22 results on '"Eva Tloušt’ová"'
Search Results
2. Pyrido-Fused Deazapurine Bases: Synthesis and Glycosylation of 4‑Substituted 9H‑Pyrido[2′,3′:4,5]- and Pyrido[4′,3′:4,5]pyrrolo[2,3‑d]pyrimidines
- Author
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Lucia Veselovská, Radek Pohl, Eva Tloušt′ová, Soňa Gurská, Petr Džubák, Marián Hajdúch, and Michal Hocek
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Chemistry ,QD1-999 - Published
- 2020
- Full Text
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3. Design, Synthesis, Biological Evaluation, and Crystallographic Study of Novel Purine Nucleoside Phosphorylase Inhibitors
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Jan Skácel, Stefan Djukic, Ondřej Baszczyňski, Filip Kalčic, Tadeáš Bílek, Karel Chalupský, Jaroslav Kozák, Alexandra Dvořáková, Eva Tloušt’ová, Zuzana Král’ová, Markéta Šmídková, Jan Voldřich, Michaela Rumlová, Petr Pachl, Jiří Brynda, Tereza Vučková, Milan Fábry, Jan Snášel, Iva Pichová, Pavlína Řezáčová, Helena Mertlíková-Kaiserová, and Zlatko Janeba
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Drug Discovery ,Molecular Medicine - Published
- 2023
4. Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery
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Marcin Drąg, Jiří Brynda, Robin Kryštůfek, Jan Konvalinka, Eva Tloušt’ová, Martin Hradilek, Michael J. Boucher, Pavel Šácha, Justyna Grzymska, Pavlína Řezáčová, Miroslav Hájek, Jana Starková, Wioletta Rut, Charles S. Craik, Hiten D. Madhani, and Pavel Majer
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Proteases ,Antifungal Agents ,Aspartic Acid Proteases ,Medicinal & Biomolecular Chemistry ,medicine.medical_treatment ,Drug Evaluation, Preclinical ,Antifungal drug ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Article ,Substrate Specificity ,Microbiology ,Fungal Proteins ,Structure-Activity Relationship ,Medicinal and Biomolecular Chemistry ,HIV Protease ,Catalytic Domain ,Drug Discovery ,medicine ,HIV Protease Inhibitor ,Protease inhibitor (pharmacology) ,Cryptococcus neoformans ,Binding Sites ,Crystallography ,Protease ,biology ,Chemistry ,Organic Chemistry ,Fungi ,HIV ,Pharmacology and Pharmaceutical Sciences ,medicine.disease ,biology.organism_classification ,Aspartyl Peptidase ,Preclinical ,Recombinant Proteins ,Infectious Diseases ,5.1 Pharmaceuticals ,6.1 Pharmaceuticals ,Cryptococcosis ,X-Ray ,HIV/AIDS ,Drug Evaluation ,Molecular Medicine ,Infection - Abstract
Cryptococcosis is an invasive infection that accounts for 15% of AIDS-related fatalities. Still, treating cryptococcosis remains a significant challenge due to the poor availability of effective antifungal therapies and emergence of drug resistance. Interestingly, protease inhibitor components of antiretroviral therapy regimens have shown some clinical benefits in these opportunistic infections. We investigated Major aspartyl peptidase 1 (May1), a secreted Cryptococcus neoformans protease, as a possible target for the development of drugs that act against both fungal and retroviral aspartyl proteases. Here, we describe the biochemical characterization of May1, present its high-resolution X-ray structure, and provide its substrate specificity analysis. Through combinatorial screening of 11,520 compounds, we identified a potent inhibitor of May1 and HIV protease. This dual-specificity inhibitor exhibits antifungal activity in yeast culture, low cytotoxicity, and low off-target activity against host proteases and could thus serve as a lead compound for further development of May1 and HIV protease inhibitors.
