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• Pecorello and Mantonico pomaces represent a useful source of bioactive compounds. • Calabrian white grape pomaces were firstly investigated for their vasoactive properties. • The effects of extracts were analyzed in in vitro experiments on rat aorta rings. • Pecorello appeared more efficacious than Mantonico as a vasorelaxant extract. The valorisation of agrochemical wastes has become a low cost and sustainable tendency for the development of functional food. In particular, these enriched products seem to be enjoyable tools to treat metabolic disorders. In this field, Calabrian autochthonous white grape pomaces (Mantonico and Pecorello cultivar) were firstly investigated for their vasoactive properties. Skins and seeds were extracted and characterized by NMR spectroscopy, revealig the presence of numerous vasoactive compounds. The effects of extracts were analyzed in in vitro experiments on rat aorta rings (with and without endothelium), contracted by phenylephrine or KCl. Seeds extracts showed, differently from skins, an appreciable endothelium-dependent, eNOS-mediated vasodilation in the range 1–100 µg/mL. From a food market point of view, all the extracts were enclosed into a pectin polymer matrix. In the same experimental conditions, the polymers demonstrated the persistance of vasodilator activity only for Pecorello seed extract, which presented the most rich chemical profile. [ABSTRACT FROM AUTHOR]

IL-7 is required for T cell differentiation and mature T cell homeostasis and promotes pro-B cell proliferation and survival. Tyrosine phosphorylation plays a central role in IL-7 signaling. We identified by two-dimensional electrophoresis followed by anti-phosphotyrosine immunoblotting and mass spectrometry sixteen tyrosine phosphorylated proteins from the IL-7-dependent cell line D1. IL-7 stimulation induced the phosphorylation of the proteins STI1, ATIC and hnRNPH, involved in pathways related to survival, proliferation and gene expression, respectively, and increased the phosphorylation of CrkL, a member of a family of adaptors including the highly homologous Crk isoforms CrkII and CrkI, important in multiple signaling pathways. We observed an increased phosphorylation of CrkL in murine pro-B cells and in murine and human T cells. In addition, IL-7 increased the association of CrkL with the transcription factor Stat5, essential for IL-7 pro-survival activity. The selective tyrosine kinase inhibitor Imatinib. counteracted the IL-7 pro-survival effect in D1 cells and decreased CrkL phosphorylation. These data suggested that CrkL could play a pro-survival role in IL-7-mediated signaling. We observed that pro-B cells also expressed, in addition to CrkL, the Crk isoforms CrkII and CrkI and therefore utilized pro-B cells conditionally deficient in all three to evaluate the role of these proteins. The observation that the IL-7 pro-survival effect was reduced in Crk/CrkL conditionally-deficient pro-B cells further pointed to a pro-survival role of these adaptors. To further evaluate the role of these proteins, gene expression studies were performed in Crk/CrkL conditionally-deficient pro-B cells. IL-7 decreased the transcription of the receptor LAIR1, which inhibits B cell proliferation, in a Crk/CrkL-dependent manner, suggesting that the Crk family of proteins may promote pro-B cell proliferation. Our data contribute to the understanding of IL-7 signaling and suggest the involvement of Crk family proteins in pathways promoting survival and proliferation. [ABSTRACT FROM AUTHOR]

In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB 1 and CB 2 receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds behaved as very potent cannabinoid receptor ligands ( K i in the nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH. Derivative 11 was a potent CB 1 and CB 2 ligand, with K i values similar to WIN 55,212, exhibiting a CB 1 and CB 2 agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain in mice, this compound showed a weak and delayed antinociceptive effect against the second phase of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14 , characterized by lower affinity but higher CB 2 selectivity than 11 , proved to behave as a weak CB 2 competitive inverse agonist. [ABSTRACT FROM AUTHOR]

