82 results on '"Tomas Kucera"'
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2. Defence cooperation and change: How defence industry integration fostered development of the European security community
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Ondrej Ditrych and Tomas Kucera
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Political Science and International Relations - Abstract
This article situates recent initiatives to deepen security and defence cooperation in the European Union in the historical perspective. It proposes a model of constitutive relationship between the process of change in a security community and the formation of a transnational defence industry community of practice which yields positive feedback (‘productive returns’) to the security community as a broader assemblage within which it was constituted. This model is applied to the paradigmatic case of European security community that formed after the World War II (WWII). The analysis shows that the key driver for defence integration traced by means of social network analysis (SNA) in this case was economic rather than political, and for an extended period of time it developed without formal institutions. The productive return of the ‘defence industry machine’ as a distinct community of practice that was constituted through the integration process consisted in the sense of deeper belonging and a shared sense of working well together in a traditionally highly nationalised defence milieu.
- Published
- 2022
3. IN SILICO LIBRARY SCREENING TO FIND NOVEL ANTICANCER AGENT WITH CHEMOSENSITIZING PROPERTIES: FOCUS ON TARGETING ATAXIA TELANGIECTASIA AND Rad3 RELATED KINASE
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Darina Muthna, Tomas Kucera, Zbynek Vecera, Lukas Gorecki, Martin Andrs, Martina Rezacova, and Jan Korabecny
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Emergency Medical Services ,Immunology and Microbiology (miscellaneous) ,Veterinary (miscellaneous) ,Public Health, Environmental and Occupational Health ,Emergency Medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) - Published
- 2023
4. PROGRESSIVE WATER TREATMENT TECHNOLOGY TO REMOVE MICROPOLLUTANTS
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Tomas Kucera and Zdenek Zeleny
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In connection with the publication of the new European directive for drinking water, some new indicators of drinking water quality from the category of micropollutants have been introduced, which will have to be eliminated during the production of drinking water. The described research focused on selected progressive technologies applicable in water treatment regarding the removal of micropollutants. It is expected that for the elimination of other micropollutants it will be possible to use existing technologies used, for example, to remove pesticides, such as activated carbon filtration, high-pressure membranes, or technologies using nanomaterials will be deployed. Increased attention is paid to the use of nano-iron for water treatment. A series of laboratory tests of selected technologies with the potential to eliminate micropollutants is presented. The article presents the overall efficiency found in selected indicators during laboratory tests, the overall efficiency of technologies and the limits and limiting factors regarding the elimination of the given pollution are discussed.
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- 2022
5. Comparison of two primary intraocular lymphoma experimental murine models
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Eva Skrlova, Eva Uherkova, Diana Malarikova, Aneta Klimova, Petra Svozilkova, Peter Kesa, Petr Matous, Vit Herynek, Tomas Kucera, Pavel Klener, and Jarmila Heissigerova
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Ophthalmology ,General Medicine - Published
- 2022
6. Allogeneic Bone Impregnated with Biodegradable Depot Delivery Systems for the Local Treatment of Joint Replacement Infections: An In Vitro Study
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Libor Prokes, Eva Snejdrova, Tomas Soukup, Jana Malakova, Vladislav Frolov, Jan Loskot, Rudolf Andrys, and Tomas Kucera
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Organic Chemistry ,Hematopoietic Stem Cell Transplantation ,Pharmaceutical Science ,Water ,Analytical Chemistry ,Anti-Bacterial Agents ,Drug Delivery Systems ,Chemistry (miscellaneous) ,Vancomycin ,Drug Discovery ,Molecular Medicine ,Humans ,drug delivery ,biocompatibility ,cell culture ,bone graft ,local antibiotic ,PLGA ,water-in-oil emulsion ,hydrogel ,Emulsions ,Physical and Theoretical Chemistry ,Arthroplasty, Replacement ,Gentamicins ,Powders - Abstract
Although progress is evident in the effective treatment of joint replacement-related infections, it still remains a serious issue in orthopedics. As an example, the local application of antibiotics-impregnated bone grafts supplies the high drug levels without systemic side effects. However, antibiotics in the powder or solution form could be a risk for local toxicity and do not allow sustained drug release. The present study evaluated the use of an antibiotic gel, a water-in-oil emulsion, and a PLGA microparticulate solid dispersion as depot delivery systems impregnating bone grafts for the treatment of joint replacement-related infections. The results of rheological and bioadhesive tests revealed the suitability of these formulations for the impregnation of bone grafts. Moreover, no negative effect on proliferation and viability of bone marrow mesenchymal stem cells was detected. An ex vivo dissolution test of vancomycin hydrochloride and gentamicin sulphate from the impregnated bone grafts showed a reduced burst and prolonged drug release. The PLGA-based formulation proved to be particularly promising, as one-day burst release drugs was only 15% followed with sustained antibiotics release with zero-order kinetics. The results of this study will be the basis for the development of a new product in the Tissue Section of the University Hospital for the treatment of bone defects and infections of joint replacements.
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- 2022
- Full Text
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7. Diffuse Reflectance Spectroscopy as a Novel Method of Caries Detection—An In Vitro Comparative Study in Permanent Teeth
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Jindrich Charvat, Ales Prochazka, Tomas Kucera, Antonin Tichy, Maksim Yurchenko, and Lucie Himmlova
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Clinical Biochemistry ,caries detection ,diffuse reflectance spectroscopy ,diagnostic ,histology ,laser fluorescence ,Diagnodent pen - Abstract
This in vitro study aimed to compare outcomes of dental caries detection using visual inspection classified according to the International Caries Detection and Assessment System (ICDAS) with objective assessments using a well-established laser fluorescence system (Diagnodent pen) and a novel diffuse reflectance spectroscopy (DRS) device. One hundred extracted permanent premolars and molars were utilized, including sound teeth, teeth with non-cavitated caries, or teeth with small cavitated lesions. A total of 300 regions of interest (ROIs) were assessed using each detection method. Visual inspection, being a subjective method, was performed by two independent examiners. The presence and extent of caries were histologically verified according to Downer’s criteria, serving as a reference for other detection methods. Histological results revealed 180 sound ROIs and 120 carious ROIs, categorized into three different extents of caries. Overall, there was no significant difference between the detection methods in sensitivity (0.90–0.93) and false negative rate (0.05–0.07). However, DRS exhibited superior performance in specificity (0.98), accuracy (0.95), and false positive rate (0.04) compared to other detection methods. Although the tested DRS prototype device exhibited limited penetration depth, it shows promise as a method, particularly for the detection of incipient caries.
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- 2023
8. Structure–Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions
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Eduard Jirkovský, Jan Korábečný, Tomáš Šimůnek, Anna Jirkovská, Veronika Skalická, Hana Bavlovič Piskáčková, Martin Štěrba, Jan Kubes, Iuliia Melnikova, Jaroslav Roh, Tomas Kucera, Caroline A. Austin, Josef Skoda, Lucie Nováková, and Galina Karabanovich
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Cardiotonic Agents ,Saccharomyces cerevisiae Proteins ,Anthracycline ,Diketopiperazines ,Saccharomyces cerevisiae ,Molecular Dynamics Simulation ,Pharmacology ,01 natural sciences ,Piperazines ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,ICRF 193 ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Topoisomerase II Inhibitors ,Structure–activity relationship ,Myocytes, Cardiac ,Cardioprotective Agent ,Rats, Wistar ,Cell Proliferation ,030304 developmental biology ,Cardioprotection ,0303 health sciences ,Cardiotoxicity ,Molecular Structure ,biology ,Topoisomerase ,Daunorubicin ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,DNA Topoisomerases, Type II ,Animals, Newborn ,chemistry ,biology.protein ,Molecular Medicine ,Dexrazoxane ,Protein Binding ,medicine.drug - Abstract
Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability. Very tight structure-activity relationships were demonstrated on stereoisomeric forms of 4,4'-(butane-2,3-diyl)bis(piperazine-2,6-dione). In contrast to its rac-form 12, meso-derivative 11 (ICRF-193) showed a favorable binding mode to topoisomerase II in silico, inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, and showed the highest cardioprotective efficiency. Importantly, the observed ICRF-193 cardioprotection did not interfere with the antiproliferative activity of anthracycline. Hence, this study identifies ICRF-193 as the new lead compound in the development of efficient cardioprotective agents.
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- 2021
9. Problematic Imaging Diagnostics of Musculoskeletal Gossypiboma with Chronic Expanding Hematoma Mimicking Malignant Lesion
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Tomas Kucera, Libor Prokes, Jiri Soukup, Jindra Brtkova, Ondrej Valtr, and Pavel Sponer
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Clinical Biochemistry - Abstract
Both musculoskeletal gossypibomas and chronic expanding hematomas have been rarely reported; the reports that do exist are usually case reports. Our objective is to demonstrate problematic imaging diagnostics of an unusual presentation mimicking a malignant lesion. We report the case of a 47-year-old man who underwent bone graft harvesting from the iliac crest for spinal fusion due to scoliosis at 18 years of age, and 29 years later, he developed a growing, painful tumor at the original donor site (a bone defect in the iliac crest). It was challenging to differentiate a hematoma from a malignant tumor based solely on clinical and radiological workup, including an ultrasound-guided needle biopsy focused on viable tissue. The definitive diagnosis of a gossypiboma with a chronic expanding hematoma was based on histopathological assessment after wide surgical resection—a chronic expanding hematoma with multiple foamy macrophages and giant cells engulfing foreign material (original surgical hemostatic sponge).
