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71.
Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs 下载免费PDF全文
Prof. Kyriacos C. Nicolaou Dr. Dionisios Vourloumis Dr. Sotirios Totokotsopoulos Dr. Athanasios Papakyriakou Dr. Holger Karsunky Hanan Fernando Dr. Julia Gavrilyuk Dr. Damien Webb Dr. Antonia F. Stepan 《ChemMedChem》2016,11(1):31-37
A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non‐aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane‐ and cubane‐containing analogues were found to possess higher themodynamic solubility, whereas cubane‐ and cyclohexyl‐containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP‐B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off‐target effects. 相似文献
72.
15‐Methylene‐Eburnamonine Kills Leukemic Stem Cells and Reduces Engraftment in a Humanized Bone Marrow Xenograft Mouse Model of Leukemia 下载免费PDF全文
Dr. Dilini C. Gunasekara Dr. Mary M. Zheng Tara Mojtahed Dr. James R. Woods Prof. Tamer E. Fandy Dr. Mark V. Riofski Prof. Carlotta A. Glackin Prof. Hazem E. Hassan Dr. Julia Kirshner Prof. David A. Colby 《ChemMedChem》2016,11(21):2392-2397
Recent studies suggest that leukemia stem cells (LSCs) play a critical role in the initiation, propagation, and relapse of leukemia. Herein we show that (?)‐15‐methylene‐eburnamonine, a derivative of the alkaloid (?)‐eburnamonine, is cytotoxic against acute and chronic lymphocytic leukemias (ALL and CLL) and acute myelogenous leukemia (AML). The agent also decreases primary LSC frequency in vitro. The cytotoxic effects appear to be mediated via the oxidative stress pathways. Furthermore, we show that the compound kills AML, ALL, and CLL stem cells. By the use of a novel humanized bone marrow murine model of leukemia (huBM/NSG), it was found to decrease progenitor cell engraftment. 相似文献
73.
N‐Benzyl‐4‐((heteroaryl)methyl)benzamides: A New Class of Direct NADH‐Dependent 2‐trans Enoyl–Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity 下载免费PDF全文
Ana Guardia Dr. Gulcin Gulten Dr. Raquel Fernandez Jesus Gómez Dr. Feng Wang Dr. Maire Convery Delia Blanco María Martínez Dr. Esther Pérez‐Herrán Marta Alonso Dr. Fátima Ortega Dr. Joaquín Rullás Dr. David Calvo Lydia Mata Dr. Robert Young Prof. James C. Sacchettini Dr. Alfonso Mendoza‐Losana Dr. Modesto Remuiñán Dr. Lluís Ballell Pages Dr. Julia Castro‐Pichel 《ChemMedChem》2016,11(7):687-701
Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug‐sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug‐resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH‐dependent 2‐trans enoyl–acyl carrier protein reductase (InhA) inhibitors based on an N‐benzyl‐4‐((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG‐related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure–activity relationships. Furthermore, a co‐crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis. 相似文献
74.
Bin Qiu Susan E. Luczak Tamara L. Wall Aaron M. Kirchhoff Yuxue Xu Mimy Y. Eng Robert B. Stewart Weinian Shou Stephen L. Boehm II Julia A. Chester Weidong Yong Tiebing Liang 《International journal of molecular sciences》2016,17(8)
FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO) mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1) Fkbp5 KO and wild-type (WT) EtOH consumption was tested using a two-bottle choice paradigm; (2) The EtOH elimination rate was measured after intraperitoneal (IP) injection of 2.0 g/kg EtOH; (3) Blood alcohol concentration (BAC) was measured after 3 h limited access of alcohol; (4) Brain region expression of Fkbp5 was identified using LacZ staining; (5) Baseline corticosterone (CORT) was assessed. Additionally, two SNPs, rs1360780 (C/T) and rs3800373 (T/G), were selected to study the association of FKBP5 with alcohol consumption in humans. Participants were college students (n = 1162) from 21–26 years of age with Chinese, Korean or Caucasian ethnicity. The results, compared to WT mice, for KO mice exhibited an increase in alcohol consumption that was not due to differences in taste sensitivity or alcohol metabolism. Higher BAC was found in KO mice after 3 h of EtOH access. Fkbp5 was highly expressed in brain regions involved in the regulation of the stress response, such as the hippocampus, amygdala, dorsal raphe and locus coeruleus. Both genotypes exhibited similar basal levels of plasma corticosterone (CORT). Finally, single nucleotide polymorphisms (SNPs) in FKBP5 were found to be associated with alcohol drinking in humans. These results suggest that the association between FKBP5 and alcohol consumption is conserved in both mice and humans. 相似文献
75.
Bjoern Titz Karsta Luettich Patrice Leroy Stephanie Boue Gregory Vuillaume Terhi Vihervaara Kim Ekroos Florian Martin Manuel C. Peitsch Julia Hoeng 《International journal of molecular sciences》2016,17(9)
Smoking is a major risk factor for several diseases including chronic obstructive pulmonary disease (COPD). To better understand the systemic effects of cigarette smoke exposure and mild to moderate COPD—and to support future biomarker development—we profiled the serum lipidomes of healthy smokers, smokers with mild to moderate COPD (GOLD stages 1 and 2), former smokers, and never-smokers (n = 40 per group) (ClinicalTrials.gov registration: ). Serum lipidome profiling was conducted with untargeted and targeted mass spectrometry-based lipidomics. Guided by weighted lipid co-expression network analysis, we identified three main trends comparing smokers, especially those with COPD, with non-smokers: a general increase in glycero(phospho)lipids, including triglycerols; changes in fatty acid desaturation (decrease in ω-3 polyunsaturated fatty acids, and an increase in monounsaturated fatty acids); and an imbalance in eicosanoids (increase in 11,12- and 14,15-DHETs (dihydroxyeicosatrienoic acids), and a decrease in 9- and 13-HODEs (hydroxyoctadecadienoic acids)). The lipidome profiles supported classification of study subjects as smokers or non-smokers, but were not sufficient to distinguish between smokers with and without COPD. Overall, our study yielded further insights into the complex interplay between smoke exposure, lung disease, and systemic alterations in serum lipid profiles. NCT01780298相似文献
76.
