scholarly journals Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions

2021 ◽  
Vol 22 (13) ◽  
pp. 7125
Author(s):  
Haider N. Sultani ◽  
Ibrahim Morgan ◽  
Hidayat Hussain ◽  
Andreas H. Roos ◽  
Haleh H. Haeri ◽  
...  
Keyword(s):  
Cell Lines ◽  
Fusidic Acid ◽  
Betulinic Acid ◽  
Multicomponent Reactions ◽  
Ros Generation ◽  
Paramagnetic Resonance ◽  
Acid Analogue ◽  
Wide Range ◽  
Electron Paramagnetic ◽  
Mitochondria Targeting

Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using this approach, which also makes them applicable in electron paramagnetic resonance (EPR) spectroscopy. Moreover, convertible amide modified spin-labelled fusidic acid derivatives were selected for post-Ugi modification utilizing a wide range of reaction conditions which kept the paramagnetic center intact. The nitroxide labelled betulinic acid analogue 6 possesses cytotoxic effects towards two investigated cell lines: prostate cancer PC3 (IC50 7.4 ± 0.7 μM) and colon cancer HT29 (IC50 9.0 ± 0.4 μM). Notably, spin-labelled fusidic acid derivative 8 acts strongly against these two cancer cell lines (PC3: IC50 6.0 ± 1.1 μM; HT29: IC50 7.4 ± 0.6 μM). Additionally, another fusidic acid analogue 9 was also found to be active towards HT29 with IC50 7.0 ± 0.3 μM (CV). Studies on the mode of action revealed that compound 8 increased the level of caspase-3 significantly which clearly indicates induction of apoptosis by activation of the caspase pathway. Furthermore, the exclusive mitochondria targeting of compound 18 was successfully achieved, since mitochondria are the major source of ROS generation.

scholarly journals DeerLab: a comprehensive software package for analyzing dipolar electron paramagnetic resonance spectroscopy data

2020 ◽  
Vol 1 (2) ◽  
pp. 209-224 ◽  
Author(s):  
Luis Fábregas Ibáñez ◽  
Gunnar Jeschke ◽  
Stefan Stoll
Keyword(s):  
Electron Paramagnetic Resonance ◽  
Software Package ◽  
Method Development ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Global Analysis ◽  
Resonance Spectroscopy ◽  
Paramagnetic Resonance ◽  
Least Squares Fit ◽  
Wide Range ◽  
Electron Paramagnetic

Abstract. Dipolar electron paramagnetic resonance (EPR) spectroscopy (DEER and other techniques) enables the structural characterization of macromolecular and biological systems by measurement of distance distributions between unpaired electrons on a nanometer scale. The inference of these distributions from the measured signals is challenging due to the ill-posed nature of the inverse problem. Existing analysis tools are scattered over several applications with specialized graphical user interfaces. This renders comparison, reproducibility, and method development difficult. To remedy this situation, we present DeerLab, an open-source software package for analyzing dipolar EPR data that is modular and implements a wide range of methods. We show that DeerLab can perform one-step analysis based on separable non-linear least squares, fit dipolar multi-pathway models to multi-pulse DEER data, run global analysis with non-parametric distributions, and use a bootstrapping approach to fully quantify the uncertainty in the analysis.

Ultra-broadband EPR spectroscopy in field and frequency domains

2018 ◽  
Vol 20 (22) ◽  
pp. 15528-15534 ◽  
Author(s):  
P. Neugebauer ◽  
D. Bloos ◽  
R. Marx ◽  
P. Lutz ◽  
M. Kern ◽  
...  
Keyword(s):  
Electron Paramagnetic Resonance ◽  
Magnetic Properties ◽  
Epr Spectroscopy ◽  
Paramagnetic Resonance ◽  
Powerful Technique ◽  
Electronic And Magnetic Properties ◽  
Wide Range ◽  
Frequency Domains ◽  
Electron Paramagnetic

Electron paramagnetic resonance (EPR) is a powerful technique to investigate the electronic and magnetic properties of a wide range of materials.

scholarly journals ROS as a novel indicator to predict anticancer drug efficacy

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Tarek Zaidieh ◽  
James R. Smith ◽  
Karen E. Ball ◽  
Qian An
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Copy Number ◽  
Drug Sensitivity ◽  
Drug Efficacy ◽  
Ros Generation ◽  
Targeting Therapy ◽  
Mitochondrial Dna Copy Number ◽  
Mitochondria Targeting

Abstract Background Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells’ response to ROS-stimulating therapy. Methods Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (mtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated. Results Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death. Conclusions Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. Doubtlessly, further studies employing a wider range of cell lines and in vivo experiments are needed to validate our results. However, this study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.

scholarly journals In situ kinetic measurements of α-synuclein aggregation reveal large population of short-lived oligomers