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- 2023
10. Amaryllidaceae alkaloids from Hippeastrum X Hybridum CV. Ferrari, and preparation of vittatine derivatives as potential ligands for Alzheimer´s disease
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Monika Schmidt, Ondřej Soukup, Daniela Hulcová, Jana Maříková, Jiří Kuneš, Lenka Pulkrabkova, Marcela Šafratová, Jiří Janoušek, Lucie Cahlíková, Tomas Kucera, Lucie Nováková, Lubomír Opletal, and L. Al Shammari
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0106 biological sciences ,chemistry.chemical_classification ,biology ,Stereochemistry ,Alkaloid ,Plant Science ,biology.organism_classification ,01 natural sciences ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Hippeastrum ,Enzyme ,chemistry ,Potency ,Amaryllidaceae Alkaloids ,IC50 ,Two-dimensional nuclear magnetic resonance spectroscopy ,010606 plant biology & botany - Abstract
Fourteen (1–14) known Amaryllidaceae alkaloids, of various structural types, have been isolated from fresh bulbs of Hippeastrum X hybridum cv. Ferrari. The chemical structures were identified by various spectroscopic (1D and 2D NMR) and mass spectrometric (GC–MS, LC-MS) methods, and by comparison with literature data. Isolated alkaloids which, up to this date have not been studied for their inhibition potency against AChE, BuChE and POP, were screened in vitro for these inhibition activities. Unfortunatelly, all natural alkaloids were inactive in the AChE/BuChE assay; only zephyranthine (14) displayed moderate inhibition activity agains POP with an IC50 value of 142 ± 10 µM. Moreover, twelve new derivatives of the haemanthamine-type alkaloid vittatine (7), isolated in gram amounts from Hippeastrum cv. Ferrari, have been designed, synthesized and tested in vitro with particular emphasis on the treatment of neurodegenerative diseases. Some of the tested compounds revealed an intriguing selective hBuChE inhibitory profile with single-digit micromolar IC50 values. The strongest hBuChE inhibition was demonstrated by 3-O-(2-methylbenzoyl)vittatine (7b), 3-O-(2-nitrobenzoyl)vittatine (7h) and 3-O-(2-chlorbenzoyl)vittatine (7m) with IC50 values 8.0 ± 0.1 µM, 1.4 ± 0.1 µM and 5.4 ± 0.1 µM, respectively. The mode of hBuChE inhibition was minutely inspected using enzyme kinetic analysis in tandem with in silico experiments, the latter elucidating crucial interaction in 7b-, 7h-, and 7m-hBuChE complexes.
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- 2021
11. 7-Azaindole, 2,7-diazaindole, and 1H-pyrazole as core structures for novel anticancer agents with potential chemosensitizing properties
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Lukas Gorecki, Darina Muthna, Sara Merdita, Martin Andrs, Tomas Kucera, Radim Havelek, Lubica Muckova, Tereza Kobrlova, Jiri Soukup, Petr Krupa, Lukas Prchal, Ondrej Soukup, Jaroslav Roh, Martina Rezacova, and Jan Korabecny
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Pharmacology ,Indoles ,Cell Line, Tumor ,Organic Chemistry ,Drug Discovery ,Humans ,Pyrazoles ,Antineoplastic Agents ,General Medicine ,Ataxia Telangiectasia Mutated Proteins ,Cisplatin - Abstract
Chemoresistance of cancer cells is a hallmark of treatment failure and the poor patient prognosis. The mechanism of resistance is often connected to the overexpression of specific kinases involved in DNA damage response cascade. Contrary, selected kinase inhibition can augment cancer cell sensitization to conventional therapy, enabling more efficient treatment. Among those kinases, ataxia-telangiectasia and Rad3-related kinase (ATR), the major responder to replication stress, stands out as one of the most attractive targets. Inspired by clinical candidates targeting ATR, we designed and prepared a small, focused library of 40 novel compounds building on 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures. All the compounds alone or combined with cisplatin (CDDP) were screened against a panel of nine cancer cell lines and one healthy cell line. Three highlighted compounds (3, 22, and 29) were selected for broad oncology panel screening containing 104 kinases. Only compound 29, the 2,7-diazaindole representative, showed ATR inhibitory efficacy with the IC
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- 2022
12. Detection of galanin receptors in the spinal cord in experimental autoimmune encephalomyelitis
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Danica Michalickova, Ivana Kramarikova, Hatice Kubra Ozturk, Tomas Kucera, Tomas Vacik, Tomas Hrncir, Nikolina Kutinova Canova, Martin Sima, and Ondrej Slanar
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General Biochemistry, Genetics and Molecular Biology - Abstract
The neuropeptide galanin is a widely distributed neurotransmitter/neuromodulator that regulates a variety of physiological processes and also participates in the regulation of stress responses. The aims of the present study were to investigate the expression of galanin receptors (GalR1, GalR2, GalR3) in the spinal cords in a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) using qPCR analysis and to determine GalR1 cellular localization (oligodendrocytes, microglia, astrocytes, ependymal cells, and endothelial cells in the capillaries) by immunohistochemistry.Twelve samples from the EAE group and 14 samples from the control group were analyzed. Spinal cords samples were obtained at the peak of the EAE disease.The GalR1 mRNA level was significantly decreased in the EAE mice compared with the controls (P=0.016), whereas the mRNA levels of GalR2 and GalR3 were not significantly different for the EAE and the control mice. No significant correlations were found between the severity of the EAE disease and the mRNA levels of GalR1, GalR2 and GalR3. Immunochemical detection of the GalR1 revealed its expression in the ependymal and endothelial cells. Additionally, a weak GalR1 immunoreactivity was occasionally detected in the oligodendrocytes.This study provides additional evidence of galanin involvement in EAE pathophysiology, but this has to be further investigated.
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- 2022
13. SEARCHING FOR NEW ANTIMICROBIAL AGENTS BY TARGETING BACTERIAL NAD METABOLISM: EVALUATION OF FRENTIZOLE DERIVATIVES SELECTED BY MOLECULAR DOCKING
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Ondrej Benek, Michaela Hympanova, Jan Korabecny, Tomas Kucera, and Jan Marek
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Emergency Medical Services ,Immunology and Microbiology (miscellaneous) ,Biochemistry ,Chemistry ,Veterinary (miscellaneous) ,NAD metabolism ,Public Health, Environmental and Occupational Health ,Emergency Medicine ,Antimicrobial ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Frentizole - Published
- 2020
14. Aromatic Esters of the Crinane Amaryllidaceae Alkaloid Ambelline as Selective Inhibitors of Butyrylcholinesterase
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Tomas Kucera, Lucie Nováková, Jan Korábečný, Eliška Kohelová, Abdullah Al Mamun, Jiří Kuneš, Aneta Ritomská, Rozálie Peřinová, Tereza Kobrlova, Lucie Cahlíková, Jana Maříková, and Daniela Hulcová
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Models, Molecular ,Aché ,Stereochemistry ,Pharmaceutical Science ,01 natural sciences ,Substrate Specificity ,Analytical Chemistry ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Potency ,heterocyclic compounds ,Butyrylcholinesterase ,Pharmacology ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Alkaloid ,Amaryllidaceae ,Organic Chemistry ,Esters ,biology.organism_classification ,Acetylcholinesterase ,language.human_language ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,Blood-Brain Barrier ,Amaryllidaceae Alkaloids ,language ,Molecular Medicine ,Cholinesterase Inhibitors - Abstract
A total of 20 derivatives (1–20) of the crinane-type alkaloid ambelline were synthesized. These semisynthetic derivatives were assessed for their potency to inhibit both acetylcholinesterase (AChE)...
- Published
- 2020
15. A Rare Case of Osteomyelitis of an Ankle Caused by Mycobacterium chelonae
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Lenka Ryskova, Rudolf Kukla, Radka Bolehovska, Libor Prokes, Milan Vajda, Tomas Kucera, Ivo Pavlik, Pavel Bostik, and Pavel Ryska
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Microbiology (medical) ,Infectious Diseases ,Pharmacology (medical) ,General Pharmacology, Toxicology and Pharmaceutics ,Biochemistry ,Microbiology - Abstract
Mycobacterium chelonae, a rapidly growing nontuberculous mycobacterium, is usually described as a causative agent of soft tissue infections (postsurgical, posttraumatic, posttransplantation, postinjection, catheter infection, etc.), but only rarely as a cause of osteomyelitis. The authors describe a case report of a 72-year-old man with osteomyelitis of the talus. Initially, the infection was assessed as a soft tissue infection, without any osteolytic changes on the X-ray. After cultivation with subsequent targeted molecular typing of the rpoB gene, M. chelonae was identified from the affected tissue. The bone involvement was subsequently detected on MRI and confirmed histologically with findings of the granulomatous tissue and acid-fast bacilli. The patient was initially treated intravenously with a combination of tigecycline, amikacin, and moxifloxacin for 4 weeks, after which the oral combination of doxycycline and moxifloxacin continued. Identification of the infecting pathogen using molecular typing thus helped to establish the correct diagnosis and represents a rarely described case of osteomyelitis caused by M. chelonae.
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- 2023
16. Abstract 11240: Capillary Rarefaction and Right Ventricular Dysfunction in Advanced HFrEF: Human Tissue Histomorphometry Analysis
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Vojtech Melenovsky, Tomas Kucera, Tomas Mracek, Tereza Havlenova, Vilma Kaplanova, Krystina Cunatova, Jan Benes, Aneta Pierzynova, JaromÃr Å rámek, and Josef Kautzner
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Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Right ventricular dysfunction (RVD) limits survival in heart failure (HF). Besides pulmonary hypertension (PH), load-independent mechanisms may contribute to RVD. In experimental PH, loss of myocardial capillary density (rarefaction) was implicated in the faster decline of RV function. Hypothesis: To elucidate the role of rarefaction in development of RVD in HFrEF. Methods: We examined RV fractional area change (RV FAC%) prior heart Tx (median -57 days) in 124 consecutive HTx candidates (non-LVAD) and harvested RV free wall at HTx from patients in the bottom (Q1: 10-17%) and top (Q4: 32-42%) quartiles of pre-HTx RV FAC%. As controls (Con), we obtained RV samples from 20 unused heart donors. Quantitative histomorphometry and mRNA gene expression were studied. Results: HF (65% non-ischemic) and Con were matched by similar age, gender and BMI. HF patients had larger and more dysfunctional RV (RVD1 46 vs 32 mm, p-2 , p=0.007), even if adjusted to CM diameter (39 vs 102 mm -1 , p=0.0005) or area (Fig). HF patients from Q1 and Q4 RV FAC differed by higher PH (mPA 37 vs 31 mmHg, p=0.01), larger RV size (48 vs 43 mm, p=0.01) and higher PCWP (27 vs 22, p=0.002), but there was no difference in capillary density (unadjusted or per CM diameter/area, Fig) or gene expression profile, HF etiology or comorbidities. Conclusions: Compared to Con, RV of HF patients shows reduced capillary density, metabolic and myofilament remodeling. Yet, HF patients with lower RV FAC% do not differ from those with less impaired RV function, suggesting that capillary rarefaction per se does not explain progression of RVD in HF.