- Published
- 2021
5. Synthesis and Antitrypanosomal Activity of 6-Substituted 7-Methyl-7-deazapurine Nucleosides
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Anna Krajczyk, Martina Slapničková, Marian Hajduch, Pavla Perlíková, Nemanja Milisavljevic, Michal Hocek, Eva Doleželová, Eva Tloušt’ová, Lenka Poštová Slavětínská, Soňa Gurská, Petr Džubák, and Alena Zíková
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0301 basic medicine ,Glycosylation ,Pyrimidine ,Stereochemistry ,030106 microbiology ,Antiprotozoal Agents ,Newly diagnosed ,Trypanosoma brucei ,03 medical and health sciences ,chemistry.chemical_compound ,Nucleophile ,parasitic diseases ,medicine ,Humans ,African trypanosomiasis ,Cytotoxicity ,biology ,Chemistry ,Nucleosides ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,Infectious Diseases ,Purines ,Alkoxy group ,Ribonucleosides - Abstract
Human African Trypanosomiasis caused by Trypanosoma brucei species is one of the most damaging neglected tropical diseases. While the number of newly diagnosed cases per year is record low, there is still high interest in the development of new antitrypanosomal agents in case of resistance to currently used drugs and their combinations, and to replace drugs with serious side effects. We report a series of 7-methyl-7-deazapurine (5-methyl-pyrrolo[2,3-d]pyrimidine) ribonucleosides bearing alkyl, methylsulfanyl, methylamino, or diverse alkoxy groups at position 6 that was prepared through glycosylation of 6-chloro-7-methyl-7-deazapurine followed by nucleophilic substitutions or cross-coupling reactions at position 6 and deprotection. Most of the title nucleosides displayed significant activity against Trypanosoma brucei brucei and T. b. gambiense at submicromolar or nanomolar concentrations and low cytotoxicity and thus represent promising candidates for further development.
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- 2021
6. Synthesis and Biological Profiling of Pyrazolo-Fused 7-Deazapurine Nucleosides
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Marian Hajduch, Lenka Poštová Slavětínská, Eva Tloušt’ová, Michal Tichý, Michal Hocek, Kateřina Bártová, Petr Pavlis, Marianne Fleuti, Soňa Gurská, and Petr Džubák
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Glycosylation ,Pyrimidine ,Stereochemistry ,Organic Chemistry ,Nucleosides ,Fluorescence ,Antiviral Agents ,In vitro ,chemistry.chemical_compound ,chemistry ,Nucleophile ,Purines ,Stereoselectivity ,Replicon ,Ribonucleosides ,Nucleoside - Abstract
A series of 8-substituted 1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[2,3-d]pyrimidine (methylpyrazolo-fused 7-deazapurine) ribonucleosides have been designed and synthesized. Two synthetic approaches to the key heterocyclic aglycon 7, (i) a six-step classical heterocyclization starting from 5-chloro-1-methyl-4-nitropyrazole and (ii) a three-step cross-coupling and cyclization approach starting from the zincated 4,6-dichloropyrimidine, gave comparable total yields of 18% vs 13%. The glycosylation of 7 was attempted by three different methods but only the Vorbruggen silyl-base protocol was efficient and stereoselective to give desired β-anomeric nucleoside intermediate 17A. Its nucleophilic substitutions or cross-coupling reactions at position 8 and deprotection of the sugar moiety gave eight derivatives of pyrazolo-fused deazapurine ribonucleosides, some of which were weakly fluorescent. Methyl, amino, and methylsulfanyl derivatives exerted submicromolar cytotoxic effects in vitro against a panel of cancer and leukemia cell lines as well as antiviral effects against hepatitis C virus in the replicon assay.
