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Abstract: Selective and effective TK2 inhibitors can be obtained by introduction of bulky lipophilic chains (acyl or alkyl entities) at the 2′ position of araT and BVaraU, nucleoside analogues naturally endowed with a low TK2 affinity. These derivatives showed a competitive inhibitory activity against TK2 in micromolar range. BVaraU nucleoside analogues, modified on the 2′-O-acyl chain with a terminal N-Boc amino-group, conserved or increased the inhibitory activity against TK2 (7l and 7m IC50: 6.4 and 3.8μM, respectively). The substitution of an ester for a carboxamide moiety at the 2′ position of araT afforded a consistent reduction of the inhibitory activity (25, IC50: 480μM). On the contrary, modifications at 2′-OH position of araC and araG, have provided inactive derivatives against TK2 and dGK, respectively. The biological activity of a representative compound, 2′-O-decanoyl-BVaraU, was also investigated in normal human fibroblasts and was found to impair mitochondrial function due to TK2 inhibition. [Copyright &y& Elsevier]

Abstract: Pivotal role in atherogenesis is played by macrophages, which are early site for lipid accumulation and mediate the inflammatory and immune response in the intima. Epidemiological evidence indicates that natural antioxidants reduce the risk of heart disease, but, so far, supplementation studies have failed to confirm any protective effects of these compounds against cardiovascular disease. This study evaluated the effects of the natural antioxidant α-tocotrienol and of the newly designed compound, FeAOX-6, which combines antioxidant structural features of both tocopherols and carotenoids into a single molecule, on macrophage functions involved in foam cell formation. FeAOX-6 or α-tocotrienol induce a strong dose-dependent reduction of cholesterol and reduce cholesterol accumulation in human macrophages. The extent of the reduction found with α-tocotrienol was greater than that induced by FeAOX-6 and did not correlate with their respective antioxidant capacities. Treatment of HMDM with α-tocotrienol or FeAOX-6 enhanced also tumor necrosis factor-α secretion. These results are consistent with a reduction in scavenger receptor activity, but we found that antioxidant treatment did not affect cholesterol uptake from modified LDL. The effects on release on pro-inflammatory prostanoid precursors, PGE2 and cytokine suggest a variety of metabolic responses that are both dependent on antioxidant compounds and macrophages activation status. [Copyright &y& Elsevier]

A new class of inhibitors of tubulin polymerization based on the 2-amino-3-(3′,4′,5′-trimethoxybenzoyl)benzo b furan molecular scaffold was synthesized and evaluated for in vivo and in vitro biological activity. These derivatives were synthesized with different electron-releasing or electron-withdrawing substituents at one of the C-4 through C-7 positions. Methoxy substitution and location on the benzene part of the benzo b furan ring played an important role in affecting antiproliferative activity, with the greatest activity occurring with the methoxy group at the C-6 position, the least with the substituent at C-4. The same effect was also observed with ethoxy, methyl or bromine at the C-6 position of the benzo b furan skeleton, with the 6-ethoxy-2-amino-3-(3′,4′,5′-trimethoxybenzoyl)benzo b furan derivative 4f as the most promising compound of the series. This compound showed remarkable antiproliferative activity (IC 50 : 5 pM) against the Daoy medulloblastoma cell line, and 4f was nearly devoid of toxicity on healthy human lymphocytes and astrocytes. The potent antiproliferative activity of 4f was derived from its inhibition of tubulin polymerization by binding to the colchicine site. The compound was also examined for in vivo activity, showing higher potency at 15 mg/kg compared with the reference compound combretastatin A-4 phosphate at 30 mg/kg against a syngeneic murine mammary tumor. Image 1 • 2-amino-3-aroylbenzo b furans are inhibitors of tubulin assembly. • Compounds 4f and 4l showed low toxicity in normal cells in comparison to tumor cells. • Compounds 4f and 4l showed potent antiproliferative activity against Daoy cells. • Compound 4f showed in vivo activity against a syngenic murine mammary tumor. • Several molecules inhibited tubulin assembly with activity superior to that of CA-4. [ABSTRACT FROM AUTHOR]