- Published
- 2021
17. Non-covalent acetylcholinesterase inhibitors: In vitro screening and molecular modeling for novel selective insecticides
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Vendula Hepnarova, Martina Hrabinova, Lubica Muckova, Tomas Kucera, Monika Schmidt, Rafael Dolezal, Lukas Gorecki, Veronika Hrabcova, Jan Korabecny, Eva Mezeiova, Daniel Jun, and Jaroslav Pejchal
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Insecticides ,Mosquito Vectors ,General Medicine ,Toxicology ,Organophosphates ,Carbofuran ,Butyrylcholinesterase ,Anopheles ,Acetylcholinesterase ,Tacrine ,Animals ,Humans ,Cholinesterase Inhibitors ,Carbamates - Abstract
Insecticides represent the most crucial element in the integrated management approach to malaria and other vector-borne diseases. The evolution of insect resistance to long-used substances and the toxicity of organophosphates (OPs) and carbamates are the main factors contributing to the development of new, environmentally safe pesticides. In our work, fourteen compounds of 7-methoxytacrine-tacrine heterodimers were tested for their insecticidal effect. Compounds were evaluated in vitro on insect acetylcholinesterase from Anopheles gambiae (AgAChE) and Musca domestica (MdAChE). The evaluation was executed in parallel with testing on human erythrocyte acetylcholinesterase (HssAChE) and human butyrylcholinesterase (HssBChE) using a modified Ellman's method. Compound efficacy was determined as IC
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- 2022
18. Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies
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Ondřej Soukup, Filip Pidaný, Rozálie Peřinová, Lubica Muckova, Jiří Kuneš, Tomas Kucera, Abdullah Al Mamun, Negar Maafi, Jan Korábečný, Rudolf Andrýs, Monika Schmidt, Jiří Janoušek, Martina Hrabinova, Jana Maříková, Lucie Cahlíková, Daniela Hulcová, Daniel Jun, Lucie Nováková, and Maria Carmen Catapano
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Pharmacology ,01 natural sciences ,chemistry.chemical_compound ,Neuroblastoma ,Tumor Cells, Cultured ,Biology (General) ,Spectroscopy ,Butyrylcholinesterase ,0303 health sciences ,biology ,Biological activity ,General Medicine ,Receptor antagonist ,Acetylcholinesterase ,Computer Science Applications ,Molecular Docking Simulation ,Chemistry ,Alzheimer’s disease ,medicine.drug_class ,QH301-705.5 ,Tyramine ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Structure-Activity Relationship ,medicine ,Humans ,Computer Simulation ,Physical and Theoretical Chemistry ,Amaryllidaceae Alkaloids ,norbelladine-type ,Molecular Biology ,IC50 ,QD1-999 ,amaryllidaceae alkaloid ,030304 developmental biology ,Cholinesterase ,Cell Proliferation ,010405 organic chemistry ,Organic Chemistry ,docking studies ,0104 chemical sciences ,chemistry ,Docking (molecular) ,biology.protein ,Cholinesterase Inhibitors - Abstract
Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1–20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.
- Published
- 2021
19. Combination of Memantine and 6-Chlorotacrine as Novel Multi-Target Compound against Alzheimer’s Disease
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Ondrej Soukup, Martina Kaniakova, Tomas Kucera, Vendula Hepnarova, Martin Horak, Jan Korabecny, Karel Vales, Tereza Kobrlova, Eugenie Nepovimova, Kristina Holubova, Kristyna Skrenkova, Lenka Kleteckova, and Zofia Chrienova
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Male ,0301 basic medicine ,Cell Survival ,Excitotoxicity ,Glutamic Acid ,Context (language use) ,CHO Cells ,Pharmacology ,Ligands ,medicine.disease_cause ,Receptors, N-Methyl-D-Aspartate ,Neuroprotection ,Capillary Permeability ,Tissue Culture Techniques ,03 medical and health sciences ,chemistry.chemical_compound ,Cricetulus ,0302 clinical medicine ,Alzheimer Disease ,Memantine ,medicine ,Animals ,Humans ,Rats, Wistar ,Cognitive decline ,Glutamate receptor ,Acetylcholinesterase ,Molecular Docking Simulation ,HEK293 Cells ,Neuroprotective Agents ,030104 developmental biology ,Neurology ,chemistry ,Blood-Brain Barrier ,Tacrine ,NMDA receptor ,Cholinesterase Inhibitors ,Neurology (clinical) ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N–methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called “multi-targeting" approach has been established. Objectives: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors. Methods: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier. Results: novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. Conclusion: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.
- Published
- 2019
20. Macrofungi on fallen oak trunks in the Białowieża Virgin Forest – ecological role of trunk parameters and surrounding vegetation
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M. Kuchaříková, R. Krzyšciak-Kosińska, D. Dvořák, Jan Holec, M. Kříž, Tomas Kucera, and J. Běťák
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Canopy ,geography ,geography.geographical_feature_category ,Ecology ,Plant Science ,Old-growth forest ,Trunk ,Mycorrhizal fungi ,visual_art ,medicine ,visual_art.visual_art_medium ,Bark ,medicine.symptom ,Vegetation (pathology) ,Ecology, Evolution, Behavior and Systematics - Published
- 2019
21. Rifampicin-loaded PLGA nanoparticles for local treatment of musculoskeletal infections: Formulation and characterization
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Eva Snejdrova, Jan Loskot, Juraj Martiska, Tomas Soukup, Libor Prokes, Vladislav Frolov, and Tomas Kucera
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Pharmaceutical Science - Published
- 2022
22. Abstract 1411: Utilizing 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures for novel cancer chemosensitizers
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Lukas Gorecki, Darina Muthna, Sara Merdita, Martin Andrs, Tomas Kucera, Tereza Kobrlova, Martina Rezacova, and Jan Korabecny
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Cancer Research ,Oncology - Abstract
A quickly developing chemoresistance is the hallmark of the standard treatment failure and the poor patient prognosis. Resistance is often connected to the overexpression of the specific kinases that are involved in DNA damage response. Contrary, their inhibition could lead to augmented cancer cell sensitization to conventional approach. Among them, ataxia-telangiectasia and Rad3-related kinase (ATR), the major replication stress responder, is one of the most attractive target. Within this study our aim was to find novel chemosensitizing agents for the cancer treatment employment. Inspired by clinical candidates targeting ATR, we designed and prepared large library of 40 novel compounds utilizing 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures. Initially, our presumption to have ATR inhibitors were confirmed by molecular dynamic study. All the compounds alone or in combination with cisplatin were screened against panel of nine cancer cell lines and one healthy cell line. The results were compared with well-known ATR inhibitor VE-821. Several compounds significantly inhibit the cell viability and some were able to potentiate cisplatin effect. From structure-activity relationship point of view, 7-azaindoles were the most cytotoxic compounds when substituted in position 3 and 5. Contrary, 2,7-diazaindoles expressed the most potent chemosensitizing capabilities. 1H-Pyrazoles were the least potent compounds within this screen. Interestingly, the status of tumor suppressor protein p53 (defect in G1) did not significantly influence chemosensitization or cytotoxic effect. Three highlighted compounds 3, 22, and 29 were selected for Broad oncology panel screening containing 104 kinases which could be potentially targeted. Only compound 29, the 2,7-diazaindole representative, showed ATR inhibitory efficacy with the IC50 around 10 µM. In contrast, the compound 22, 7-azaindole and the most cytotoxic one, expressed the multi-kinase activity with the substantial inhibitory capability against vascular endothelial growth factor receptor 3 protein (VEGFR-3). VEGFR-3 is also very attractive anticancer target with several inhibitors already approved. Finally, several compounds showed chemosensitizing potencies for temozolomide against secondary astrocytoma cell line. In overall, we showed that both, 7-azaindoles, and 2,7-diazaindoles, could be effectively utilized as novel anticancer agents. Whereas 2,7-diazaindoles could become efficient ATR inhibitors, 7-azaindoles have potential as antiangiogenics, VEGFR-3 inhibitors. Besides, both structures could be used for a glioblastoma treatment as temozolomide sensitizers. More research is currently ongoing to fully exploit potential of these compounds. Citation Format: Lukas Gorecki, Darina Muthna, Sara Merdita, Martin Andrs, Tomas Kucera, Tereza Kobrlova, Martina Rezacova, Jan Korabecny. Utilizing 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures for novel cancer chemosensitizers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1411.
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- 2022
23. Challenges of total knee arthroplasty in osteogenesis imperfecta: case report and literature review
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Pavel Sponer, Martin Korbel, and Tomas Kucera
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Adult ,Knee Joint ,Biochemistry (medical) ,Humans ,Female ,Knee ,Cell Biology ,General Medicine ,Middle Aged ,Osteoarthritis, Knee ,Osteogenesis Imperfecta ,Arthroplasty, Replacement, Knee ,Biochemistry - Abstract
The majority of adults with mild osteogenesis imperfecta report significant functional impairment due to musculoskeletal concerns. Knee osteoarthritis is common in these patients. Although total knee arthroplasty has become a highly efficient surgical technique for osteoarthritis, this procedure remains uncommon in patients with osteogenesis imperfecta. This current case report describes the important clinical aspects of osteogenesis imperfecta that must be considered during the planning and performance of a total knee replacement. A 62-year-old female patient with a history of osteogenesis imperfecta suffered from severe osteoarthritis of the knee with valgus deformity. Two years after posterior stabilized total knee arthroplasty, her Hospital for Special Surgery knee score had improved from preoperative 53 points to 85 points at the final follow-up. The current case report describes the crucial technical aspects of a successful total knee replacement in this uncommon scenario. Underlying deformities and concomitant pathologies constitute specific surgical challenges. Special care should be taken to protect the patient from potential complications.
