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61.
Potent,Metabolically Stable 2‐Alkyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands 下载免费PDF全文
Dr. Silvia Pace Dr. Giandomenico Brogin Dr. Maria Antonietta Stasi Dr. Teresa Riccioni Franco Borsini Dr. Francesca Capocasa Dr. Francesco Manera Carlo Tallarico Dr. Pietro Grossi Dr. Federica Vacondio Dr. Michele Bassi Dr. Francesca Bartoccini Dr. Simone Lucarini Dr. Giovanni Piersanti Prof. Giorgio Tarzia Walter Cabri Dr. Patrizia Minetti 《ChemMedChem》2015,10(7):1149-1152
Inhibition of adenosine A2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9H‐purine, ST1535, as a potent A2AR antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω‐1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω‐1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A2AR was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A2AR (Ki=0.4 nM and 2 nM , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours). 相似文献
62.
Characterisation of CYP102A25 from Bacillus marmarensis and CYP102A26 from Pontibacillus halophilus: P450 Homologues of BM3 with Preference towards Hydroxylation of Medium‐Chain Fatty Acids 下载免费PDF全文
Dr. Joanne L. Porter Jack Manning Selina Sabatini Michele Tavanti Prof. Nicholas J. Turner Prof. Sabine L. Flitsch 《Chembiochem : a European journal of chemical biology》2018,19(5):513-520
Cytochrome P450 monooxygenases are highly desired biocatalysts owing to their ability to catalyse a wide variety of chemically challenging C?H activation reactions. The CYP102A subfamily of enzymes are natural catalytically self‐sufficient proteins consisting of a haem and FMN‐FAD reductase domain fused in a single‐component system. They catalyse the oxygenation of saturated and unsaturated fatty acids to produce primarily ω?1, ω?2 and ω?3 hydroxy acids. These monooxygenases have potential applications in biotechnology; however, their substrate range is still limited and there is a continued need to add diversity to this class of biocatalysts. Herein, we present the characterisation of two new members of this class of enzymes, CYP102A25 (BMar) from Bacillus marmarensis and CYP102A26 (PHal) from Pontibacillus halophilus, both of which express readily in a recombinant bacterial host. BMar exhibits the highest activity toward myristic acid and shows moderate activity towards unsaturated fatty acids. PHal exhibits broader activity towards mid‐chain‐saturated (C14–C18) and unsaturated fatty acids. Furthermore, PHal shows good regioselectivity for the hydroxylation of myristic acid, targeting the ω?2 position for C?H activation. 相似文献
63.
Michele Iuliani Sonia Simonetti Giulia Ribelli Andrea Napolitano Umile Giuseppe Longo Bruno Vincenzi Paolo Orsaria Vincenzo Denaro Giuseppe Tonini Daniele Santini Pantano Francesco 《International journal of molecular sciences》2022,23(5)
The CDK4/6 inhibitors (CDKi) palbociclib, ribociclib, and abemaciclib are currently approved in combination with anti-estrogen therapy for the treatment of advanced and/or metastatic hormone receptor-positive/HER2-neu-negative breast cancer patients. Given the high incidence of bone metastases in this population, we investigated and compared the potential effects of palbociclib, ribociclib, and abemaciclib on the breast cancer bone microenvironment. Primary osteoclasts (OCs) and osteoblasts (OBs) were obtained from human monocyte and mesenchymal stem cells, respectively. OC function was evaluated by tartrate-resistant acid phosphatase assay and real-time PCR; OB activity was assessed by an alizarin red assay. OB/breast cancer co-culture models were generated via the seeding of MCF-7 cells on a layer of OBs, and tumor cell proliferation was analyzed using flow cytometry. Here, we showed that ribociclib, palbociclib, and abemaciclib exerted similar inhibitory effects on the OC differentiation and expression of bone resorption markers without affecting OC viability. On the other hand, the three CDKi did not affect the ability of OB to produce bone matrix, even if the higher doses of palbociclib and abemaciclib reduced the OB viability. In OB/MCF-7 co-culture models, palbociclib demonstrated a lower anti-tumor effect than ribociclib and abemaciclib. Overall, our results revealed the direct effects of CDKi on the tumor bone microenvironment, highlighting differences potentially relevant for clinical practice. 相似文献
64.
Elvira Sondo Federico Cresta Cristina Pastorino Valeria Tomati Valeria Capurro Emanuela Pesce Mariateresa Lena Michele Iacomino Ave Maria Baffico Domenico Coviello Tiziano Bandiera Federico Zara Luis J. V. Galietta Renata Bocciardi Carlo Castellani Nicoletta Pedemonte 《International journal of molecular sciences》2022,23(6)
Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators. 相似文献
65.