The pathogenesis and progression of several lung disorders is propagated by inflammatory and oxidative processes, which can be controlled by adjunctive inhaled therapies. The present study aimed to develop an inhalable dry powder formulation consisting of co-spray-dried urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate (SD HA-CL–SAP), a novel combination which was recently shown to possess anti-inflammatory, antioxidant, and wound healing properties. Native HA and SAP were co-spray dried (SD HA–SAP) and evaluated as control formulation. Yield (Y%) and encapsulation efficiency (EE%) were 67.0 ± 4.8% and 75.5 ± 7.2% for SD HA–SAP, 70.0 ± 1.5% and 66.5 ± 5.7% for SD HA-CL–SAP, respectively. Both formulations were shown to be suitable for lung delivery in terms of morphology, particle size (median volumetric diameter ∼ 3.4 μm), physical and thermal stability, in vitro aerosol performance - respirable fraction: 30.5 ± 0.7% for SD HA–SAP and 35.3 ± 0.3% for SD HA-CL–SAP. SAP release was investigated using Franz cells and air-interface Calu-3 cell model (>90% of SAP transported within 4 h). The innovative SD HA-CL–SAP formulation holds potential as inhalable dry powder for the treatment of inflammatory lung disorders. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract An innovative lyophilized dry powder formulation consisting of urea-crosslinked hyaluronic acid (HA-CL) and sodium ascorbyl phosphate (SAP) – LYO HA-CL – SAP- was prepared and characterized in vitro for physico-chemical and biological properties. The aim was to understand if LYO HA-CL – SAP could be used as adjuvant treatment for nasal inflammatory diseases. LYO HA-CL – SAP was suitable for nasal delivery and showed to be not toxic on human nasal septum carcinoma-derived cells (RPMI 2650 cells) at the investigated concentrations. It displayed porous, polygonal particles with unimodal, narrow size distribution, mean geometric diameter of 328.3 ± 27.5 µm, that is appropriate for nasal deposition with no respirable fraction and 88.7% of particles with aerodynamic diameter >14.1 µm. Additionally, the formulation showed wound healing ability on RPMI 2650 cells, and reduced interleukin-8 (IL-8) level in primary nasal epithelial cells pre-induced with lipopolysaccharide (LPS). Transport study across RPMI 2650 cells showed that HA-CL could act not only as carrier for SAP and active ingredient itself, but potentially also as mucoadhesive agent. In conclusion, these results suggest that HA-CL and SAP had anti-inflammatory activity and acted in combination to accelerate wound healing. Therefore, LYO HA-CL – SAP could be a potential adjuvant in nasal anti-inflammatory formulations. [ABSTRACT FROM AUTHOR]

New benzofuranhydrazones 3–12 were easily prepared and assayed for their radical-scavenging ability. Hydrazones 3–12 showed different extent antioxidant activity in DPPH, FRAP and ORAC assays. Good antioxidant activity is related to the number and position of hydroxyl groups on the arylidene moiety. High antioxidant activity is showed by the 2-hydroxy-4-(diethylamino)benzylidene derivative 11 . Furthermore, hydrazones 3–12 showed photoprotective capacities with satisfactory in vitro SPF as compared to the commercial PBSA sunscreen filter. The antiproliferative effects of the hydrazones 3–12 was tested on erythroleukemia K562 and Colo-38 melanoma human cells. All the compounds showed growth inhibition in the micromolar to sub micromolar concentration range. If taken together these results points to benzofuran hydrazones as potential multifunctional molecules especially in the treatment of neoplastic diseases being the good antioxidant properties of 5 , 7 and 11 correlated to their high antiproliferative activity. [ABSTRACT FROM AUTHOR]

This in vitro study evaluated, for the first time, the safety and the biological activity of a novel urea-crosslinked hyaluronic acid component and sodium ascorbyl phosphate (HA-CL – SAP), singularly and/or in combination, intended for the treatment of inflammatory lung diseases. The aim was to understand if the combination HA-CL – SAP had an enhanced activity with respect to the combination native hyaluronic acid (HA) – SAP and the single SAP, HA and HA-CL components. Sample solutions displayed pH, osmolality and viscosity values suitable for lung delivery and showed to be not toxic on epithelial Calu-3 cells at the concentrations used in this study. The HA-CL – SAP displayed the most significant reduction in interleukin-6 (IL-6) and reactive oxygen species (ROS) levels, due to the combined action of HA-CL and SAP. Moreover, this combination showed improved cellular healing (wound closure) with respect to HA – SAP, SAP and HA, although at a lower rate than HA-CL alone. These preliminary results showed that the combination HA-CL - SAP could be suitable to reduce inflammation and oxidative stress in lung disorders like acute respiratory distress syndrome, asthma, emphysema and chronic obstructive pulmonary disease, where inflammation is prominent. [ABSTRACT FROM AUTHOR]