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- 2022
24. Synthesis of New Biscoumarin Derivatives, In Vitro Cholinesterase Inhibition, Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells
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Daniel Jun, Monika Hudáčová, Juraj Ševc, Jana Vargová, Jana Janockova, Mária Kožurková, Veronika Ihnatova, Jan Korábečný, Petr Bzonek, Lucie Junova, Nikola Novakova, Eva Konkoľová, Kamil Kuca, Ondrej Soukup, Rastislav Jendželovský, Slávka Hamuľaková, Peter Fedoročko, and Tomas Kucera
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0301 basic medicine ,Models, Molecular ,Chemistry Techniques, Synthetic ,Pharmacology ,blood–brain barrier ,lcsh:Chemistry ,chemistry.chemical_compound ,0302 clinical medicine ,A549 ,Coumarins ,lcsh:QH301-705.5 ,Spectroscopy ,Butyrylcholinesterase ,Molecular Structure ,Cell Cycle ,General Medicine ,Cell cycle ,Acetylcholinesterase ,Computer Science Applications ,Blood-Brain Barrier ,030220 oncology & carcinogenesis ,Alzheimer’s disease ,antiproliferative activity ,cholinesterase ,Cell Survival ,Antineoplastic Agents ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Structure-Activity Relationship ,Alzheimer Disease ,Humans ,MTT assay ,Physical and Theoretical Chemistry ,Molecular Biology ,A549 cell ,biscoumarin ,Dose-Response Relationship, Drug ,Cell growth ,Organic Chemistry ,In vitro ,Enzyme Activation ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,A549 Cells ,Cancer cell ,Cholinesterase Inhibitors - Abstract
A series of novel C4-C7-tethered biscoumarin derivatives (12a–e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC50 = 6.30 µM) and butyrylcholinesterase (BChE, IC50 = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood–brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer’s disease.
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- 2021
25. Structure Elucidation and Cholinesterase Inhibition Activity of Two New Minor Amaryllidaceae Alkaloids
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Daniela Hulcová, Lucie Cahlíková, Milan Pour, Jan Korábečný, Eliška Kohelová, Jana Maříková, Michaela Vaskova, Milan Malaník, Abdullah Al Mamun, Tomas Kucera, Jiří Kuneš, Latifah Al Shammari, and Lucie Nováková
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Circular dichroism ,Stereochemistry ,Pharmaceutical Science ,01 natural sciences ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Alkaloids ,Hippeastrum ,lcsh:Organic chemistry ,Alzheimer Disease ,Catalytic Domain ,Drug Discovery ,Cholinesterases ,Humans ,Physical and Theoretical Chemistry ,9-O-demethyllycorenine ,Amaryllidaceae Alkaloids ,Butyrylcholinesterase ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Molecular Structure ,biology ,Circular Dichroism ,Alkaloid ,Organic Chemistry ,Amaryllidaceae ,biology.organism_classification ,Acetylcholinesterase ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Enzyme ,chemistry ,Chemistry (miscellaneous) ,Molecular Medicine ,Cholinesterase Inhibitors ,Alzheimer’s disease ,narciabduliine - Abstract
Two new minor Amaryllidaceae alkaloids were isolated from Hippeastrum × hybridum cv. Ferrari and Narcissus pseudonarcissus cv. Carlton. The chemical structures were identified by various spectroscopic (one- and two-dimensional (1D and 2D) NMR, circular dichroism (CD), high-resolution mass spectrometry (HRMS) and by comparison with literature data of similar compounds. Both isolated alkaloids were screened for their human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) inhibition activity. One of the new compounds, a heterodimer alkaloid of narcikachnine-type, named narciabduliine (2), showed balanced inhibition potency for both studied enzymes, with IC50 values of 3.29 ± 0.73 µM for hAChE and 3.44 ± 0.02 µM for hBuChE. The accommodation of 2 into the active sites of respective enzymes was predicted using molecular modeling simulation.
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- 2021
26. (±)- BIGI-3h: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3β Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease
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Vendula Hepnarova, Kamil Musilek, Aurélie Baguet, Daniel Jun, José Marco-Contelles, Lhassane Ismaili, Emmanuel Haffen, Tomas Kucera, Jan Korabecny, Jana Janockova, Angela De Simone, Eva M. García-Frutos, Vincenza Andrisano, Manuela Bartolini, B. Refouvelet, Lucía Viejo, Cristóbal de los Ríos, Adeline Etievant, Ondrej Soukup, Rudolf Andrys, Julie Monnin, Raquel L Arribas, Conseil régional of Franche-Comté, Czech Science Foundation, Ministry of Education, Youth and Sports (Czech Republic), Ismaili L., Monnin J., Etievant A., Arribas R.L., Viejo L., Refouvelet B., Soukup O., Janockova J., Hepnarova V., Korabecny J., Kucera T., Jun D., Andrys R., Musilek K., Baguet A., Garcia-Frutos E.M., De Simone A., Andrisano V., Bartolini M., De Los Rios C., Marco-Contelles J., and Haffen E.
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cholinesterase ,Physiology ,Monoamine oxidase ,Cognitive Neuroscience ,Ligand ,Pharmacology ,Ligands ,Calcium Channel ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,In vivo ,GSK-3 ,Humans ,Cholinesterases ,Cholinesterase Inhibitor ,Biginelli reaction ,Alzheimer's disease ,calcium channel ,cholinesterases ,GSK 3β ,MAO ,Calcium Channel Blockers ,Calcium Channels ,Cholinesterase Inhibitors ,Glycogen Synthase Kinase 3 beta ,Monoamine Oxidase ,GSK3B ,030304 developmental biology ,Cholinesterase ,0303 health sciences ,Voltage-dependent calcium channel ,biology ,Chemistry ,Calcium channel ,Cell Biology ,General Medicine ,Calcium channel, GSK 3β, MAO ,biology.protein ,Monoamine oxidase A ,Calcium Channel Blocker ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Human - Abstract
Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits., L.I. thanks the Regional Council of Franche-Comté (2016YC- 04540 and 04560) for financial support, Mrs. M.-J. Henriot (PHV Pharma) for her support in the HPLC analyses, and Vincent Luzet for preliminary results in synthesis. O.S., J.J., and J.K. acknowledge the support from the grant by Czech Science Foundation no. 20-29633J. T.K., D.J., and V.H. acknowledge support from the Long-term Development Plan (Faculty of Military Health Sciences). R.A. and K.M. thank the Ministry of Education, Youth and Sports of the Czech Republic (ERDF no. CZ.02.1.01/0.0/0.0/16_025/0007444).
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- 2021
27. 7-phenoxytacrine is a dually acting drug with neuroprotective efficacy in vivo
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Kristina Hakenova, Katarina Lichnerova, Martin Horak, Barbora Krausova, Vendula Hepnarova, Karel Vales, Jan Korabecny, Barbora Svobodova, Tomas Kucera, Lukas Prchal, Lenka Kleteckova, Ondrej Soukup, Kristina Holubova, Martin Novák, Rafael Dolezal, Martina Kaniakova, and Marketa Chvojkova
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0301 basic medicine ,Male ,Excitotoxicity ,Neurotransmission ,Pharmacology ,medicine.disease_cause ,Biochemistry ,Neuroprotection ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine ,Animals ,Humans ,Rats, Wistar ,Receptor ,business.industry ,Glutamate receptor ,Acetylcholinesterase ,Rats ,030104 developmental biology ,HEK293 Cells ,Neuroprotective Agents ,nervous system ,chemistry ,030220 oncology & carcinogenesis ,Excitatory postsynaptic potential ,Tacrine ,Cholinergic ,business - Abstract
N-methyl-D-aspartaterecepro receptor (NMDARs) are a subclass of glutamate receptors, which play an essential role in excitatory neurotransmission, but their excessive overactivation by glutamate leads to excitotoxicity. NMDARs are hence a valid pharmacological target for the treatment of neurodegenerative disorders; however, novel drugs targeting NMDARs are often associated with specific psychotic side effects and abuse potential. Motivated by currently available treatment against neurodegenerative diseases involving the inhibitors of acetylcholinesterase (AChE) and NMDARs, administered also in combination, we developed a dually-acting compound 7-phenoxytacrine (7-PhO-THA) and evaluated its neuropsychopharmacological and drug-like properties for potential therapeutic use. Indeed, we have confirmed the dual potency of 7-PhO-THA, i.e. potent and balanced inhibition of both AChE and NMDARs. We discovered that it selectively inhibits the GluN1/GluN2B subtype of NMDARs via an ifenprodil-binding site, in addition to its voltage-dependent inhibitory effect at both GluN1/GluN2A and GluN1/GluN2B subtypes of NMDARs. Furthermore, whereas NMDA-induced lesion of the dorsal hippocampus confirmed potent anti-excitotoxic and neuroprotective efficacy, behavioral observations showed also a cholinergic component manifesting mainly in decreased hyperlocomotion. From the point of view of behavioral side effects, 7-PhO-THA managed to avoid these, notably those analogous to symptoms of schizophrenia. Thus, CNS availability and the overall behavioral profile are promising for subsequent investigation of therapeutic use.
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- 2020
28. Pursuing the Complexity of Alzheimer's Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and
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Jan, Konecny, Anna, Misiachna, Martina, Hrabinova, Lenka, Pulkrabkova, Marketa, Benkova, Lukas, Prchal, Tomas, Kucera, Tereza, Kobrlova, Vladimir, Finger, Marharyta, Kolcheva, Stepan, Kortus, Daniel, Jun, Marian, Valko, Martin, Horak, Ondrej, Soukup, and Jan, Korabecny
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N-methyl-d-aspartate receptor ,Fluorenes ,multi-target directed ligands ,in vitro ,CHO Cells ,acetylcholinesterase ,Receptors, N-Methyl-D-Aspartate ,Article ,fluorene ,Cricetulus ,Alzheimer Disease ,Blood-Brain Barrier ,in silico ,Butyrylcholinesterase ,butyrylcholinesterase ,Animals ,Humans ,Computer Simulation ,Cholinesterase Inhibitors ,Enzyme Inhibitors ,Alzheimer’s disease - Abstract
Alzheimer’s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood–brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.