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245548
Author(s):  
Enrico Zurlo ◽  
Pravin Kumar ◽  
Georg Meisl ◽  
Alexander J. Dear ◽  
Dipro Mondal ◽  
...  
Keyword(s):  
Self Assembly ◽  
Large Population ◽  
Paramagnetic Resonance ◽  
Kinetic Measurements ◽  
Toxic Species ◽  
Self Assembling ◽  
Wide Range ◽  
Electron Paramagnetic

Knowledge of the mechanisms of assembly of amyloid proteins into aggregates is of central importance in building an understanding of neurodegenerative disease. Given that oligomeric intermediates formed during the aggregation reaction are believed to be the major toxic species, methods to track such intermediates are clearly needed. Here we present a method, electron paramagnetic resonance (EPR), by which the amount of intermediates can be measured over the course of the aggregation, directly in the reacting solution, without the need for separation. We use this approach to investigate the aggregation of α-synuclein (αS), a synaptic protein implicated in Parkinson’s disease and find a large population of oligomeric species. Our results show that these are primary oligomers, formed directly from monomeric species, rather than oligomers formed by secondary nucleation processes, and that they are short-lived, the majority of them dissociates rather than converts to fibrils. As demonstrated here, EPR offers the means to detect such short-lived intermediate species directly in situ. As it relies only on the change in size of the detected species, it will be applicable to a wide range of self-assembling systems, making accessible the kinetics of intermediates and thus allowing the determination of their rates of formation and conversion, key processes in the self-assembly reaction.

Electron paramagnetic resonance study of the reactions of the spin trap 3,5-dibromo-4-nitrosobenzenesulfonate

1988 ◽  
Vol 66 (5) ◽  
pp. 1153-1158 ◽  
Author(s):  
Peter Smith ◽  
Jill Suzanne Robertson
Keyword(s):  
Electron Paramagnetic Resonance ◽  
Aqueous Solutions ◽  
Electron Paramagnetic Resonance Study ◽  
Oxidation Mechanism ◽  
Azo Compounds ◽  
Electronic Effects ◽  
Paramagnetic Resonance ◽  
Wide Range ◽  
Methacrylic Monomers ◽  
Electron Paramagnetic

Using rapid-mixing, continuous-flow TiCl3-based techniques and also by means of static-sample studies involving the thermal decomposition of symmetric aliphatic azo compounds, we have characterized by electron paramagnetic resonance 22 spin adducts of 3,5-dibromo-4-nitrosobenzenesulphonate, 1, in aqueous solution at 25 °C. These spin adducts, all nitroxides, exhibit a moderately wide range of a-nitrogen and β-CH proton splitting constants, which we discuss in terms of steric and electronic effects. In connection with these studies, blank experiments showed that aqueous solutions of 1 gave no radicals when exposed to light and heat. In addition, we have studied by electron paramagnetic resonance at 25 °C static samples of aqueous solutions of 1 both by itself and in the presence of each of several acrylic and methacrylic monomers and in both the presence and absence of light. These solutions yielded radicals, namely, nitroxides, only when containing methacrylic monomers, the presence of light having no effect. These observations support the "ene" addition/oxidation mechanism of nitroxide formation.

scholarly journals ROS as a Novel Indicator to Predict Anticancer Drug Efficacy

2019 ◽  
Author(s):  
Tarek Zaidieh ◽  
James Smith ◽  
Karen Ball ◽  
Qian An
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Copy Number ◽  
Drug Sensitivity ◽  
Drug Efficacy ◽  
Ros Generation ◽  
Targeting Therapy ◽  
Mitochondrial Dna Copy Number ◽  
Mitochondria Targeting

Abstract Background Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells’ response to ROS-stimulating therapy. Methods Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (mtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated. Results Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death. Conclusions Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. Doubtlessly, further studies employing a wider range of cell lines and in vivo experiments are needed to validate our results. However, this study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.

scholarly journals Acquisition of ionic copper by a bacterial outer membrane protein

2020 ◽  
Author(s):  
Satya Prathyusha Bhamidimarri ◽  
Tessa R. Young ◽  
Muralidharan Shanmugam ◽  
Sandra Soderholm ◽  
Bastien Belzunces ◽  
...  
Keyword(s):  
Metal Binding ◽  
Paramagnetic Resonance ◽  
Copper Crystal ◽  
Ionic Copper ◽  
Icp Ms ◽  
Wide Range ◽  
Copper Storage ◽  
And Function ◽  
Electron Paramagnetic ◽  
Copper Import