Abstract: Stem cells are able to generate both cells that differentiate and cells that remain undifferentiated but potentially have the same developmental program. The prolonged duration of the protective immune memory for infectious diseases such as polio, small pox, and measles, suggested that memory T cells may have stem cell properties. Understanding the molecular basis for the life-long persistence of memory T cells may be useful to project targeted therapies for immune deficiencies and infectious diseases and to formulate vaccines. In the last decade evidence from different laboratories shows that memory T cells may share self-renewal pathways with bone marrow hematopoietic stem cells. In stem cells the intrinsic self-renewal activity, which depends on gene expression, is known to be modulated by extrinsic signals from the environment that may be tissue specific. These extrinsic signals for stemness of memory T cells include cytokines such as IL-7 and IL-15 and there are other cytokine signals for maintaining the cytokine signature (TH1, TH2, etc.) of memory T cells. Intrinsic and extrinsic pathways that might be common to bone marrow hematopoietic stem cells and memory T lymphocytes are discussed and related to self-renewal functions. [Copyright &y& Elsevier]

In acute rejection after renal transplant, glomerulitis is characterized by mononuclear cells in glomerular capillaries and endothelial cell enlargement. In association with C4d deposition in peritubular capillaries, glomerulitis is a feature of acute antibody-mediated rejection. Prognosis in C4d+ rejection is poorer than in C4d- rejection. We measured the glomerular endothelial cell area in C4d+ and C4d- acute rejections by morphometry. In 90 acute rejection biopsies, glomerulitis was present in 36 cases (group G) and absent in 54 (group G0). In biopsies without rejections and in C4d- biopsies of group G0, glomerular endothelial cell area was not significantly different. In C4d- and C4d+ biopsies of group G, the area in inflamed glomeruli was greater than that in C4d- biopsies of group G0 (P b .02 and P b .006, respectively). In C4d+ biopsies of group G0, it was, unexpectedly, greater than in C4d- biopsies of group G (P b .01). Circulating posttransplant anti-human leukocyte antigen class I and class II antibodies correlated with increased endothelial cell area (P b .02). Glomerulitis was associated with diffuse C4d deposition (odds ratio [OR], 4.27; P b .004); C4d deposition was associated with steroid resistance (OR, 4.97; P b .002). Only in C4d+ rejections did the presence of glomerulitis increase this association (OR, 9.17; P b .02). In conclusion, we quantified an increase of endothelial cell area in glomerulitis of C4d+ and C4d- acute rejections (group G). An increase of this area in C4d+ biopsies without glomerulitis (group G0) suggests complement-mediated damage in the absence of mononuclear cell margination. [ABSTRACT FROM AUTHOR]

Abstract: A series of 9H-pyrrolo[1,2-a]indol-9-ones have been prepared via in-situ sequential oxidation of [2-(1H-pyrrol-1-yl)phenyl]methanols promoted by active manganese dioxide. The procedure led to title compounds in good yields under mild conditions, without the need to isolate the intermediate aldehydes. [Copyright &y& Elsevier]

Abstract: Recently, we discovered a novel class of anticancer compounds with remarkable potency in a panel of cancer cell lines. A prototype compound, SC144, showed significant in vivo efficacy in mice xenograft models of human breast cancer cells. Herein, we report on a new synthetic route to SC144 and the synthesis of several of its analogues in order to understand required features for activity. A one-step coupling of 7-fluoro-4-chloropyrrolo[1,2-a]quinoxaline with pyrazin-2-carbohydrazide improved the yield significantly. Although several of the analogues showed significant activities, modification of the heteroacyl moiety had a dramatic effect on potency. [Copyright &y& Elsevier]

Thiazolothiazepines are among the smallest and most constrained inhibitors of human immunodeficiency virus type-1 integrase (HIV-1 IN) inhibitors (J. Med. Chem. 1999, 42, 3334). Previously, we identified two thiazolothiazepines lead IN inhibitors with antiviral activity in cell-based assays. Structural optimization of these molecules necessitated the design of easily synthesizable analogs. In order to design similar molecules with least number of substituent, herein we report the synthesis of 10 novel analogs. One of the new compounds (1) exhibited similar potency as the reference compounds, confirming that a thiazepinedione fused to a naphthalene ring system is the best combination for the molecule to accommodate into the IN active site. Thus, the replacement of sulfur in the thiazole ring with an oxygen does not seem considerably affect potency. On the other hand, the introduction of an extra methyl group at position 1 of the polycyclic system or the shift from a thiazepine to an oxazepine skeleton decreased potency. In order to understand their mode of interactions with IN active site, we docked all the compounds onto the previously reported X-ray crystal structure of IN. We observed that compounds 7–9 occupied an area close to D64 and Mg2+ and surrounded by amino acid residues K159, K156, N155, E152, D116, H67, and T66. The oxygen atom of the oxazolo ring of 7 and 8 could chelate Mg2+. These results indicate that the new analogs potentially interact with the highly conserved residues important for IN catalytic activities. [Copyright &y& Elsevier]