- Published
- 2020
7. Synthesis and Cytostatic and Antiviral Profiling of Thieno-Fused 7-Deazapurine Ribonucleosides
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Radek Pohl, Klára Hejtmánková, Tomáš Oždian, Marian Hajduch, Sabina Smoleń, Michal Hocek, Petr Džubák, Michal Tichý, Soňa Gurská, Eva Tloušt’ová, and Barbora Lišková
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Glycosylation ,010405 organic chemistry ,Stereochemistry ,Negishi coupling ,Antineoplastic Agents ,Hepacivirus ,010402 general chemistry ,Antiviral Agents ,Hepatitis C ,01 natural sciences ,In vitro ,Leukemia cell line ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Nucleophile ,Purines ,Cell culture ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Cancer cell ,Humans ,Molecular Medicine ,Ribonucleosides - Abstract
Two isomeric series of new thieno-fused 7-deazapurine ribonucleosides (derived from 4-substituted thieno[2',3':4,5]pyrrolo[2,3-d]pyrimidines and thieno[3',2':4,5]pyrrolo[2,3-d]pyrimidines) were synthesized by a sequence involving Negishi coupling of 4,6-dichloropyrimidine with iodothiophenes, nucleophilic azidation, and cyclization of tetrazolopyrimidines, followed by glycosylation and cross-couplings or nucleophilic substitutions at position 4. Most nucleosides (from both isomeric series) exerted low micromolar or submicromolar in vitro cytostatic activities against a broad panel of cancer and leukemia cell lines and some antiviral activity against HCV. The most active were the 6-methoxy, 6-methylsulfanyl, and 6-methyl derivatives, which were highly active to cancer cells and less toxic or nontoxic to fibroblasts.
- Published
- 2017
8. Physicochemical and biological properties of novel amide-based steroidal inhibitors of NMDA receptors
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Eva Kudova, Hana Chodounska, Pavla Hubalkova, Vojtech Vyklicky, Santosh Kumar Adla, Martin Svoboda, Markéta Šmídková, Kristina Holubova, Eva Tloušt’ová, Karel Vales, Milos Budesinsky, Michaela Nekardova, Barbora Krausova, Barbora Slavikova, and Ladislav Vyklicky
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0301 basic medicine ,Magnetic Resonance Spectroscopy ,Neuroactive steroid ,Stereochemistry ,Clinical Biochemistry ,Endogeny ,Receptors, N-Methyl-D-Aspartate ,Biochemistry ,Neuroprotection ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Amide ,Humans ,Structure–activity relationship ,Molecular Biology ,Pharmacology ,Pregnanolone ,Neurotransmitter Agents ,Molecular Structure ,Chemistry ,Organic Chemistry ,Glutamate receptor ,Hep G2 Cells ,Amides ,030104 developmental biology ,Blood-Brain Barrier ,NMDA receptor ,Caco-2 Cells ,Reactive Oxygen Species ,030217 neurology & neurosurgery - Abstract
Herein, we report a new class of amide-based inhibitors (1–4) of N-methyl- d -aspartate receptors (NMDARs) that were prepared as analogues of pregnanolone sulfate (PAS) and pregnanolone glutamate (PAG) – the steroidal neuroprotective NMDAR inhibitors. A series of experiments were conducted to evaluate their physicochemical and biological properties: (i) the inhibitory effect of compounds 3 and 4 on NMDARs was significantly improved (IC50 = 1.0 and 1.4 μM, respectively) as compared with endogenous inhibitor – pregnanolone sulfate (IC50 = 24.6 μM) and pregnanolone glutamate (IC50 = 51.7 μM); (ii) physicochemical properties (logP and logD) were calculated; (iii) Caco-2 assay revealed that the permeability properties of compounds 2 and 4 are comparable with pregnanolone glutamate; (iv) compounds 1–4 have minimal or no adverse hepatic effect; (v) compounds 1–4 cross blood-brain-barrier.