A comprehensive study on essential oils extracted from different samples of Melissa officinalis L. subsp. altissima (Sibth. & Sm.) Arcang. (Lamiaceae) collected in Tarquinia (Italy) is reported. In this study, the 24-h steam distillation procedure for essential oil preparation, in terms of different harvesting periods and extraction times was applied. The GC/MS analysis showed cis -caryophyllene and its oxide as the major essential oil’s constituents. A great impact of phenological stage on chemical profile of essential oil was observed. Regarding the duration of the extraction process, prolonged distillation led to chemically more diverse oil samples. Preliminary microbiological evaluations of the essential oils samples revealed the lack of significant efficacy against Candida albicans . [ABSTRACT FROM AUTHOR]

In this work the synthesis, structure–activity relationship (SAR) and biological evaluation of a novel series of triazole-containing 5-lipoxygenase (5-LO) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent 5-LO inhibition with IC 50 of 0.2 and 3.2 μ m in cell-based and cell-free assays, respectively. Optimization of binding and functional potencies resulted in the identification of compound 13d , which showed an enhanced activity compared to the parent bioactive compound caffeic acid 5 and the clinically approved zileuton 3 . Compounds 15 and 16 were identified as lead compounds in inhibiting 5-LO products formation in neutrophils. Their interference with other targets on the arachidonic acid pathway was also assessed. Cytotoxicity tests were performed to exclude a relationship between cytotoxicity and the increased activity observed after structure optimization. [ABSTRACT FROM AUTHOR]

Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids, consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet. Rutin is a common dietary flavonoid that is widely consumed worldwide from plant-derived beverages and foods as traditional and folk medicine remedy as well. Rutin exhibit important pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Here, we present the synthesis, antimicrobial, antiproliferative and pro-apoptotic effect on human leukemic K562 cells of compound R2 , a new semi-synthetic derivative of Rutin as compared to Rutin itself. The new derivative was also included in finished topical formulations to evaluate a potential application to the dermatology field in view of the antioxidant/antimicrobial/antiinflammatory properties. Stability studies were performed by HPLC; PCL assay and ORAC tests were used to determine the antioxidant activity. R2 presented an antioxidant activity very close to that of the parent Rutin while bearing much better lipophilic character. Regarding antiproliferative effects on the human K562 cell line, R2 was found to be more effective than parent Rutin. Preliminary experiments demonstrated that R2 inhibits NF-kB activity and promotes cellular apoptosis. [ABSTRACT FROM AUTHOR]

A novel series of twenty-seven cinnamides constituted by cinnamic acid derivatives liked to 1-aryl piperazines were synthesized and evaluated for their potential inhibitory diphenolase activity of mushroom tyrosinase. Among them, the presence of a 3-chloro-4-fluorophenyl moiety at the N -1 position of piperazine ring was essential for a potent tyrosinase inhibitory effect, with the 3-nitrocinnamoyl (19p) and 2-chloro-3-methoxycinnamoyl (19t) derivatives as the most potent compounds of the series, with IC 50 of 0.16 and 0.12 μM, respectively, resulting much active than kojic acid, whose IC 50 value was 17.76 μM. In general, all compounds characterized by the presence of a 1-(3-chloro-4-fluorophenyl)piperazine moiety showed an excellent potency, and the nature, position and number of the substituents on the aryl of the cinnamic acid did not affect significantly the anti-tyrosinase activity. The molecular docking to the active site of the enzyme has been also performed to investigate the nature of enzyme-inhibitor interactions. Furthermore, for selected highly active compounds, their ability to inhibit melanogenesis in the A375 human melanoma cells and in vivo zebrafish model was also evaluated. One of the most potent compounds of series (19t) significantly reduced the pigmentation of zebrafish at 50 μM, unfortunately showing 100% mortality in the Fish Embryo Acute Toxicity (FET) test at the same concentration, Moreover, the zebrafish assay reveals that also compound 19r (IC 50 :0.51 μM against mushroom tyrosinase) effectively reduces melanogenesis with no acute toxicity effects and it could be proposed as potential candidate to treat tyrosinase-mediated hyperpigmentation. The presence of 3-chloro-4-fluorophenyl moiety at the N-1 position of piperazine was associated to a potent tyrosinase inhibitory activity, with IC 50 values ranging from 0.12 to 0.53 μM. Compound 19r reduced pigmentation in zebrafish embryos and displayed low acute toxicity. [Display omitted] • The activity is associated to the presence of a 1-(3-chloro-4-fluorophenyl)piperazine moiety. • Substituents on the phenyl ring tethered to the piperazine exert a fundamental influence on the activity. • Several compounds were more active than kojic acid against mushroom tyrosinase. • Compound 19r inhibits melanogenesis of zebrafish embryos. [ABSTRACT FROM AUTHOR]