Computational results were obtained for turbulent flow and heat transfer in curved pipes, representative of helically coiled heat exchangers. Following a grid refinement study, grid independent predictions from alternative turbulence models (k–?, SST k–ω and RSM–ω) were compared with DNS results and experimental pressure drop and heat transfer data. Using the SST k–ω and RSM–ω models, pressure drop results were in excellent agreement with literature data and the Ito correlation. For heat transfer, the literature is not comparably complete or accurate, but a satisfactory agreement was obtained in the range of available data. Unsatisfactory results, both for pressure drop and heat transfer, were given by the k–? model with wall functions. Following the validation study, the RSM–ω model was used to compute friction coefficients and Nusselt numbers in the range Re = 1.4·104–8·104, Pr = 0.7–5.6 and δ (coil curvature) = 3·10?3–0.3. Power-law correlations were found unsuitable to fit the Re-, Pr- and δ-dependence of the Nusselt number, while the use of a properly formulated momentum-heat transfer analogy collapsed all results with high accuracy. 相似文献
66.
In recent years, a peculiar homelessness policy that goes under the name of ‘Housing First’ has become increasingly popular all over the world. Epitomising a quintessential case of policy-mobility, Housing First can today be considered an heterogeneous assemblage of experiences and approaches that sometimes have little in common with each other. Introducing and commenting upon this heterogeneity, the paper critically analyses why and how Housing First has become a planetary success and what are the issues at stake with its widespread implementation. If recent scholarship published in this journal has granted us a fine understanding of Housing First’s functioning in the US, this paper offers something currently absent from the debate: a nuanced and critical understanding of the ambiguities related to the international success of this policy, with specific references to the challenges associated to its translation in the Italian case. 相似文献
67.
Cristina Jansen-Alves Karina F. Fernandes Michele M. Crizel-Cardozo Fernanda D. Krumreich Caroline D. Borges Rui C. Zambiazi 《Food and Bioprocess Technology》2018,11(7):1422-1436
Propolis presents several health benefits due to the presence of bioactive compounds, mainly phenolic compounds; however, its application in food is limited due to undesirable odor and low water solubility. The bioactive compounds are usually susceptible to degradation by exposure to light, heat, or oxygen or by interaction with other compounds, which may limit its biological activity. The study aimed the propolis extract microencapsulation using rice, pea, soybean, and ovoalbumin proteins as wall material by spray drying and to analyze their in vitro digestion. The propolis extract presented a high concentration of apigenin. Encapsulation efficiency was greater than 70%, and it was maintained the antioxidant activity of propolis (88% inhibition of DPPH for propolis extract and >?73% for the microparticles). The DSC, ATR-FTIR, and X-ray diffraction techniques confirmed the encapsulation. The microparticles showed different shapes, sizes, and physical characteristics. The microparticles encapsulated with pea protein could be used in formulations of Minas Frescal cheese due to the controlled released, whereas the other microparticles could be used in pudding formulations. 相似文献
68.
Arceo Aldrick Rosano Michele Biswas Wahidul K. 《Clean Technologies and Environmental Policy》2018,20(3):463-475
Clean Technologies and Environmental Policy - Remote area power supply (RAPS) systems in Western Australia account for more than 56% of total off-grid electricity supply in Australia and utilise... 相似文献
69.
Da-Wei Luo P. V. Pyshkin Michele Modugno Mike Guidry J. Q. You Lian-Ao Wu 《Quantum Information Processing》2018,17(9):238
We propose an exact mathematical mapping that can be useful for making an analog quantum simulator that uses ion-based systems to realize the many-body electron–electron Coulomb interaction of an electron gas. This exact mathematical mapping allows us to deal with a system that is difficult to solve and control using a potentially more experimentally feasible setup. We show that ions can efficiently simulate electronic Coulomb interactions by using a unitary dilatation transform. The transformation does not need to be physically implemented if only the energy spectrum is desired, eliminating the complexity overhead. This proposal works in any number of dimensions and could be used to simulate different topological phases of electrons in graphene-like structures, by using ions confined in honeycomb lattices. 相似文献
70.
Benedicta Normanna Limata Lucio Gialanella Nicola De Cesare Antonio D’Onofrio G. Gyurky Mario Romano Detlef Rogalla Michele Russo Filippo Terrasi 《Nuclear instruments & methods in physics research. Section B, Beam interactions with materials and atoms》2008,266(10):2117-2121
A pure 7Be beam with an energy E = 1-8 MeV is available for nuclear and applied physics at the 3 MV Pelletron tandem accelerator CIRCE in Caserta. The beam is produced using an offline technique. Typical analyzed beam intensities are about 2 ppA, using cathodes with an activity of the order of 200 MBq. The 7Be implantation has been used for both fundamental nuclear physics and applied physics. In particular, different metals have been implanted with 7Be in order to study the influence of the chemical composition and of the number of quasi-free electrons of the host material on the 7Be half-life. In the field of applied physics, the 7Be implantation turns out to be very interesting for wear measurement. In fact, in this case 7Be is used as a depth-sensitive tracer. The continuous detection of the sample activity during the wear allows a high sensitivity measurement of wearing speed. The 7Be beam production at CIRCE, the implantation procedure and the results obtained from the 7Be half-life measurements and the wear characterization of implanted steel samples are described. 相似文献