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- 2017
9. Correction to 'Synthesis and Cytotoxic and Antiviral Profiling of Pyrrolo- and Furo-Fused 7-Deazapurine Ribonucleosides'
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Sabina Smoleń, Yiqian Wenren, Pavla Perlíková, Noor-Ul-Ain Khalid, Barbora Lišková, Blanka Klepetářová, Ivo Frydrych, Petr Džubák, Anna Tokarenko, Michal Tichý, Soňa Gurská, Marian Hajduch, Michal Hocek, Helena Mertlíková-Kaiserová, Pawel Znojek, Natálie Táborská, Eva Tloušt’ová, Lenka Poštová Slavětínská, Rebecca R. Laposa, and Radek Pohl
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Chemistry ,Drug Discovery ,Molecular Medicine ,Profiling (information science) ,Cytotoxic T cell ,Computational biology - Published
- 2019
10. Synthesis and Cytotoxic and Antiviral Profiling of Pyrrolo- and Furo-Fused 7-Deazapurine Ribonucleosides
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Anna Tokarenko, Petr Džubák, Sabina Smoleń, Yiqian Wenren, Rebecca R. Laposa, Marian Hajduch, Noor-Ul-Ain Khalid, Soňa Gurská, Michal Tichý, Helena Mertlíková-Kaiserová, Pavla Perlíková, Barbora Lišková, Blanka Klepetářová, Eva Tloušt’ová, Ivo Frydrych, Natálie Táborská, Radek Pohl, Michal Hocek, Lenka Poštová Slavětínská, and Pawel Znojek
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0301 basic medicine ,Glycosylation ,Pyrimidine ,Stereochemistry ,DNA damage ,Antineoplastic Agents ,Chemistry Techniques, Synthetic ,010402 general chemistry ,01 natural sciences ,Antiviral Agents ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Nucleophile ,Cell Line, Tumor ,Drug Discovery ,Structure–activity relationship ,Humans ,Nucleotide ,Pyrroles ,Furans ,chemistry.chemical_classification ,RNA ,0104 chemical sciences ,Addition/Correction ,030104 developmental biology ,chemistry ,Purines ,Molecular Medicine ,Ribonucleosides ,DNA - Abstract
Three series of isomeric pyrrolo- and furo-fused 7-deazapurine ribonucleosides were synthesized and screened for cytostatic and antiviral activity. The synthesis was based on heterocyclizations of hetaryl-azidopyrimidines to form the tricyclic heterocyclic bases, followed by glycosylation and final derivatizations through cross-coupling reactions or nucleophilic substitutions. The pyrrolo[2',3':4,5]pyrrolo[2,3- d]pyrimidine and furo[2',3':4,5]pyrrolo[2,3- d]pyrimidine ribonucleosides were found to be potent cytostatics, whereas the isomeric pyrrolo[3',2',4,5]pyrrolo[2,3- d]pyrimidine nucleosides were inactive. The most active were the methyl, methoxy, and methylsulfanyl derivatives exerting submicromolar cytostatic effects and good selectivity toward cancer cells. We have shown that the nucleosides are activated by intracellular phosphorylation and the nucleotides get incorporated to both RNA and DNA, where they cause DNA damage. They represent a new type of promising candidates for preclinical development toward antitumor agents.
- Published
- 2018
11. Pregn-5-en-3β-ol and androst-5-en-3β-ol dicarboxylic acid esters as potential therapeutics for NMDA hypofunction: In vitro safety assessment and plasma stability
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Eva Tloušt’ová, Marika Matousova, Radko Souček, Eva Kudova, Helena Mertlíková-Kaiserová, Hana Chodounska, and Barbora Slavikova
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Neuroactive steroid ,Autism Spectrum Disorder ,Cell Survival ,Clinical Biochemistry ,030209 endocrinology & metabolism ,Neurotransmission ,Pharmacology ,Biochemistry ,Receptors, N-Methyl-D-Aspartate ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Drug Stability ,In vivo ,Intellectual Disability ,mental disorders ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Dicarboxylic Acids ,Rats, Wistar ,Receptor ,Molecular Biology ,Neurons ,Androstenols ,Molecular Structure ,Chemistry ,Organic Chemistry ,Long-term potentiation ,Esters ,Hep G2 Cells ,medicine.disease ,Mitochondria ,Rats ,Mitochondrial toxicity ,Cholesterol ,Neuroprotective Agents ,nervous system ,030220 oncology & carcinogenesis ,Pregnenolone ,Toxicity ,Schizophrenia ,NMDA receptor - Abstract
Neurosteroids are endogenous steroidal compounds that can modulate neuronal receptors. N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that are of particular interest, as they participate in synaptic transmission and are implicated in various processes, such as learning, memory, or long-term neuronal potentiation. Positive allosteric modulators that increase the activity of NMDARs may provide a therapeutic aid for patients suffering from neuropsychiatric disorders where NMDAR hypofunction is thought to be involved, such as intellectual disability, autism spectrum disorder, or schizophrenia. We recently described a new class of pregn-5-ene and androst-5-ene 3β-dicarboxylic acid hemiesters (2–24) as potent positive modulators of NMDARs. Considering the recommended guidelines for the early stage development of new, potent compounds, we conducted an in vitro safety assessment and plasma stability screening to evaluate their druglikeness. First, compounds were screened for their hepatotoxicity and mitochondrial toxicity in a HepG2 cell line. Second, toxicity in primary rat postnatal neurons was estimated. Next, the ability of compounds 2–24 to cross a Caco-2 monolayer was also studied. Finally, rat and human plasma stability screening revealed an unforeseen high stability of the C-3 hemiester moiety. In summary, by using potency/efficacy towards NMDARs data along with toxicity profile, Caco-2 permeability and plasma stability, compounds 14 and 15 were selected for further in vivo animal studies.
