidant activity and the phenolic and α-tocopherol content of 10 Northern Italian mono- and multi-varietal extra virgin olive oils (EVOOs), after early and late olive harvests, was analyzed. A hierarchical cluster analysis was used to evaluate sample similarity. Secoiridoids (SIDs), lignans and flavonoids were the most abundant phenolic compounds identified. The organic Casaliva (among mono-cultivar) and the organic multi-varietal (among blended oils) EVOOs had the higher total phenol content both in early (263.13 and 326.19 mg/kg, respectively) and late harvest (241.88 and 292.34 mg/kg, respectively) conditions. In comparison to late harvest EVOOs, early harvest EVOOs, in particular the organic mono-cultivar Casaliva, showed both higher antioxidant capacity (up to 1285.97 Oxygen Radicals Absorbance Capacity/ORAC units), probably due to the higher SID fraction (54% vs. 40%), and higher α-tocopherol content (up to 280.67 mg/kg). Overall, these results suggest that SIDs and α-tocopherol mainly contribute to antioxidant properties of the studied EVOOs. In light of this, the authors conclude that early harvest, organic mono-cultivar Casaliva EVOO represents the most interesting candidate to explicate healthy effects ascribed to these functional constituents, particularly regarding oxidative stress-related pathologies.

Dendrimer-functionalized multi-walled carbon nanotubes (MWCNT) for heavy metal ion removal from wastewaters were developed. Triazole dendrimers (TD) were built directly onto the carbon nanotube surface by successive click chemistry reactions affording the zero- and first-generation dendrimer-functionalized MWCNT (MWCNT-TD1 and MWCNT-TD2). The Moedritzer-Irani reaction carried out on the amino groups present on the MWCNT-TD2 sample gave the corresponding α-aminophosphonate nanosystem MWCNT-TD2P. Both MWCNT-TD2 and MWCNT-TD2P nanosystems have been characterized by physical, chemical, and morphological analyses. Their chelating abilities towards the toxic metal ions Pb2+, Hg2+, and Ni2+ and the harmless Ca2+ ion have been experimentally evaluated in the two different sets of experiments and at the salt concentrations of 1 mg/mL or 1 μg/mL by inductively coupled plasma mass spectrometry (ICP-MS). The results of these studies pointed out the interesting chelating behavior for the phosphonated nanosystem towards the Hg2+ ion. The complexation mode of the best chelating system MWCNT-TD2P with mercury was investigated through density functional theory (DFT) calculations, suggesting a chelation mechanism involving the two oxygen atoms of the phosphate group. The synthesized dendrimers, supported on the multi-walled carbon nanotubes, have shown the potential to be used for the selective toxic metal ion removal and recovery.

New calix[4]arene conjugates that present polycyclic aromatic hydrocarbons (PAHs) at their exo rims have been synthesized by esterification of a cone-shaped calix[4]arenedicarboxylic acid with trans- or cis-pyrenylisoxazolidinyl alcohols prepared by a 1,3-dipolar cycloaddition methodology. The in vitro cytotoxic activities of all compounds were evaluated with three different human tumor cell lines, and the most potent one reached an IC50 of 95 nM. The different biological activities of the synthesized compounds were explained by docking and circular dichroism studies, which evidenced their intercalating abilities from the DNA minor groove.

1,2,3-Triazole-appended N,O-nucleosides have been synthesized by an approach combining a 1,3-dipolar cycloaddition process and an alkyne–azide click chemistry reaction. Biological assays, performed on six tumor cell lines, revealed the antiproliferative activity of the synthesized compounds. The effect was more evident in the U87MG human glioblastoma cell line. Thus, these nucleoside analogues could be promising scaffolds for the construction of new anticancer agents.

The pyrimidine nucleus is a versatile core in the development of antiretroviral agents. On this basis, a series of pyrimidine-2,4-diones linked to an isoxazolidine nucleus have been synthesized and tested as nucleoside analogs, endowed with potential anti-HIV (human immunodeficiency virus) activity. Compounds 6a&ndash, c, characterized by the presence of an ethereal group at C-3, show HIV reverse transcriptase (RT) inhibitor activity in the nanomolar range as well as HIV-infection inhibitor activity in the low micromolar with no toxicity. In the same context, compound 7b shows only a negligible inhibition of RT HIV.

Selective reductions of semicyclic imides either to hemiaminals (endo carbonyl reduction) or to aldehydes and amines (exo carbonyl reduction) in high yields by Schwartz’s reagent (Cp2ZrHCl) are reported. Mechanistic aspects of these reactions have been investigated at the DFT ab initio level with consideration of implicit solvent effects and thermal and pressure corrections to 298 K/1 atm. The reactions proceed from the reagents to very stable final Zr-oxo intermediates through the formation of σ complexes and subsequent fourcenter transition state structures (1,2-migratory insertion). The energetic barriers for the insertion steps depend strongly on the natures of the ancillary groups at the reducing carbonyl groups. N-Carbamoyl groups are reduced to hemiaminals whereas N-acyl groups react at the exo carbonyl groups.