The simultaneous quantitative assay of 1,4-dihydropyridine calcium antagonist manidipine and its main photodegradation by-product has been defined by using a multivariate calibration on UV spectra based on a classical least squares regression. Optimization of the procedure was achieved by means of a calibration model using suitable wavelength ranges singled out from a fractionation scheme thereat defined. Recovery values of 99 and 96% for the drug and the by-product, respectively, were found either in appropriately prepared mixtures and commercial formulations. Quantification limit for the photoproduct concentration was estimated as 1.0% for the reference samples. [Copyright &y& Elsevier]

Abstract: A series of fused heterocyclic compounds based on a fluorazone structure has been prepared from anthranilic or ortho-aminoheteroaryl carboxylic acids by one-pot sequential pyrrolation/cyclization catalyzed by 4-chloropyridine hydrochloride, in generally good yield. [Copyright &y& Elsevier]

• Endocannabinoid system is a complex and dynamic pharmacological target. • Cannabinoid receptor interaction and selectivity. • The alkylresorcinol skeleton is a suitable scaffold for cannabinoid receptor ligands. • Alkylresorcinols endowed with antinociceptive activity in vivo. • Dual TRPV1/cannabinoid ligands. Focusing on the importance of the free phenolic hydroxyl moiety, a family of 23 alkylresorcinol-based compounds were developed and evaluated for their cannabinoid receptor binding properties. The non-symmetrical hexylresorcinol derivative 29 turned out to be a CB2-selective competitive antagonist/inverse agonist endowed with good potency. Both the olivetol- and 5-(2-methyloctan-2-yl)resorcinol-based derivatives 23 and 24 exhibited a significant antinociceptive activity. Interestingly, compound 24 proved to be able to activate both cannabinoid and TRPV1 receptors. Even if cannabinoid receptor subtype selectivity remained a goal only partially achieved, results confirm the validity of the alkylresorcinol nucleus as skeleton for the identification of potent cannabinoid receptor modulators. [ABSTRACT FROM AUTHOR]

Abstract: A series of fused heterocyclic compounds based on a pyrrolizinone structure have been prepared from ortho-(1H-pyrrol-1-yl)aryl and heteroaryl carboxylic acids by intramolecular Friedel–Crafts acylation promoted by bis(trichloromethyl) carbonate, in generally good yield without using Lewis acid catalysts. [Copyright &y& Elsevier]

Abstract: IL-7 is essential for the development and survival of T lymphocytes. This review is primarily from the perspective of the cell biology of the responding T cell. Beginning with IL-7 receptor structure and regulation, the major signaling pathways appear to be via PI3K and Stat5, although the requirement for either has yet to be verified by published knockout experiments. The proliferation pathway induced by IL-7 differs from conventional growth factors and is primarily through posttranslational regulation of p27, a Cdk inhibitor, and Cdc25a, a Cdk-activating phosphatase. The survival function of IL-7 is largely through maintaining a favorable balance of bcl-2 family members including Bcl-2 itself and Mcl-1 on the positive side, and Bax, Bad and Bim on the negative side. There are also some remarkable metabolic effects of IL-7 withdrawal. Studies of IL-7 receptor signaling have yet to turn up unique pathways, despite the unique requirement for IL-7 in T cell biology. There remain significant questions regarding IL-7 production and the major producing cells have yet to be fully characterized. [Copyright &y& Elsevier]