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- 2020
29. The pathogenic S688Y mutation in the ligand-binding domain of the GluN1 subunit regulates the properties of NMDA receptors
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Barbora Krausova, Jae man Song, Stepan Kortus, Katarina Hemelikova, Young Ho Suh, Marharyta Kolcheva, Jakub Netolicky, Martin Horak, Jan Korabecny, Tomas Kucera, Martina Kaniakova, and Kristyna Skrenkova
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Models, Molecular ,Glycine ,Excitotoxicity ,lcsh:Medicine ,Nerve Tissue Proteins ,Neurotransmission ,Ligands ,Molecular neuroscience ,medicine.disease_cause ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,Ion channels in the nervous system ,Article ,Protein Domains ,medicine ,Animals ,Humans ,Missense mutation ,Rats, Wistar ,lcsh:Science ,Receptor ,Neurons ,Mutation ,Multidisciplinary ,Chemistry ,lcsh:R ,Glutamate receptor ,Glycine Agents ,Rats ,Cell biology ,HEK293 Cells ,nervous system ,NMDA receptor ,lcsh:Q ,Ionotropic effect - Abstract
Although numerous pathogenic mutations have been identified in various subunits of N-methyl-D-aspartate receptors (NMDARs), ionotropic glutamate receptors that are central to glutamatergic neurotransmission, the functional effects of these mutations are often unknown. Here, we combined in silico modelling with microscopy, biochemistry, and electrophysiology in cultured HEK293 cells and hippocampal neurons to examine how the pathogenic missense mutation S688Y in the GluN1 NMDAR subunit affects receptor function and trafficking. We found that the S688Y mutation significantly increases the EC50 of both glycine and d-serine in GluN1/GluN2A and GluN1/GluN2B receptors, and significantly slows desensitisation of GluN1/GluN3A receptors. Moreover, the S688Y mutation reduces the surface expression of GluN3A-containing NMDARs in cultured hippocampal neurons, but does not affect the trafficking of GluN2-containing receptors. Finally, we found that the S688Y mutation reduces Ca2+ influx through NMDARs and reduces NMDA-induced excitotoxicity in cultured hippocampal neurons. These findings provide key insights into the molecular mechanisms that underlie the regulation of NMDAR subtypes containing pathogenic mutations.
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- 2020
30. Development of versatile and potent monoquaternary reactivators of acetylcholinesterase
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José A. Dias, Tereza Kobrlova, Vendula Hepnarova, Tomas Kucera, Daniel Jun, Lubica Muckova, Florian Nachon, David Malinak, Jan Korabecny, Kamil Musilek, Franz Worek, Martina Hrabinova, Lukas Gorecki, Ondrej Soukup, Charlotte Courageux, Jana Zdarova Karasova, and Lukas Prchal
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0301 basic medicine ,Male ,Cholinesterase Reactivators ,Health, Toxicology and Mutagenesis ,Antidotes ,010501 environmental sciences ,Pharmacology ,Molecular Dynamics Simulation ,Toxicology ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Oximes ,medicine ,Animals ,Butyrylcholinesterase ,0105 earth and related environmental sciences ,Tabun ,Nerve agent ,Mice, Inbred BALB C ,General Medicine ,Acetylcholinesterase ,In vitro ,Acute toxicity ,030104 developmental biology ,chemistry ,Toxicity ,Female ,medicine.drug - Abstract
To date, the only treatments developed for poisoning by organophosphorus compounds, the most toxic chemical weapons of mass destruction, have exhibited limited efficacy and versatility. The available causal antidotes are based on reactivation of the enzyme acetylcholinesterase (AChE), which is rapidly and pseudo-irreversibly inhibited by these agents. In this study, we developed a novel series of monoquaternary reactivators combining permanently charged moieties tethered to position 6- of 3-hydroxypyridine-2-aldoxime reactivating subunit. Highlighted representatives (21, 24, and 27; also coded as K1371, K1374, and K1375, respectively) that contained 1-phenylisoquinolinium, 7-amino-1-phenylisoquinolinium and 4-carbamoylpyridinium moieties as peripheral anionic site ligands, respectively, showed efficacy superior or comparable to that of the clinically used standards. More importantly, these reactivators exhibited wide-spectrum efficacy and were minutely investigated via determination of their reactivation kinetics in parallel with molecular dynamics simulations to study their mechanisms of reactivation of the tabun-inhibited AChE conjugate. To further confirm the potential applicability of these candidates, a mouse in vivo assay was conducted. While K1375 had the lowest acute toxicity and the most suitable pharmacokinetic profile, the oxime K1374 with delayed elimination half-life was the most effective in ameliorating the signs of tabun toxicity. Moreover, both in vitro and in vivo, the versatility of the agents was substantially superior to that of clinically used standards. Their high efficacy and broad-spectrum capability make K1374 and K1375 promising candidates that should be further investigated for their potential as nerve agents and insecticide antidotes.
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- 2020
31. Tacrine - Benzothiazoles: Novel class of potential multitarget anti-Alzheimeŕs drugs dealing with cholinergic, amyloid and mitochondrial systems
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Jana Janockova, Jana Kubackova, Karel Vales, Petr Jost, João Pina, Zuzana Bednarikova, Jan Korabecny, Katarina Motykova, Eugenie Nepovimova, Luísa Cortes, Zofia Chrienova, Kamil Musilek, Carlos Serpa, Rafael Dolezal, Lucie Svobodova, Lucie Junova, Laura Aitken, Vendula Hepnarova, Martin Vališ, Katarina Chalupova, Ondrej Soukup, Danijela Rostohar, Marketa Chvojkova, Daniel Jun, Lubica Muckova, Catarina S. H. Jesus, Zuzana Gazova, Kamil Kuca, Rebecca E. Hughes, and Tomas Kucera
- Subjects
Amyloid ,Cholinergic Agents ,Pharmacology ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Protein Aggregates ,Structure-Activity Relationship ,In vivo ,Alzheimer Disease ,Drug Discovery ,medicine ,Humans ,Benzothiazoles ,Enzyme Inhibitors ,Molecular Biology ,IC50 ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,3-Hydroxyacyl CoA Dehydrogenases ,Acetylcholinesterase ,In vitro ,0104 chemical sciences ,Mitochondria ,010404 medicinal & biomolecular chemistry ,Neuroprotective Agents ,Benzothiazole ,chemistry ,Tacrine ,Cholinergic ,medicine.drug - Abstract
A series of tacrine – benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid β (Aβ) aggregation and mitochondrial enzyme ABAD, whose interaction with Aβ leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aβ aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 µM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound – 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.
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- 2020
32. Interaction of Cucurbit[7]uril with Oxime K027, Atropine, and Paraoxon: Risky or Advantageous Delivery System?
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Zbynek Vecera, Tomas Kucera, Jiri Kassa, Vit Sestak, Jana Zdarova Karasova, and Martin Mzik
- Subjects
cucurbit[7]uril ,Atropine ,Bridged-Ring Compounds ,Cholinesterase Reactivators ,medicine.medical_treatment ,Pyridinium Compounds ,Pharmacology ,Catalysis ,Article ,Paraoxon ,lcsh:Chemistry ,Inorganic Chemistry ,chemistry.chemical_compound ,Mice ,In vivo ,Oximes ,medicine ,Toxicokinetics ,Animals ,Computer Simulation ,Physical and Theoretical Chemistry ,Antidote ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,mouse ,pesticide ,Chemistry ,cucurbiturils ,Organic Chemistry ,K027 ,Imidazoles ,General Medicine ,acetylcholinesterase ,CB7 ,Oxime ,Acetylcholinesterase ,Computer Science Applications ,Molecular Docking Simulation ,in vivo ,lcsh:Biology (General) ,lcsh:QD1-999 ,Blood-Brain Barrier ,Drug delivery ,antidote ,medicine.drug - Abstract
Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood&ndash, brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC&mdash, pharmacokinetics, toxicokinetics, acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.
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- 2020
33. Amaryllidaceae Alkaloids of Belladine-Type from Narcissus pseudonarcissus cv. Carlton as New Selective Inhibitors of Butyrylcholinesterase
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Jan Korábečný, Jiří Kuneš, Jiří Janoušek, Marcela Šafratová, Martina Hrabinova, Abdullah Al Mamun, Lucie Nováková, Lucie Cahlíková, Tomas Kucera, Daniela Hulcová, and Jana Maříková
- Subjects
Aché ,Stereochemistry ,Narcissus pseudonarcissus cv. Carlton ,lcsh:QR1-502 ,Oligopeptidase ,alkaloids ,01 natural sciences ,Biochemistry ,lcsh:Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,Amaryllidaceae Alkaloids ,Molecular Biology ,Butyrylcholinesterase ,030304 developmental biology ,0303 health sciences ,biology ,010405 organic chemistry ,Amaryllidaceae ,Active site ,docking studies ,biology.organism_classification ,Acetylcholinesterase ,language.human_language ,In vitro ,0104 chemical sciences ,carltonine A–C ,chemistry ,butyrylcholinesterase ,biology.protein ,language ,Alzheimer’s disease - Abstract
Thirteen known (1&ndash, 12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13&ndash, 15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated in sufficient amounts, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE, E.C. 3.1.1.7), butyrylcholinesterase (BuChE, E.C. 3.1.1.8) and prolyl oligopeptidase (POP, E.C. 3.4.21.26) inhibition activities. Significant human BuChE (hBUChE) inhibitory activity was demonstrated by newly described alkaloids carltonine A (13) and carltonine B (14) with IC50 values of 913 ±, 20 nM and 31 ±, 1 nM, respectively. Both compounds displayed a selective inhibition pattern for hBuChE with an outstanding selectivity profile over AChE inhibition, higher than 100. The in vitro data were further supported by in silico studies of the active alkaloids 13 and 14 in the active site of hBuChE.
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- 2020
34. Is It the Twilight of BACE1 Inhibitors?
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Martina Hrabinova, Daniel Jun, Ondrej Soukup, Jaroslav Pejchal, Monika Schmidt, and Tomas Kucera
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Amyloid beta ,Skin rashes ,Disease ,Bioinformatics ,Placebo ,Weight loss ,Alzheimer Disease ,Aricle ,mental disorders ,inhibitors ,Medicine ,Aspartic Acid Endopeptidases ,Humans ,β-secretase ,Pharmacology (medical) ,Prospective Studies ,Adverse effect ,substrates ,Pharmacology ,clinical trials ,Amyloid beta-Peptides ,biology ,business.industry ,General Medicine ,Clinical trial ,amyloid beta ,Psychiatry and Mental health ,Neurology ,β secretase ,biology.protein ,Neurology (clinical) ,medicine.symptom ,Amyloid Precursor Protein Secretases ,business ,Alzheimer’s disease - Abstract
β-secretase (BACE1) has been regarded as a prime target for the development of amyloid beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited. Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis, the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are classified into four generations. Those that underwent clinical trials displayed adverse effects, including weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo. We still believe that drugs targeting BACE1 may still hide some potential, but a different approach to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational modification should now be followed.