Abstract: Nucleoside derivatives are largely synthesized and tested to investigate their influence on platelet aggregation. It''s well known that P2Y receptors play an important role in the regulation of platelet function and, as consequence, in controlling atherothrombotic events. The research of compounds that antagonize P2Y1 and, in particular, P2Y12 receptors is of great interest in the aim to obtain platelet aggregation inhibitors that are effective in the prevention and treatment of arterial thrombosis. In this study we present the synthesis and in vitro metabolic stability in human blood and rat liver homogenate of a new class of nucleoside derivatives, in particular 5′-phosphonate adenosine, inosine, guanosine and thioadenosine analogues also modified at the ribose moiety. On the basis of the results obtained we can hypothesize compounds 4 and 18 to have in vivo a relatively high stability. [Copyright &y& Elsevier]

Abstract: Following the recent output of scientific publications in the matter of synergic activity between different antioxidants, we have undertaken the present study with the aim to synthesize new molecules with radical-scavengers activity based on the conjugation of bioactive portions (i.e. phenols, cysteine, methionine or tyrosine), characterized by different structures and mechanisms of action, to promote the simultaneous quenching of different radical species in the site of the oxidative damage. In this context, derivatives of phenolic acid, aminoacids and dopamine have been also prepared. The newly synthesized compounds were evaluated in vitro applying specific and complementary antioxidant test such as DPPH assay and ORAC test. As emerged from the evaluation, prerequisites for the activity of the synthesized molecules were: i) the maintenance of at least two hydroxylic groups on the aromatic moiety of phenolic portion, ii) the presence of a spacer between the aromatic moiety and the carbonilic group. [Copyright &y& Elsevier]

Abstract: Although the metabolism of vitamin E has been extensively studied in cell culture, animals, and humans, biochemical analyses of intermediate metabolites are scarce. We here describe the synthesis and proapoptotic properties of long-chain metabolites of α- and δ-tocopherol. Several long-chain vitamin E metabolites, namely 13′-hydroxy- and 13′-carboxychromanols, were synthesized from garcinoic acid, a δ-tocotrienol derivative extracted from the African bitter nut Garcinia kola. Both α- and δ-13′-carboxychromanol induced cell death in HepG2 cells at EC50 of 13.5 and 6.5μM, respectively. Apoptosis was quantified by annexin V/7-AAD staining and flow cytometry analysis. By immunoblot analyses, we observed activation of both caspase-3 and caspase-9 as well as PARP-1 cleavage. Parameters of mitochondrial dysfunction including reduced mitochondrial membrane potential and increased intracellular and intramitochondrial reactive oxygen species formation were observed after metabolite treatment. Last, long-chain hydroxychromanols were readily metabolized to the corresponding carboxychromanols in HepG2 cells. Taken together, these results indicate that long-chain metabolites may be responsible for antiproliferative properties of vitamin E vitamers. [Copyright &y& Elsevier]

Abstract: A full study on the synthesis of 3-azabicyclo[4.1.0]heptane-1-carboxylic acid is described. Three different approaches were investigated in order to achieve an efficient synthesis of this unnatural aminoacid. The optimized synthetic route relies upon three key steps: (i) diazomalonate insertion on 4-phtalimido 1-butene, (ii) intramolecular cyclization and (iii) chemoselective reduction of the resulting lactam. Due to its bicyclic nature and conformational constraints, this aminoacid may be an useful building block in medicinal chemistry. [Copyright &y& Elsevier]