- Published
- 2018
12. Synthesis, Cytostatic, Antimicrobial, and Anti-HCV Activity of 6-Substituted 7-(Het)aryl-7-deazapurine Ribonucleosides
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Petr Konečný, Milan Kolář, Eva Tloušt’ová, Pavla Perlíková, Marian Hajduch, Petr Nauš, Petr Džubák, Michal Hocek, Lenka Poštová Slavětínská, Jana Vrbkova, Kateřina Bogdanová, and Olga Caletková
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Stereochemistry ,Hepatitis C virus ,Antitubercular Agents ,Hepacivirus ,Virus Replication ,medicine.disease_cause ,Antiviral Agents ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Cytotoxic T cell ,Structure–activity relationship ,Replicon ,Cytotoxicity ,Cytotoxins ,Chemistry ,Aryl ,Biological activity ,Purine Nucleosides ,Cytostatic Agents ,Antimicrobial ,Mycobacterium bovis ,Anti-Bacterial Agents ,Molecular Medicine ,Ribonucleosides - Abstract
A series of 80 7-(het)aryl- and 7-ethynyl-7-deazapurine ribonucleosides bearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl, or oxo group at position 6, or 2,6-disubstituted derivatives bearing a methyl or amino group at position 2, were prepared, and the biological activity of the compounds was studied and compared with that of the parent 7-(het)aryl-7-deazaadenosine series. Several of the compounds, in particular 6-substituted 7-deazapurine derivatives bearing a furyl or ethynyl group at position 7, were significantly cytotoxic at low nanomolar concentrations whereas most were much less potent or inactive. Promising activity was observed with some compounds against Mycobacterium bovis and also against hepatitis C virus in a replicon assay.
- Published
- 2014
13. Synthesis and biological activity of benzo-fused 7-deazaadenosine analogues. 5- and 6-substituted 4-amino- or 4-alkylpyrimido[4,5-b]indole ribonucleosides
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Gina Bahador, Michal Hocek, Jan Weber, Yu-Jen Lee, Radek Pohl, Eva Tloušt’ová, and Michal Tichý
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Adenosine ,Indoles ,Cell Survival ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,HL-60 Cells ,Hepacivirus ,Antiviral Agents ,Biochemistry ,Catalysis ,Cell Line, Tumor ,Drug Discovery ,Nucleophilic substitution ,Humans ,Molecular Biology ,Indole test ,Chemistry ,Ligand ,Organic Chemistry ,Biological activity ,Hep G2 Cells ,Dengue Virus ,Stille reaction ,Molecular Medicine ,Ribonucleosides ,Palladium ,HeLa Cells - Abstract
Two series of new 4-aminopyrimido[4,5-b]indole ribonucleosides bearing phenyl or hetaryl group at position 5 or 6 have been prepared by Suzuki or Stille cross-coupling reactions employing X-Phos ligand with (het)arylboronic acids or stannanes. A series of 4-substituted nucleosides has been also prepared by Pd-catalyzed cross-couplings or nucleophilic substitution. Some of these compounds displayed moderate antiviral activities against HCV and dengue viruses.