AbstractCopper, while toxic in excess, is an essential micronutrient in all kingdoms of life due to its essential role in the structure and function of many proteins. Proteins mediating ionic copper import are known in eukaryotes, but have not yet been described in prokaryotes. Here we show that Pseudomonas aeruginosa OprC is a TonB-dependent transporter that mediates acquisition of ionic copper. Crystal structures of wild type and mutant OprC variants with silver and copper, as well as ICP-MS and electron paramagnetic resonance (EPR), suggest that binding of Cu(I) occurs via a surface-exposed methionine track leading towards an unprecedented CxxxM-HxM metal binding site that binds Cu(I) directly and can facilitate reduction of Cu(II) via the cysteine thiol. Together with quantitative proteomics and growth assays, our data identify OprC as an abundant component of bacterial copper biology that enables copper acquisition and potentially copper storage under a wide range of environmental conditions.

scholarly journals Проекционный спиновый шум в оптических квантовых датчиках на тепловых атомах

2020 ◽  
Vol 90 (8) ◽  
pp. 1243
Author(s):  
А.К. Вершовский ◽  
С.П. Дмитриев ◽  
Г.Г. Козлов ◽  
А.С. Пазгалев ◽  
М.В. Петренко
Keyword(s):  
Experimental Study ◽  
Electron Paramagnetic Resonance ◽  
Optical Pumping ◽  
Paramagnetic Resonance ◽  
Fundamental Limitations ◽  
Frequency Standards ◽  
Wide Range ◽  
Resonance Line Width ◽  
Electron Paramagnetic ◽  
Rms Amplitude

The paper theoretically and experimentally investigates the fundamental limitations imposed by spin (or atomic) quantum projection noise on the sensitivity of optical quantum sensors based on thermal atoms (this class of devices includes frequency standards, magnetometers, and gyroscopes using optical detection of electron paramagnetic resonance). The effect of increasing the rms amplitude of the projection noise in the magnetometric scheme under the influence of strong optical pumping is demonstrated, its explanation is proposed and experimentally tested - it is shown that in a wide range of pump intensities this effect is explained by the invariance of the projection noise integral power with respect to the magnetic resonance line width. An experimental study of the parameters of projection noise in a magnetometric quantum sensor was carried out, recommendations were given for optimizing the sensor parameters.

scholarly journals EPR Oximetry of Cetuximab-Treated Head-and-Neck Tumours in a Mouse Model

2017 ◽  
Vol 75 (3-4) ◽  
pp. 299-309 ◽  
Author(s):  
H. Gustafsson ◽  
A. Kale ◽  
A. Dasu ◽  
A. Lund ◽  
P.-H. Edqvist ◽  
...  
Keyword(s):  
Electron Paramagnetic Resonance ◽  
Cell Lines ◽  
Oxygen Pressure ◽  
Tumour Growth ◽  
Tumour Volume ◽  
Partial Oxygen Pressure ◽  
Paramagnetic Resonance ◽  
Growth Metabolism ◽  
Electron Paramagnetic ◽  
Partial Oxygen

Abstract Head and neck squamous cell carcinoma (HNSCC) tumours are associated with high mortality despite advances in therapy. The monoclonal antibody cetuximab (Erbitux®) has been approved for the treatment of advanced HNSCC. However, only a subset of HNSC patients receiving cetuximab actually responds to treatment, underlining the need for a means to tailor treatments of individual patients. The aim of the present study was to investigate the effect of cetuximab treatment on tumour growth, on tumour partial oxygen pressure as measured by LiPc electron paramagnetic resonance oximetry and on the expression of proteins involved in tumour growth, metabolism and hypoxia. Two HNSCC cell lines, UT-SCC-2 and UT-SCC-14, were used to generate xenografts on female BALB/c (nu/nu) nude mice. Mice with xenografts were given three injections of intraperitoneal cetuximab or phosphate-buffered saline, and the tumour volume was recorded continuously. After treatment the tumour partial oxygen pressure was measured by LiPc electron paramagnetic resonance oximetry and the expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, Ki-67, MCT1, MCT4, GLUT1, CAIX and HIF-1α were investigated by immunohistochemistry. In xenografts from both cell lines (UT-SCC-2 and UT-SCC-14) cetuximab had effect on the tumour volume but the effect was more pronounced on UT-SCC-14 xenografts. A higher tumour oxygenation was measured in cetuximab-treated tumours from both cell lines compared to untreated controls. Immunocytochemical staining after cetuximab treatment shows a significantly decreased expression of EGFR, pEGFR, Ki67, CAIX and nuclear HIF-1α in UT-SCC-14 tumours compared to untreated controls. MCT1 and GLUT1 were significantly decreased in tumours from both cell lines but more pronounced in UT-SCC-14 tumours. Taken together, our results show that cetuximab treatment decreases the tumour growth and increases the tumour partial oxygen pressure of HNSCC xenografts. Furthermore we found a potential connection between the partial oxygen pressure of the tumours and the expression of proteins involved in tumour growth, metabolism and hypoxia.

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