Abstract: In this study, we have designed novel chromanyl derivatives that share with α-tocopherol a chromanyl head but differ in the lateral chain in: (i) length and saturation (FEBL-45, 50, 70), (ii) position of double bonds in Z or E (FEBL-50 and 53 and their respective 6-chromanyl methyl derivatives FEBL-161 and 162), or (iii) presence of additional antioxidant molecules, such as the catechol compound hydroxytyrosol (FEBL-80) or dopamine (FEBL-82, 95). The efficiency of these compounds in preventing free-radical-induced oxidative stress was investigated in isolated membranes as well as intact cells. The results of this study clearly show that all compounds synthesized were active in: (i) inhibiting AAPH- or tert-BOOH-induced lipid peroxidation in microsomes and (ii) preventing H2O2-induced ROS production, cell damage, and heat-shock protein expression in immortalized RAT-1 fibroblasts. Such effects were dose- and time-dependent. Independent of the kind of pro-oxidant used, differences in the antioxidant potency of these compounds were found in relation to the chemical structure with respect to the natural α-tocopherol: (1) The concomitant presence of a chromanyl head and an additional aromatic ring markedly increased the antioxidant potency of the molecule. In particular, FEBL-82 and FEBL-95, resulting from the molecular combination of trolox and dopamine, were much more potent than α-tocopherol, α-tocotrienol, and the other synthetic compounds. Moreover, they were also more potent than trolox and dopamine, used alone or in combination, suggesting synergistic cooperative interactions in the molecule between chromanyl and catechol moieties. (2) The length of the side chain affected the antioxidant properties of the molecule: FEBL-70, which displays a bulky squalene side chain, was less effective than the natural α-tocotrienol and the synthetic FEBL-45 and FEBL-50. (3) The presence of polyunsaturated double bonds in the side chain in the Z configuration (FEBL-53, FEBL-162) increased the antioxidant potency of the molecule with respect to the E configuration (FEBL-50, FEBL-161). [Copyright &y& Elsevier]

Abstract: The number of methods to measure antioxidants in botanicals, foods, nutraceuticals and other dietary supplements are increased considerably in the last 10 years. However most techniques require long experimental times and high costs to determine antioxidant capacity of hydrophilic or lipophilic compound in a food mixture. By means of a photochemiluminescence method, we assessed the Integral Antioxidant Capacity (IAC) which represents the sum of the antioxidant capacity of hydrophilic and lipophilic antioxidants. In this study the IAC of extracts from Adansonia digitatata (i.e. red fiber, fruit pulp and leaves), was assessed in comparison to those deriving from other natural sources of antioxidants (i.e. orange, kiwi, apple and strawberry). When compared, IAC values for the examined product resulted as follows: Adansonia digitata red fibre⋙ Adansonia digitata fruit pulp≫ Adansonia digitata fresh leaves≫ Adansonia digitata seeds⩾ Adansonia digitata radix cuticle⩾orange fresh pulp≫strawberry fresh fruit pulp> Adansonia digitata radix>bilberry fresh pulp⩾kiwi fruit pulp. Results clearly indicate the interesting antioxidants properties of Adansonia digitata red fibre, in particular the IAC value of baobab red fibre was 66 time higher than that of orange pulp, with value of 1617.3μmol/g and 24.3μmol/g, respectively. [Copyright &y& Elsevier]

Abstract: Eleven essential oils, namely, Cananga odorata (Annonaceae), Cupressus sempervirens (Cupressaceae), Curcuma longa (Zingiberaceae), Cymbopogon citratus (Poaceae), Eucalyptus globulus (Myrtaceae), Pinus radiata (Pinaceae), Piper crassinervium (Piperaceae), Psidium guayava (Myrtaceae), Rosmarinus officinalis (Lamiaceae), Thymus x citriodorus (Lamiaceae) and Zingiber officinale (Zingiberaceae), were characterized by means of GC and GC–MS and evaluated for their food functional ingredient related properties. These properties were compared to those of Thymus vulgaris essential oil, used as a reference ingredient. Antioxidant and radical-scavenging properties were tested by means of 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, β-carotene bleaching test and luminol-photochemiluminescence (PCL) assay. In the DPPH assay, C. odorata, C. citratus, R. officinalis and C. longa showed major effectiveness, with a radical inhibition ranging from 59.6±0.42–64.3±0.45%. In the β-carotene bleaching test, C. odorata (75.5±0.53%), R. officinalis (81.1±0.57%) and C. longa (72.4±0.51%) gave the best inhibition results. Similar results were obtained for the same essential oils in the PCL assay. Antimicrobial properties were obtained on five food-spoilage yeasts: Candida albicans ATCC 48274, Rhodotorula glutinis ATCC 16740, Schizosaccharomyces pombe ATCC 60232, Saccharomyces cerevisiae ATCC 2365, Yarrowia lypolitica ATCC 16617 . C. citratus and T. x citriodorus were the most effective against the tested strains. Suggestions on relationships between chemical composition and biological activities are outlined. [Copyright &y& Elsevier]