- Published
- 2013
14. Alpha anomer of 5-aza-2′-deoxycytidine down-regulates hTERT mRNA expression in human leukemia HL-60 cells
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Marcela Krečmerová, Eva Tloušt’ová, Antonín Holý, Miroslav Hájek, and Ivan Votruba
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Antimetabolites, Antineoplastic ,S-Adenosylmethionine ,Telomerase ,Anomer ,Down-Regulation ,Decitabine ,HL-60 Cells ,Biology ,Biochemistry ,chemistry.chemical_compound ,Gene expression ,medicine ,Humans ,Telomerase reverse transcriptase ,RNA, Messenger ,Pharmacology ,Dose-Response Relationship, Drug ,Reverse Transcriptase Polymerase Chain Reaction ,Stereoisomerism ,DNA ,Methylation ,DNA Methylation ,S-Adenosylhomocysteine ,Molecular biology ,chemistry ,DNA methylation ,Azacitidine ,medicine.drug - Abstract
DNA methylation inhibitors are being extensively studied as potential anticancer agents. In the present study, we compared the capability of alpha anomer of 5-aza-2′-deoxycytidine (α-5-azadCyd) to induce down-regulation of hTERT expression in HL-60 cells with other nucleoside analogs that act as DNA methylation inhibitors: β-5-azadCyd (decitabine), ( S )-9-(2,3-dihydroxypropyl)adenine [( S )-DHPA], isobutyl ester of ( R,S )-3-(adenin-9-yl)-2-hydroxypropanoic acid [( R,S )-AHPA- ibu ] and prospective DNA methylation inhibitors ( S )-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine [( S )-HPMPazaC] and 5-fluoro-zebularine (F-PymRf). Exposure to α-5-azadCyd induced the down-regulation of hTERT expression in low micromolar concentrations (0.05–50 μM). A more cytotoxic beta anomer caused a transient up-regulation of hTERT and a subsequent reduction in hTERT mRNA levels at concentrations more than 10 times below its GIC 50 value. In this respect, ( S )-DHPA and ( R,S )-AHPA- ibu were less efficient, since a similar effect was achieved at concentrations above their GIC 50 . In contrast, F-PymRf treatment resulted in up to a three-fold induction of hTERT expression within a broad range of concentrations. In all cases, the down-regulation of hTERT expression was concentration-dependent. The correlation was found between c- myc overexpression and transiently elevated hTERT expression after treatment with all tested compounds except for α-5-azadCyd and ( S )-HPMPazaC. Although the primary task of hypomethylating agents in anticancer therapy lies in reactivation of silenced tumour-suppressor genes, the inhibition of hTERT expression might also be a fruitful clinical effect of this approach.
- Published
- 2008
15. Discovery of 5-Substituted-6-chlorouracils as Efficient Inhibitors of Human Thymidine Phosphorylase
- Author
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Antonín Holý, Hubert Hrebabecký, Petr Jansa, Radim Nencka, Milena Masojídková, Kveta Horská, Eva Tloušt’ová, and Ivan Votruba
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Models, Molecular ,chemistry.chemical_classification ,Thymidine Phosphorylase ,biology ,Active site ,Angiogenesis Inhibitors ,Uracil ,Chemical synthesis ,Kinetics ,Structure-Activity Relationship ,chemistry.chemical_compound ,Enzyme ,chemistry ,Biochemistry ,Enzyme inhibitor ,Drug Discovery ,Glycosyltransferase ,biology.protein ,Humans ,Molecular Medicine ,Structure–activity relationship ,Thymidine phosphorylase - Abstract
Thymidine phosphorylase plays an important role in angiogenesis, which is an attractive target for therapy of cancer and other diseases. In our continuous effort to develop novel inhibitors of thymidine phosphorylase, we have discovered that 6-halouracils substituted at position C5 by certain hydrophobic groups exhibit significant inhibitory activity against this enzyme. The most potent compounds bear a five- or six-membered cyclic substituent containing a pi-electron system at C5 and a chlorine atom attached at C6. 6-Chloro-5-cyclopent-1-en-1-yluracil 7a is the most efficient derivative in this study, with Ki = 0.20 +/- 0.03 microM (Ki/dThdKm = 0.0017) for thymidine phosphorylase expressed in V79 cells and Ki = 0.29 +/- 0.04 microM (Ki/dThdKm = 0.0024) for the enzyme purified from placenta.