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- 2020
35. Substituted Piperazines as Novel Potential Radioprotective Agents
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Miroslav Psotka, Jaroslav Pejchal, Tomas Kucera, Zuzana Šinkorová, Ales Tichy, Natalie Zivna, Jana Cizkova, Marcela Jeličová, Alzbeta Filipova, Lubica Muckova, Darja Koutová, Lukas Prchal, Radim Havelek, Jan Marek, Martina Majorosova, and Martina Rezacova
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Models, Molecular ,synthesis de novo ,Cell Survival ,Radioprotective Agent ,Molecular Conformation ,Pharmaceutical Science ,Pharmacology ,Piperazines ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,lcsh:Organic chemistry ,In vivo ,Cell Line, Tumor ,Radiation, Ionizing ,Drug Discovery ,Humans ,Physical and Theoretical Chemistry ,Cytotoxicity ,Cell survival ,030304 developmental biology ,0303 health sciences ,radiation-protective agents ,maximum tolerated dose ,Dose-Response Relationship, Drug ,Molecular Structure ,Low toxicity ,Chemistry ,Organic Chemistry ,piperazine ,Survival Analysis ,In vitro ,Piperazine ,Chemistry (miscellaneous) ,Apoptosis ,030220 oncology & carcinogenesis ,Molecular Medicine ,cytotoxicity - Abstract
The increasing risk of radiation exposure underlines the need for novel radioprotective agents. Hence, a series of novel 1-(2-hydroxyethyl)piperazine derivatives were designed and synthesized. Some of the compounds protected human cells against radiation-induced apoptosis and exhibited low cytotoxicity. Compared to the previous series of piperazine derivatives, compound 8 exhibited a radioprotective effect on cell survival in vitro and low toxicity in vivo. It also enhanced the survival of mice 30 days after whole-body irradiation (although this increase was not statistically significant). Taken together, our in vitro and in vivo data indicate that some of our compounds are valuable for further research as potential radioprotectors.
- Published
- 2020
36. Functionalized aromatic esters of the Amaryllidaceae alkaloid haemanthamine and their in vitro and in silico biological activity connected to Alzheimer's disease
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Jaroslav Jenčo, Abdullah Al Mamun, Vincenza Andrisano, Jana Markova, Jana Maříková, Daniela Hulcová, Negar Maafi, Tomas Kucera, Angela De Simone, Marcela Šafratová, Rozálie Peřinová, Lucie Cahlíková, Jiří Kuneš, Ana Martínez, Daniel Jun, Lucie Nováková, Jan Korábečný, Eliška Kohelová, Rozálie Peřinová, Negar Maafi, Jan Korábečný, Eliška Kohelová, Angela De Simone, Abdullah Al Mamun, Daniela Hulcová, Jana Marková, Tomáš Kučera, Daniel Jun, Marcela Šafratová, Jana Maříková, Vincenza Andrisano, Jaroslav Jenčo, Jiří Kuneš, Ana Martinez, Lucie Nováková, Lucie Cahlíková, Charles University (Czech Republic), University Hospital Hradec Králové, Ministerio de Ciencia, Innovación y Universidades (España), Czech Science Foundation, Peřinová, Rozálie [0000-0002-3919-5082], Maafi, Negar [0000-0002-4227-7855], Korábečný, Jan [0000-0001-6977-7596], Kohelová, Eliška [0000-0003-1365-0283], De Simone, Angela [0000-0003-1915-458X], Hulcová, Daniela [0000-0003-2414-3551], Jun, Daniel [0000-0002-0882-6304], Safratova, Marcela [0000-0003-4690-5107], Maříková, Jana [0000-0001-9758-2067], Andrisano, Vincenza [0000-0003-4396-1904], Jenco, Jaroslav [0000-0001-8667-8303], Kuneš, Jiří [0000-0001-7257-0641], Martínez, Ana [0000-0002-2707-8110], Nováková, Lucie [0000-0003-3570-5871], Cahlíková, Lucie [0000-0002-1555-8870], Peřinová, Rozálie, Maafi, Negar, Korábečný, Jan, Kohelová, Eliška, De Simone, Angela, Hulcová, Daniela, Jun, Daniel, Safratova, Marcela, Maříková, Jana, Andrisano, Vincenza, Jenco, Jaroslav, Kuneš, Jiří, Martínez, Ana, Nováková, Lucie, and Cahlíková, Lucie
- Subjects
Haemanthamine ,In silico ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Alzheimer Disease ,Acetylcholinesterase Alzheimer’s disease Amaryllidaceae Butyrylcholinesterase Docking studies Haemanthamine ,Drug Discovery ,Humans ,Docking studies ,Molecular Biology ,IC50 ,Butyrylcholinesterase ,chemistry.chemical_classification ,Binding Sites ,010405 organic chemistry ,Alkaloid ,Organic Chemistry ,Amaryllidaceae ,Biological activity ,Esters ,Alzheimer's disease ,Acetylcholinesterase ,In vitro ,0104 chemical sciences ,Phenanthridines ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Kinetics ,Enzyme ,chemistry ,Blood-Brain Barrier ,Amaryllidaceae Alkaloids ,Cholinesterase Inhibitors ,Alzheimer’s disease - Abstract
23 p.-6 fig.-1 tab., A novel series of aromatic esters (1a-1m) related to the Amaryllidaceae alkaloid (AA) haemanthamine were designed, synthesized and tested in vitro with particular emphasis on the treatment of neurodegenerative diseases. Some of the synthesized compounds revealed promising acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory profile. Significant human AChE (hAChE) inhibition was demonstrated by 11-O-(3-nitrobenzoyl)haemanthamine (1j) with IC50value of 4.0 ± 0.3 µM. The strongest human BuChE (hBuChE) inhibition generated 1-O-(2-methoxybenzoyl)haemanthamine (1g) with IC50 value 3.3 ± 0.4 µM. Moreover, 11-O-(2-chlorbenzoyl)haemanthamine (1m) was able to inhibit both enzymes in dose-dependent manner. The mode of hAChE and hBuChE inhibition was minutely inspected using enzyme kinetic analysis in tandem with in silico experiments, the latter elucidating crucial interaction in 1j-, 1m-hAChE and 1g-, 1m-hBuChE complexes. The blood–brain barrier (BBB) permeability was investigated applying the parallel artificial membrane permeation assay (PAMPA) to predict the CNS availability of the compounds., This project was supported by Charles University grants (GA UK Nr. 178518, SVV UK 260412, 260 401; Progres/UK Q40 and Q42), by MH CZ - DRO (University Hospital Hradec Kralove, Nr. 00179906), by Long-term development plan (Faculty of Military Health Sciences), and by EFSA-CDN (Nr.CZ.02.1.01/0.0/0.0/16_019/0000841) co-funded by ERDF, by MICU (grant Nr. SAF2016-76693-R to A.M.), and by Czech Science Foundation (Nr. 20-29633 J). Computational resources were provided by the CESNET LM2015042 and the CERIT Scientific Cloud LM2015085, provided under the program “Projects of Large Research,Development, and Innovations Infrastructures”., preprint
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- 2020
37. Cysteine-Targeted Insecticides against A. gambiae Acetylcholinesterase Are Neither Selective nor Reversible Inhibitors
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Rudolf Andrys, Vendula Hepnarova, Jan Korabecny, Barbora Svobodova, Petr Bzonek, Kamil Kuca, Tomas Kucera, Veronika Hrabcova, Lukas Gorecki, Miroslav Psotka, Monika Schmidt, Kamil Musilek, and Daniel Jun
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chemistry.chemical_classification ,biology ,Anopheles gambiae ,Organic Chemistry ,Anopheles ,biology.organism_classification ,Biochemistry ,Acetylcholinesterase ,Combinatorial chemistry ,chemistry.chemical_compound ,Enzyme ,chemistry ,Succinimide ,Drug Discovery ,parasitic diseases ,Moiety ,Maleimide ,Cysteine - Abstract
[Image: see text] Acetylcholinesterase cysteine-targeted insecticides against malaria vector Anopheles gambia and other mosquitos have already been introduced. We have applied the olefin metathesis for the preparation of cysteine-targeted insecticides in high yields. The prepared compounds with either a succinimide or maleimide moiety were evaluated on Anopheles gambiae and human acetylcholinesterase with relatively high irreversible inhibition of both enzymes but poor selectivity. The concept of cysteine binding was not proved by several methods, and poor stability was observed of the chosen most potent/selective compounds in a water/buffer environment. Thus, our findings do not support the proposed concept of cysteine-targeted selective insecticides for the prepared series of succinimide or maleimide compounds.
- Published
- 2019
38. The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer's disease
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Eugenie Nepovimova, Ondřej Soukup, Tomas Kucera, Daniel Kaping, Ngoc Lam Pham, Katarina Spilovska, Daniel Jun, L. Matouskova, M. Kerhartova, Eva Mezeiova, Lubica Muckova, Petr Jost, Kamil Kuca, Vendula Hepnarova, Frantisek Staud, Martina Hrabinova, Jan Korabecny, Rafael Dolezal, and N. Vykoukalova
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0301 basic medicine ,Stereochemistry ,Carboxylic acid ,Cell Line ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Cricetulus ,0302 clinical medicine ,Alzheimer Disease ,Drug Discovery ,Muscarinic acetylcholine receptor ,medicine ,Animals ,Humans ,Moiety ,Butyrylcholinesterase ,Cholinesterase ,Pharmacology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Organic Chemistry ,General Medicine ,Acetylcholinesterase ,030104 developmental biology ,chemistry ,Docking (molecular) ,Tacrine ,Quinolines ,biology.protein ,Cholinesterase Inhibitors ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line. All the novel tacrine-BQCA hybrids were able to block the action of hAChE and hBChE in micromolar to nanomolar range. The hAChE kinetic profile of 5p was found to be mixed-type which is consistent with our docking experiments. Moreover, selected ligands were assessed for their potential hepatotoxicity on HepG2 cell line and presumable permeation through the blood-brain barrier by PAMPA assay. Expected agonistic profile towards M1 mAChRs delivered by BQCA moiety was not confirmed. From all the hybrids, 5o can be highlighted as non-selective cholinesterase inhibitor (hAChE IC50 = 74.5 nM; hBChE IC50 = 83.3 nM) with micromolar antagonistic activity towards M1 mAChR (IC50 = 4.23 μM). A non-selective pattern of cholinesterase inhibition is likely to be valuable during the onset as well as later stages of AD.