The G-protein-coupled receptor 40 (GPR40) is an attractive molecular target for the treatment of type 2 diabetes mellitus. Previously, based on the natural oleic acid substrate, an exogenous ligand for this receptor, named AV1 , was synthesized. In this context, here we validated the activity of AV1 as a full agonist, while the corresponding catechol analogue, named AV2 , was investigated for the first time. The ligand-protein interaction between this new molecule and the receptor was highlighted in the lower portion of the GPR40 groove that generally accommodates DC260126. The functional assays performed have demonstrated that AV2 is a suitable GPR40 partial agonist, showing a therapeutic potential and representing a useful tool in the management of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Sesquiterpene compounds are widely known for their numerous pharmacological activities. Herein the focus of the authors was on α-Santonin, a sesquiterpene lactone from the Artemisia genus: the aim was to determine whether α-Santonin could be considered in the treatment of inflammation and pain. To this purpose, a small series of derivatives was designed and screened in silico against the enzyme COX-2 along with the parent compound. Drug-likeness parameters were also assessed. The compounds were eventually synthesized, and few were tested to determine their efficacy in the inhibition of COX-2 activity and expression. Overall, compound A2 was the only one with a detectable inhibitory potential of COX-2 activity whilst two of its ether derivatives demonstrated improved ability in the inhibition of COX-2 expression. [ABSTRACT FROM AUTHOR]

Nowadays there is a folk medicine branch called apitherapy that aims to treat diseases with bee products, including honey. Honey has long been known for its medicinal and health promoting properties. It encloses numerous types of phytochemicals with high phenolic and flavonoid content, which contribute to its antioxidant and anti-inflammatory activities. Varieties and variants of polyphenols in honey showed antiproliferative property against several types of cancer. This review focuses on the latest discoveries about the key role of honey in different stages of carcinogenesis, initiation, proliferation and progression, both in vitro and in vivo , as well as on its adjuvant effect in cancer therapy. Although a possible application of honey and its active compounds as drugs against cancer is still far away from clinical practice, scientific results highlight that they could be used as immune booster for patients undergoing chemotherapy. They showed protective effects against the common exasperating and disabling side effects, mostly mucositis. [ABSTRACT FROM AUTHOR]

In this study, we investigate the anti-proliferative activity of a small library of 7-substituted 5 H -pyrrolo[1,2- a ][3,1]benzoxazin-5-one derivatives, against a panel of human cancer cell lines. We reported the synthesis of these compounds in a previous work. 7-Bromo-5 H -benzo[ d ]pyrrolo[2,1- b ][1,3]oxazin-5-one showed a promising anti-proliferative effect. As starting material for Suzuki-Miyaura cross coupling reaction, it was selected for the design and the synthesis of six further derivatives, with the aim to better define structure-activity relationships. The anti-proliferative MTT assay revealed a dose-dependent reduction of cell viability, especially for 7-([1,1′-biphenyl]-4-yl)-5 H -benzo[ d ]pyrrolo[2,1- b ][1,3]oxazin-5-one. Cell cycle and western blotting analysis suggested apoptosis as possible mechanism for its anti-proliferative activity. These preliminary results encourage our interest for further optimizations. [ABSTRACT FROM AUTHOR]

Abstract: The hitherto unknown lactone 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one and six of its substituted derivatives have been prepared by active manganese dioxide promoted oxidative cyclization of the corresponding 2-(1H-pyrrol-1-yl)benzoic acids, under mild conditions, in moderate yields. The method was successfully extended to the cyclization of some ortho-(1H-pyrrol-1-yl)heteroaryl carboxylic acids and 2-(1H-indol-1-yl)benzoic acids. [Copyright &y& Elsevier]

[Display omitted] The progress made so far in the elucidation of the structure of free fatty acid receptor 1 (FFAR1) and its secondary and ternary complexes with partial and full allosteric ligands led to the discovery of various putative binding regions on the FFAR1 surface. Attempts to develop FFAR1 agonists culminated with the identification of TAK-875 (1), whose phase 3 clinical trials were terminated due to potential liver toxicity. In the search of safer agonists, numerous classes of new compounds were designed, synthesized, and tested. Chemical decoration of the scaffolds was rationalized to reach a good balance between lipophilicity, activity, and toxicity. Today, targeting FFAR1 with positive modulators represents an attractive pharmacological tool for the treatment of type 2 diabetes mellitus (T2DM), mainly because of the lack of hypoglycaemic side effects associated with several antidiabetic drugs currently available. Moreover, considering the involvement of FFAR1 in many physio-pathological processes, its agonists are also emerging as possible therapeutic tools for alleviating organ inflammation and fibrosis, as well as for the treatment of CNS disorders, such as Alzheimer's disease and dementia. [ABSTRACT FROM AUTHOR]