Abstract: GW196771 is a potent antagonist of the modulatory glycine site of the N-methyl-d-aspartate (NMDA) receptor exhibiting outstanding in vivo profile in different animal models of chronic pain. With the aim to maximize the drug delivery to the target organs a suitable “pro-drug approach” was attempted; in this regards two conjugates of GW196771 with nutrients actively transported into the brain, namely adenosine and glucose, were prepared and investigated. These compounds, were evaluated in vitro in terms of their stability in rat plasma and in vivo on rats. Although an improvement was observed in terms of brain penetration of the esters vs. the parent compound, the amount of the latter did not increase significantly, probably due to some degradation events in the brain, different from the expected ester hydrolysis, resulting in a reduced availability of GW196771. [Copyright &y& Elsevier]

We report a preliminary study concerning the encapsulation modalities in nanoparticles of the anti-ischemic drug N6-cyclopentyladenosine (CPA) and its pro-drug 5′-octanoyl-CPA (Oct-CPA). The release of these compounds and the related pro-drug stability effects in human whole blood have been tested. Moreover, the influence of the delivery systems on CPA interaction toward human adenosine A1 receptor has been analysed. The nanospheres were prepared by nanoprecipitation or double emulsion solvent evaporation method using poly(lactic acid) and recovered by gel filtration or ultracentrifugation or dialysis. Free and encapsulated Oct-CPA was incubated in fresh blood and its stability was analysed with HPLC. Quite spherical nanoparticles with mean diameters ranging between 210±50 and 390±90 nm were obtained. No encapsulation occurred when CPA was used. Satisfactory results concerning drug content (0.1–1.1% w/w) and encapsulation efficiency (6–56%) were achieved when Oct-CPA was employed. The controlled release of the pro-drug was achieved, being released within a range of 1–4 h, or very slowly, depending on nanoparticle preparations. The hydrolysis rate of Oct-CPA in human whole blood appeared stabilized in human whole blood with modalities related to the release patterns. The presence of all nanoparticle preparations did not interfere with CPA interaction at its action site. [Copyright &y& Elsevier]

Abstract: Ascorbic acid (AA) or 6-Br-ascorbate (BrAA) conjugation has been investigated as a tool to improve brain drug delivery by the Vitamin C transporter SVCT2. To this aim, the effects of AA- or BrAA-conjugation on drug affinity and uptake have been assessed in vitro, by using human retinal pigment epithelium (HRPE) cells, and compared in vivo on mice. Nipecotic, kynurenic and diclofenamic acids were chosen as model drugs. Kinetic and inhibition experiments referred to [14C]AA uptake into HRPE cells showed that nipecotic and kynurenic acids became able to interact with SVCT2, as competitive inhibitors, only when conjugated to AA or BrAA. Surprisingly, diclofenamic acid itself appeared able to interact with SVCT2, with an affinity that was significantly increased or decreased by AA or BrAA conjugation, respectively. HPLC analysis, performed on HRPE cells, confirmed the SVCT2 mediated transport for the BrAA-conjugate of nipecotic acid, whereas kynurenic acids conjugates although interacting with the transporter did not enter the cells. In accordance, only the nipecotic acid conjugates showed anticonvulsant activity after systemic injection in mice. [Copyright &y& Elsevier]

Several lines of evidence suggest potential benefits by a combination of carotenoids and tocopherols in chronic diseases. Therefore, we have designed FeAOX-6, a novel antioxidant that combines into a single molecule the chroman head of tocopherols and a fragment of lycopene, consisting of a polyisoprenyl sequence of four conjugated double bonds. The ability of FeAOX-6 in inhibiting lipid peroxidation and reactive oxygen species (ROS) production induced by different sources of free radicals (t-BOOH, AAPH, and H2O2) in arachidonic acid solution and in isolated thymocytes was investigated. Its antioxidant efficiency was also compared with that of α-tocopherol, lycopene, and a mixture of the two antioxidants. The results strongly suggest that FeAOX-6 can act as a potent antioxidant in our models, by inhibiting malondialdehyde production and ROS generation in a dose- and a time-dependent manner. In the cell model, the compound also provides a higher antioxidant capacity than α-tocopherol and lycopene, alone or in combination, suggesting the possibility of an oxidative intramolecular cooperation. [Copyright &y& Elsevier]