Enhanced transport properties of Sn-substituted proton-conducting BaZr0.8Sc0.2O3–δ ceramic materials
Inna A. Zvonareva Anna V. Kasyanova Artem P. Tarutin Gennady K. Vdovin Julia G. Lyagaeva Dmitry A. Medvedev 《Journal of the American Ceramic Society》2022,105(3):2105-2115
High-temperature proton conductors based on acceptor-doped barium zirconate exhibit excellent chemical stability in atmospheres containing CO2 or H2O. However, due to their refractory nature, these conductors have a low grain growth rate, which negatively affects the overall electrical conductivity. A possible strategy for increasing the ionic conductivity of zirconates lies in the partial substitution of Zr-ions with other isovalent dopants. In this work, we carried out systematic studies of the crystal structure, microstructure, hydration capacity, transport, and thermal properties of BaZr0.8–xSnxSc0.2O3–δ (x = 0, 0.1, and 0.2). According to X-ray powder diffraction and scanning electron microscopy data, all studied ceramic samples have a cubic perovskite structure, whose average grain size decreases with tin doping. It is found that the composition with x = 0.1 exhibits the highest values in terms of total, ionic, grain, and grain-boundary conductivities. The complex analysis of the obtained data shows that a low-level substitution of Zr4+- with Sn4+-ions is a competent approach for designing new proton-conducting electrolytes attractive for high-temperature applications. 相似文献
77.
de Melo Henrique João Miller Isidro Julia Saez Cristina Dos Santos Elisama V. Rodrigo Manuel A. 《Journal of Applied Electrochemistry》2022,52(9):1317-1326
Journal of Applied Electrochemistry - This paper evaluates the remediation of soil spiked with lindane using a combined treatment consisting of electrokinetic soil flushing (EKSF) with air... 相似文献
78.
A considerable body of knowledge now exists from studies involving the development of lead‐free piezoelectric ceramics and a number of high potential alternatives to current lead‐based materials have been identified. Stability under cyclic electric fields is an important property of piezoelectric materials. Here, we review the research to date which shows that fatigue under cyclic electrical loading is prevalent in many lead‐free piezoelectric ceramic compositions. However, the variety of compositions and mechanisms for piezoelectric behavior in these materials corresponds to significant variances in the nature of fatigue degradation and the likely mechanisms thereof, which do not directly parallel those of well‐studied lead‐based materials. In particular, the use of field‐induced phase changes as an actuation mechanism provides distinctive fatigue behaviors. Particular attention is given to fatigue of ferroelectric and relaxor (ergodic and nonergodic) structures and their dependence upon temperature and electric field and the potential design of materials with high fatigue resistance. 相似文献
79.
Adeel Nasir Peter Rolf Richter Aude Le Bail Viktor Daiker Julia Stoltze Binod Prasad Sebastian Michael Strauch Michael Lebert 《International journal of molecular sciences》2022,23(5)
Euglena gracilis is a photosynthetic flagellate. To acquire a suitable position in its surrounding aquatic environment, it exploits light and gravity primarily as environmental cues. Several physiological studies have indicated a fine-tuned relationship between gravity sensing (gravitaxis) and light sensing in E. gracilis. However, the underlying molecular mechanism is largely unknown. The photoreceptor photoactivated adenylyl cyclase (PAC) has been studied for over a decade. Nevertheless, no direct/indirect interaction partner (upstream/downstream) has been reported for PAC. It has been shown that a specific protein, kinase A (PKA), showed to be involved in phototaxis and gravitaxis. The current study reports the localization of the specific PKA and its relationship with PAC. 相似文献
80.
Anna Carla Culla Corina Vater Xinggui Tian Julia Bolte Tilman Ahlfeld Henriette Bretschneider Alexander Pape Stuart B. Goodman Michael Gelinsky Stefan Zwingenberger 《International journal of molecular sciences》2022,23(6)
To treat critical-size bone defects, composite materials and tissue-engineered bone grafts play important roles in bone repair materials. The purpose of this study was to investigate the bone regenerative potential of hybrid scaffolds consisting of macroporous calcium phosphate cement (CPC) and microporous mineralized collagen matrix (MCM). Hybrid scaffolds were synthetized by 3D plotting CPC and then filling with MCM (MCM-CPC group) and implanted into a 5 mm critical size femoral defect in rats. Defects left empty (control group) as well as defects treated with scaffolds made of CPC only (CPC group) and MCM only (MCM group) served as controls. Eight weeks after surgery, micro-computed tomography scans and histological analysis were performed to analyze the newly formed bone, the degree of defect healing and the activity of osteoclasts. Mechanical stability was tested by 3-point-bending of the explanted femora. Compared with the other groups, more newly formed bone was found within MCM-CPC scaffolds. The new bone tissue had a clamp-like structure which was fully connected to the hybrid scaffolds and thereby enhanced the biomechanical strength. Together, the biomimetic hybrid MCM-CPC scaffolds enhanced bone defect healing by improved osseointegration and their differentiated degradation provides spatial effects in the process of critical-bone defect healing. 相似文献