[Display omitted] Ca V 1.2 channels play a fundamental role in the regulation of vascular smooth muscle tone. The aim of the present study was to synthesize morin derivatives bearing the nitrophenyl moiety of dihydropyridine Ca2+ antagonists to increase the flavonoid vasorelaxant activity. The effects of morin and its derivatives were assessed on Ca V 1.2 and K Ca 1.1 channels, both in vitro and in silico , as well as on the contractile responses of rat aorta rings. All compounds were effective Ca V 1.2 channel blockers, positioning in the α 1C subunit region where standard blockers bind. Among the four newly synthesized morin derivatives, the penta-acetylated morin-1 was the most efficacious Ca2+ antagonist, presenting a vasorelaxant profile superior to that of the parent compound and, contrary to morin, antagonized also the release of Ca2+ from the sarcoplasmic reticulum; surprisingly, it also stimulated K Ca 1.1 channel current. Computational analysis demonstrated that morin-1 bound close to the K Ca 1.1 channel S6 segment. In conclusion, these findings open a new avenue for the synthesis of valuable multi-functional, vasorelaxant morin derivatives capable to target several pathways underpinning the pathogenesis of hypertension. [ABSTRACT FROM AUTHOR]

• A set of 39 piperazine-derived thioureas was evaluated against colistin-resistant Acinetobacter baumannii clinical strains. • Six derivatives inhibited bacterial growth of 46% of the A. baumannii strains at low micromolar concentrations. • Bactericidal activity (time kill curve) was tested for compound 41 against two colistin-resistant A. baumannii strains. • Compound 41 was also tested for synergistic combination with colistin against the same two clinical strains. • Their potential anti-inflammatory activity was assessed by their ability to inhibit the production of nitric oxide. A. baumannii is one of the most important multidrug-resistant microorganisms in hospital units. It is resistant to many classes of antibiotics and the development of new therapeutic strategies is necessary. The aim of this study was to evaluate the antibacterial activity of a set of piperazine-derived thioureas against 13 clinical strains of colistin-resistant A. baumannii. Six derivatives were identified to inhibit bacterial growth of 46% of the A. baumannii strains at low micromolar concentrations (Minimum Inhibitory Concentration from 1.56 to 6.25 μM). A common structural feature in most active compounds was the presence of a 3,5-bis-trifluoromethyl phenyl ring at the thiourea function. In addition, the ability of the compounds to inhibit production of nitric oxide (NO) was examined in RAW 264.7 murine macrophages, highlighting the potential of piperazine-derived thioureas as promising scaffolds for the design of new combined anti-bacterial/anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

In recent years, human adenovirus (HAdV) infections have shown a high clinical impact in both immunosuppressed and immunocompetent patients. The research into specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients constitutes a principal objective for medicinal chemistry due to the lack of any specific secure drug to treat these infections. In this study, we report a small-molecule library (67 compounds) designed from an optimization process of piperazine-derived urea privileged structures and their biological evaluation: antiviral activity and cytotoxicity. The active compounds selected were further evaluated to gain mechanistic understanding for their inhibition. Twelve derivatives were identified that inhibited HAdV infections at nanomolar and low micromolar concentrations (IC 50 from 0.6 to 5.1 μM) with low cytotoxicity. In addition, our mechanistic assays suggested differences in the way the derivatives exert their anti -HAdV activity targeting transcription, DNA replication and later steps in the HAdV replication cycle. Furthermore, eight of the 12 studied derivatives blocked human cytomegalovirus (HCMV) DNA replication at low micromolar concentrations. The data provided herein indicates that the 12 thiourea/urea piperazine derivatives studied may represent potential lead compounds for clinical evaluation and development of new anti -HAdV drugs. Image 1 • Design, synthesis and evaluation of a small library through an optimization process. • The synthesis was carried out following a short and high yielded methodology. • Twelve derivatives were identified to inhibit HAdV replication (IC 50 from 0.6 to 5.1 μM) with low cytotoxicity. • They targeted different steps on the HAdV replicative cycle. • Six compounds have been selected for further in vivo studies in Syriam Hamster model. [ABSTRACT FROM AUTHOR]