Three different series of cis -restricted analogues of combretastatin A-4 (CA-4), corresponding to thirty-nine molecules that contained a pyrrole nucleus interposed between the two aryl rings, were prepared by a palladium-mediated coupling approach and evaluated for their antiproliferative activity against six human cancer cell lines. In the two series of 1,2-diaryl pyrrole derivatives, results suggested that the presence of the 3′,4′,5′-trimethoxyphenyl moiety at the N -1 position of the pyrrole ring was more favorable for antiproliferative activity. In the series of 3,4-diarylpyrrole analogues, three compounds (11i-k) exhibited maximal antiproliferative activity, showing excellent antiproliferative activity against the CA-4 resistant HT-29 cells. Inhibition of tubulin polymerization of selected 1,2 pyrrole derivatives (9a , 9c , 9o and 10a) was similar to that observed with CA-4, while the isomeric 3,4-pyrrole analogues 11i-k were generally from 1.5- to 2-fold more active than CA-4. Compounds 11j and 11k were the only compounds that showed activity as inhibitors of colchicine binding comparable to that CA-4. Compound 11j had biological properties consistent with its intracellular target being tubulin. This compound was able to block the cell cycle in metaphase and to induce significant apoptosis at a concentration of 25 nM, following the mitochondrial pathway, with low toxicity for normal cells. More importantly, compound 11j exerted activity in vivo superior to that of CA-4P, being able to significantly reduce tumor growth in a syngeneic murine tumor model even at the lower dose tested (5.0 mg/kg). We have discovered a new class of structurally simple synthetic inhibitors of tubulin polymerization analogues of CA-4, based on 1 H -pyrrole skeleton as heterocycle to fix cis -orientation of 3′,4′,5′-trimethoxybenzene and phenyl substituted ring. Image 1 • Pyrrole-bridged CA-4 analogues modified at the 1-, 2- and 3-position were evaluated. • The position of trimethoxyphenyl on the pyrrole was critical for the activity. • Several compounds were more active than CA-4 against A549 and HT-29 cancer cells. • Several molecules inhibited tubulin assembly with activity superior to that of CA-4. [ABSTRACT FROM AUTHOR]

The seaweed food has always been important in Asia, but recently increased in the Western diet. Superfood known for health benefits and rich in essential elements, can also accumulate high contents of heavy metals and iodine from the environment, becoming a health hazard. In particular for iodine, an appropriate labelling of seaweed is needed to warn the consumer of the potential risks. The aim of the study was to analyze the content of 20 heavy metals in seaweeds, distributed in Italy, by ICP-MS, also determining iodine and arsenic (total and inorganic fraction). A total of 72 samples of European and Asian seaweed of 8 genera were analyzed and the results correlated the content of heavy metals to genus, geographical origin and type of sample; 8.33% of the products lacked in the label of the indications of allergens, while 9.72% had irregularities in the label language. The highest concentration of elements was found in the Rhodophyta. The Aluminum level was the highest in the mixed seaweed (165.39 mg/kg) and for the Cadmium in the Asian seaweed (1.16 mg/kg). The amounts of Iron, Zinc and Magnesium, was highest in the Asian seaweed. The values of Arsenic (total and inorganic contents) were compared with the limits: 2.78% exceeds France and USA limits for inorganic, while higher content of total was found in Phaeophyta, which also showed the highest Iodine content (6770.80 mg/kg) that can be dangerous if not reported correctly in the label. • Analysis of 20 essential and non essential elements was performed by ICP-MS. • Seaweeds are a source of essential dietary elements, particularly Mg and Fe. • Found irregularities on the label of seaweeds about the language and allergens. • Results obtained from the speciation of arsenic: Phaeophyta had the highest content. • Brown seaweeds showed remarkably high values of iodine. [ABSTRACT FROM AUTHOR]

Abstract: The first synthesis of 6-phenyl-2,6-diazabicyclo[3.2.0]heptane 1 and its orthogonally protected precursor 2 is herein reported. Our strategy enables to chemically address the two nitrogen atoms of 2,6-diazabicyclo[3.2.0]heptane core individually and selectively, thus allowing rapid access to several subsets of widely substituted fused azetidines. [Copyright &y& Elsevier]