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- 2018
39. Derivatives of montanine-type alkaloids and their implication for the treatment of Alzheimer's disease: Synthesis, biological activity and in silico study
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Tomas Kucera, Filip Pidaný, Jiří Kuneš, Latifah Al Shammari, Jiří Janoušek, Lucie Cahlíková, Marko Mecava, Jaroslav Jenčo, Jana Maříková, Lucie Nováková, Maria Carmen Catapano, Monika Schmidt, Negar Maafi, Jan Korábečný, Marcel Špulák, Eliška Kohelová, Daniela Hulcová, and Lukas Prchal
- Subjects
In silico ,Clinical Biochemistry ,Pharmaceutical Science ,Disease ,Pharmacology ,Biochemistry ,law.invention ,Structure-Activity Relationship ,chemistry.chemical_compound ,Alkaloids ,Alzheimer Disease ,law ,Drug Discovery ,Humans ,Amaryllidaceae Alkaloids ,Molecular Biology ,IC50 ,Butyrylcholinesterase ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Biological activity ,Isoquinolines ,Acetylcholinesterase ,Molecular Docking Simulation ,Blood-Brain Barrier ,Recombinant DNA ,Molecular Medicine ,Cholinesterase Inhibitors - Abstract
Alzheimeŕs disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC50
- Published
- 2021
40. Huprine Y – Tryptophan heterodimers with potential implication to Alzheimer’s disease treatment
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Daniel Jun, Ondrej Soukup, Jana Hroudová, Lukas Prchal, Eva Mezeiova, Lubica Muckova, Martina Hrabinova, Tomas Kucera, Vendula Hepnarova, Zdena Kristofikova, Jan Korabecny, Katarina Chalupova, Jana Janockova, Lukas Gorecki, and Jiri Kunes
- Subjects
Amyloid beta ,Clinical Biochemistry ,Pharmaceutical Science ,Heterocyclic Compounds, 4 or More Rings ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Docking (dog) ,Alzheimer Disease ,Drug Discovery ,Humans ,Molecular Biology ,Cholinesterase ,chemistry.chemical_classification ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Organic Chemistry ,Tryptophan ,Acetylcholinesterase ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Neuroprotective Agents ,Enzyme ,Alzheimer's disease treatment ,chemistry ,Aminoquinolines ,biology.protein ,Molecular Medicine ,Cholinesterase Inhibitors ,Neuronal Nitric Oxide Synthase - Abstract
The search for novel and effective therapeutics for Alzheimer's disease (AD) is the main quest that remains to be resolved. The goal is to find a disease-modifying agent able to confront the multifactorial nature of the disease positively. Herewith, a family of huprineY-tryptophan heterodimers was prepared, resulting in inhibition of cholinesterase and neuronal nitric oxide synthase enzymes, with effect against amyloid-beta (Aβ) and potential ability to cross the blood-brain barrier. Their cholinesterase pattern of behavior was inspected using kinetic analysis in tandem with docking studies. These heterodimers exhibited a promising pharmacological profile with strong implication in AD.
- Published
- 2021
41. Bis-isoquinolinium and bis-pyridinium acetylcholinesterase inhibitors: in vitro screening of probes for novel selective insecticides
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Lenka Matouskova, Rafael Dolezal, Tomas Kucera, Kamil Kuca, Lukas Gorecki, Jan Korabecny, Brigita Manyova, Kamil Musilek, Veronika Hrabcova, Eugenie Nepovimova, and Daniel Jun
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0301 basic medicine ,chemistry.chemical_classification ,Aché ,General Chemical Engineering ,General Chemistry ,Pharmacology ,Pesticide ,Acetylcholinesterase ,language.human_language ,In vitro ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Enzyme ,chemistry ,Biochemistry ,Docking (molecular) ,Toxicity ,language ,Pyridinium - Abstract
Insects have a huge impact on quality of life around the world. They play roles in transmitting diseases, crop-destruction, and as residential pests. Their increased resistance to the existing pesticides and the toxicity of carbamates (CA) and organophosphates (OP) has led to the development of new environmentally safe insecticides. In our study, thirty different bis-isoquinolinium and bis-pyridinium acetylcholinesterase inhibitors were tested as candidates for potential new selective pesticides. Our compounds were evaluated in vitro on insect acetylcholinesterase (AChE) from Musca domestica and human erythrocyte AChE using the modified Ellman's method. The values of IC50 were compared and expressed via a selectivity index (SI) towards the insect enzyme. K299, K416, and K423 provided a high SI and seem to be suitable as new lead structures of novel selective anticholinesterase insecticides. Docking studies further provided the rational background uncovering the disparities in the ligand–enzyme binding modes for each AChE enzyme. In vitro assessments as well as docking studies highlighted K299 and K416 as suitable candidates for lead structures of novel pesticides. However, further evaluation is needed to confirm this statement.
- Published
- 2017
42. Development of 3,5-Dinitrophenyl-Containing 1,2,4-Triazoles and Their Trifluoromethyl Analogues as Highly Efficient Antitubercular Agents Inhibiting Decaprenylphosphoryl-β-d-ribofuranose 2'-Oxidase
- Author
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Katarína Mikušová, Galina Karabanovich, Věra Klimešová, Alexandr Hrabálek, Karin Savková, Jan Dušek, Jaroslav Roh, Jana Korduláková, Ivona Pavkova, Oto Pavliš, Zuzana Konyariková, Tomas Kucera, Kateřina Vávrová, Jiřina Stolaříková, Jan Korábečný, Petr Pavek, Klára Konečná, Ondřej Jand’ourek, Hana Vlčková, and Stanislav Huszár
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Models, Molecular ,Hydrocarbons, Fluorinated ,Stereochemistry ,medicine.drug_class ,Antitubercular Agents ,Antimycobacterial ,01 natural sciences ,Mycobacterium tuberculosis ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Bacterial Proteins ,Drug Development ,Drug Discovery ,medicine ,Structure–activity relationship ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Oxidase test ,Trifluoromethyl ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Triazoles ,biology.organism_classification ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Alcohol Oxidoreductases ,Dinitrobenzenes ,Enzyme ,Docking (molecular) ,Molecular Medicine ,Dinitrophenyl - Abstract
We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 μM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-β-d-ribofuranose 2'-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.
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- 2019
43. A novel class of small molecule inhibitors with radioprotective properties
- Author
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Tomas Kucera, Alzbeta Filipova, Radim Havelek, Zuzana Šinkorová, Ales Tichy, Lenka Andrejsová, Lubica Muckova, Martina Seifrtova, Martina Rezacova, Lukas Prchal, Jan Marek, and Jaroslav Pejchal
- Subjects
Radioprotective Agent ,Propanols ,Apoptosis ,Radiation-Protective Agents ,Pharmacology ,01 natural sciences ,Ionizing radiation ,Small Molecule Libraries ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Immunological status ,Animals ,Humans ,Progenitor cell ,Cytotoxicity ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,General Medicine ,Small molecule ,In vitro ,0104 chemical sciences ,Mice, Inbred C57BL ,Molecular Docking Simulation ,Cell culture - Abstract
The goal of this study was to develop novel radioprotective agents targeting the intrinsic apoptotic pathway and thus decreasing the radiation-induced damage. For that purpose, we designed, synthesized and analyzed ten new compounds based on the 1-(4-(2-hydroxyethyl)piperazin-1-yl)-3-phenoxypropan-2-ol leading structure. The cytotoxicity of the newly synthesized substances was tested in vitro on cell lines derived from different progenitor cells by WST-1 proliferation assay. MTT test was utilized to assess half-maximal inhibitory concentrations and maximum tolerated concentrations of novel compounds in A-549 cells. Screening for radioprotective properties was performed using flow-cytometry in MOLT-4 cells exposed to 60Co ionizing gamma radiation. Selected candidates underwent in vivo testing in C57Bl/6 J mice having a positive impact on their immunological status. In summary, we report here promising compounds with radioprotective effect in vivo.
- Published
- 2019
44. Isoquinoline alkaloids from berberis vulgaris as potential lead compounds for the treatment of alzheimer's disease
- Author
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Vincenza Andrisano, Daniel Jun, Jan Korabecny, Jana Marikova, Daniel I. Perez, Lucie Nováková, Tomas Kucera, Lucie Cahlíková, Tomáš Siatka, Jiri Kunes, Daniela Hulcová, Lubomír Opletal, Anna Hošt'álková, Hostalkova A., Marikova J., Opletal L., Korabecny J., Hulcova D., Kunes J., Novakova L., Perez D.I., Jun D., Kucera T., Andrisano V., Siatka T., and Cahlikova L.
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Berberis ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Plant Exudates ,Pharmaceutical Science ,Oligopeptidase ,Berbamine ,01 natural sciences ,Analytical Chemistry ,chemistry.chemical_compound ,Alkaloids ,Alzheimer Disease ,Drug Discovery ,Humans ,Isoquinoline ,IC50 ,Butyrylcholinesterase ,Pharmacology ,010405 organic chemistry ,Organic Chemistry ,Isoquinoline alkaloids, lead compounds, alzheimer's disease ,Nuclear magnetic resonance spectroscopy ,Isoquinolines ,Acetylcholinesterase ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,chemistry ,Blood-Brain Barrier ,Molecular Medicine ,Cholinesterase Inhibitors ,Two-dimensional nuclear magnetic resonance spectroscopy - Abstract
Three new alkaloids, bersavine (3), muraricine (4), and berbostrejdine (8), together with seven known isoquinoline alkaloids (1-2, 5-7, 9, and 10) were isolated from an alkaloidal extract of the root bark of Berberis vulgaris. The structures of the isolated compounds were determined by spectroscopic methods, including 1D and 2D NMR techniques, HRMS, and optical rotation, and by comparison of the obtained data with those in the literature. The NMR data of berbamine (5), aromoline (6), and obamegine (7) were completely assigned employing 2D NMR experiments. Alkaloids isolated in sufficient amounts were evaluated for their in vitro acetylcholinesterase, butyrylcholinesterase (BuChE), prolyl oligopeptidase, and glycogen synthase kinase-3β inhibitory activities. Selected compounds were studied for their ability to permeate through the blood-brain barrier. Significant human BuChE ( hBuChE) inhibitory activity was demonstrated by 6 (IC50 = 0.82 ± 0.10 μM). The in vitro data were further supported by computational analysis that showed the accommodation of 6 in the active site of hBuChE.
- Published
- 2019
45. Total knee arthroplasty associated with tibial tubercle and simultaneous femoral and tibial osteotomies for severe extra-articular deformity: a case report
- Author
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Pavel, Sponer and Tomas, Kucera
- Subjects
musculoskeletal diseases ,osteoarthritis ,total knee arthroplasty ,femoral osteotomy ,extra-articular deformity ,Case Report ,musculoskeletal system ,tibial osteotomy - Abstract
The restoration of the lower extremity mechanical axis in patients with osteoarthritis in knee and extra-articular deformity requires careful pre-operative planning. An extra-articular deformity may be corrected inside the knee by arthroplasty with intra-articular correction or outside of the knee by osteotomy alone or by arthroplasty combined with extra-articular corrective osteotomy. In this study, we described a unique case of simultaneous femoral and tibial osteotomies at the time of primary total knee arthroplasty in a 45-year-old woman. To prevent unnecessary bone loss, the intra-articular bone resections were made parallelly to the preexisting joint obliquity prior to the corrective tibial and femoral osteotomies. After restoration of the mechanical axis and healing of all osteotomies, a successful clinical and radiological outcome was achieved during the mid-term 5-year follow-up. The preoperative analysis of patients with an extra-articular deformity is invaluable and should include long-standing radiographs from the center of the femoral head to the center of the ankle. Although different osteotomy principles (opening wedge vs closing wedge) and fixation methods (stemmed revision prosthesis, intramedullary nail, locking plates) have been reported in the literature, the use of a tapered fluted long stem offers several benefits, including ease of application, rotational control, and possible early weight bearing. Total knee arthroplasty in combination with simultaneous extra-articular osteotomy is technically difficult but effective. This technique helps to preserve bone stock and ligament stability. A single intervention leads to less recovery time, reduced risk to the patients by avoiding two separate applications of anesthesia, and reduced costs. Based on the literature search, this is the first report describing the detailed surgical technique of simultaneous femoral and tibial osteotomies at the time of primary total knee arthroplasty associated with tibial tubercle osteotomy, achieving a comprehensive correction.
- Published
- 2018
46. Alkaloids of Zephyranthes citrina (Amaryllidaceae) and their implication to Alzheimer's disease: Isolation, structural elucidation and biological activity
- Author
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Aneta Ritomská, Daniel Jun, Lucie Nováková, Jakub Chlebek, Kateřina Breiterová, Jiří Kuneš, Milan Malaník, Jaroslav Jenčo, Lubomír Opletal, Marcela Šafratová, Rozálie Peřinová, Jan Korábečný, Eliška Kohelová, Jana Maříková, Daniela Hulcová, Martina Hrabinova, Lucie Cahlíková, and Tomas Kucera
- Subjects
Magnetic Resonance Spectroscopy ,Stereochemistry ,Molecular Conformation ,Oligopeptidase ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Alkaloids ,Alzheimer Disease ,Catalytic Domain ,Drug Discovery ,Humans ,Amaryllidaceae Alkaloids ,Molecular Biology ,Butyrylcholinesterase ,Binding Sites ,biology ,010405 organic chemistry ,Chemistry ,Alkaloid ,Amaryllidaceae ,Organic Chemistry ,Biological activity ,biology.organism_classification ,Acetylcholinesterase ,0104 chemical sciences ,Molecular Docking Simulation ,Kinetics ,010404 medicinal & biomolecular chemistry ,Blood-Brain Barrier ,Zephyranthes citrina ,Cholinesterase Inhibitors - Abstract
Twenty known Amaryllidaceae alkaloids of various structural types, and one undescribed alkaloid of narcikachnine-type, named narcieliine (3), have been isolated from fresh bulbs of Zephyranthes citrina. The chemical structures of the isolated alkaloids were elucidated by a combination of MS, HRMS, 1D and 2D NMR, and CD spectroscopic techniques, and by comparison with literature data. The absolute configuration of narcieliine (3) has also been determined. Compounds isolated in a sufficient quantity were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8), and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human AChE/BuChE (hAChE/hBuChE) inhibitory activity was demonstrated by the newly described alkaloid narcieliine (3), with IC50 values of 18.7 ± 2.3 µM and 1.34 ± 0.31 µM, respectively. This compound is also predicted to cross the blood–brain barrier (BBB) through passive diffusion. The in vitro data were further supported by in silico studies of 3 in the active site of hAChE/hBuChE.
- Published
- 2021
47. Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists
- Author
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Tomas Kucera, Daniel Jun, Lenka Pulkrabkova, Marketa Benkova, Stepan Kortus, Vladimir Finger, Marharyta Kolcheva, Martina Hrabinova, Jan Konecny, Tereza Kobrlova, Ondrej Soukup, Jan Korabecny, Martin Horak, Anna Misiachna, Lukas Prchal, and Marian Valko
- Subjects
In silico ,multi-target directed ligands ,lcsh:QR1-502 ,Pharmacology ,Biochemistry ,lcsh:Microbiology ,N-methyl-d-aspartate receptor ,fluorene ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Receptor ,Molecular Biology ,Butyrylcholinesterase ,030304 developmental biology ,Cholinesterase ,0303 health sciences ,biology ,Chemistry ,in vitro ,acetylcholinesterase ,Acetylcholinesterase ,in silico ,Docking (molecular) ,Tacrine ,butyrylcholinesterase ,biology.protein ,NMDA receptor ,Alzheimer’s disease ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Alzheimer&rsquo, s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood&ndash, brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.
- Published
- 2020
48. Enzymatic Degradation of Organophosphorus Pesticides and Nerve Agents by EC: 3.1.8.2
- Author
-
Marek Matula, Ondrej Soukup, Jaroslav Pejchal, and Tomas Kucera
- Subjects
Chemical Warfare Agents ,organophosphate ,enzymatic decontamination ,lcsh:Chemical technology ,010402 general chemistry ,nerve agents ,01 natural sciences ,Catalysis ,lcsh:Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,lcsh:TP1-1185 ,Physical and Theoretical Chemistry ,Organophosphorus acid anhydrolase ,Diisopropyl-fluorophosphatase ,030304 developmental biology ,Nerve agent ,chemistry.chemical_classification ,0303 health sciences ,biology ,Organophosphate ,Active site ,Human decontamination ,organophosphorus acid anhydrolase ,0104 chemical sciences ,Enzyme ,diisopropyl fluorophosphatase ,lcsh:QD1-999 ,Biochemistry ,chemistry ,biology.protein ,medicine.drug - Abstract
The organophosphorus substances, including pesticides and nerve agents (NAs), represent highly toxic compounds. Standard decontamination procedures place a heavy burden on the environment. Given their continued utilization or existence, considerable efforts are being made to develop environmentally friendly methods of decontamination and medical countermeasures against their intoxication. Enzymes can offer both environmental and medical applications. One of the most promising enzymes cleaving organophosphorus compounds is the enzyme with enzyme commission number (EC): 3.1.8.2, called diisopropyl fluorophosphatase (DFPase) or organophosphorus acid anhydrolase from Loligo Vulgaris or Alteromonas sp. JD6.5, respectively. Structure, mechanisms of action and substrate profiles are described for both enzymes. Wild-type (WT) enzymes have a catalytic activity against organophosphorus compounds, including G-type nerve agents. Their stereochemical preference aims their activity towards less toxic enantiomers of the chiral phosphorus center found in most chemical warfare agents. Site-direct mutagenesis has systematically improved the active site of the enzyme. These efforts have resulted in the improvement of catalytic activity and have led to the identification of variants that are more effective at detoxifying both G-type and V-type nerve agents. Some of these variants have become part of commercially available decontamination mixtures.
- Published
- 2020
49. VIRTUAL SCREENING IN DRUG DESIGN - OVERVIEW OF MOST FREQUENT TECHNIQUES
- Author
-
Tomas Kucera
- Subjects
Drug ,Emergency Medical Services ,medicine.medical_specialty ,Virtual screening ,Computer science ,Veterinary (miscellaneous) ,media_common.quotation_subject ,Public Health, Environmental and Occupational Health ,Immunology and Microbiology (miscellaneous) ,Emergency Medicine ,medicine ,Medical physics ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,media_common - Published
- 2016
50. Discovery of novel berberine derivatives with balanced cholinesterase and prolyl oligopeptidase inhibition profile
- Author
-
Martina Hrabinova, Jana Janockova, Lukas Prchal, Marketa Benkova, Ondrej Soukup, Ondrej Benek, Eva Mezeiova, Daniel Jun, Katerina Sobolova, Vendula Hepnarova, Jan Korabecny, Rafael Dolezal, Tereza Kobrlova, and Tomas Kucera
- Subjects
Quantitative structure–activity relationship ,Berberine ,Amyloid beta ,Oligopeptidase ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,Cholinesterases ,Humans ,Cytotoxicity ,Butyrylcholinesterase ,030304 developmental biology ,Pharmacology ,0303 health sciences ,biology ,010405 organic chemistry ,Organic Chemistry ,General Medicine ,Acetylcholinesterase ,0104 chemical sciences ,chemistry ,Biochemistry ,Blood-Brain Barrier ,Docking (molecular) ,Drug Design ,biology.protein ,Cholinesterase Inhibitors ,Prolyl Oligopeptidases - Abstract
Berberine, a naturally occurring compound, possesses an interesting multipotent pharmacological profile potentially applicable for Alzheimer’s disease (AD) treatment. In this study, a series of novel 22 berberine derivatives was developed and tested in vitro. Berberine core was substituted at position 9-O of its aromatic ring region. All the hybrids under the study revealed multi-targeted profile inhibiting prolyl oligopeptidase, acetylcholinesterase and butyrylcholinesterase highlighting 4a, 4g, 4j, 4l and 4s possessing balanced activities in the micromolar range. The top-ranked candidates in terms of the most pronounced potency against POP, AChE and BChE can be classified as 4d, 4u and 4v, bearing 4-methylbenzyl, (naphthalen-2-yl)methylene and 1-phenoxyethyl moieties, respectively. In vitro data were corroborated by detailed kinetic analysis of the selected lead molecules. 4d, 4u and 4v were also inspected for their potential to inhibit aggregation of two abberant proteins in AD, namely amyloid beta and tau, indicating their potential disease-modifying properties. To explain the results of our study, we carried out docking simulation to the active sites of the respective enzyme with the best berberine derivatives, along with QSAR study. We also investigated compounds’ potential permeability through blood-brain barrier by applying parallel artificial membrane permeation assay and addressed their cytotoxicity profile.
- Published
- 2020
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