- Published
- 2007
16. Inhibition of thymidine phosphorylase (PD-ECGF) from SD-lymphoma by phosphonomethoxyalkyl thymines
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Otová B, Antonín Holý, Karel Pomeisl, Eva Tloušt’ová, and Ivan Votruba
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Organophosphonates ,Thymopoietins ,Lymphoma, T-Cell ,Biochemistry ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,chemistry.chemical_compound ,Glycosyltransferase ,Animals ,Structure–activity relationship ,Nucleotide ,Enzyme Inhibitors ,Thymidine phosphorylase ,Phosphorolysis ,Pharmacology ,chemistry.chemical_classification ,Thymidine Phosphorylase ,biology ,Stereoisomerism ,Molecular biology ,Rats ,Thymine ,Enzyme ,chemistry ,biology.protein ,Thymidine - Abstract
A series of thymine phosphonomethoxyalkyl derivatives were evaluated for their ability to inhibit thymidine phosphorylase (dThdPase) purified from rat spontaneous T-cell lymphoma. A kinetic study of thymidine phosphorolysis catalyzed by dThdPase was performed with thymidine and/or inorganic phosphate as substrates. Data show that the substantial inhibitory effect of these acyclic nucleotide analogues is decreasing in the order of (R)-FPMPT>(S)-FPMPT>or=(R)-HPMPT>(S)-PMPT>(S)-HPMPT>PMET>or=(R)-PMPT. The inhibitory potency (K(i)/(dThd)K(m)) of the most efficient inhibitors from this series against T-cell lymphoma enzyme is 0.0026 for (R)-FPMPT and 0.0048 for (S)-FPMPT. The studied compounds do not inhibit Escherichia coli and human enzyme and possess lower inhibitory potency against rat liver thymidine phosphorylase.
- Published
- 2005
17. Abstract 5100: AB61, a new potent nucleoside cytostatic: Molecular mechanisms of action and preclinical activity
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Petr Dzubak, Monika Harvanova, Pavla Perlíková, Marian Hajduch, Pawel Znojek, Dalibor Dolezal, Tomáš Elbert, Lenka Slavetinska, Eva Tloušt’ová, Petr Nauš, Jan Hlaváč, Michal Hocek, Kamil Motyka, Aurelie Bourderioux, Gabriela Rylova, Alice Nova, and Michal Siler
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Cancer Research ,Ribonucleotide ,biology ,DNA damage ,Chemistry ,DNA polymerase ,RNA ,Molecular biology ,chemistry.chemical_compound ,Oncology ,Mechanism of action ,Gene expression ,medicine ,biology.protein ,medicine.symptom ,Nucleoside ,DNA - Abstract
7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild (micromolar) activities against normal fibroblasts. The selectivity of AB61 was found to be due to inefficient phosphorylation of AB61 in normal fibroblasts. The phosphorylation of AB61 in the leukemic CCRF-CEM cell line proceeds well and it was shown that AB61 is incorporated into both DNA and RNA, preferentially as a ribonucleotide. It was further confirmed that a triphosphate of AB61 is a substrate for both RNA and DNA polymerases in enzymatic assays. Gene expression analysis suggests that AB61 affects DNA damage pathways and protein translation/folding machinery. Indeed, the formation of large 53BP1 foci was observed in nuclei of AB61-treated U2OS-GFP-53BP1 cells indicating DNA damage. Random incorporation of AB61 into RNA blocked its translation in an in vitro assay and reduction of reporter protein expression was also observed in mice after 4-hour treatment with AB61. AB61 also significantly reduced tumor volume in mice bearing SK- OV-3, BT-549, HT-29 and MDA-MB231 xenografts. The results indicate that AB61 is a promising compound with the unique mechanism of action and deserves further development as an anticancer agent. This work was supported by the Ministry of Education of the Czech Republic (LO1304). Citation Format: Petr Dzubak, Marian Hajduch, Pavla Perlikova, Gabriela Rylová, Petr Naus, Tomas Elbert, Eva Tloustova, Aurelie Bourderioux, Lenka Slavetinska, Kamil Motyka, Dalibor Dolezal, Pawel Znojek, Alice Nova, Monika Harvanova, Michal Siler, Jan Hlavac, Michal Hocek. AB61, a new potent nucleoside cytostatic: Molecular mechanisms of action and preclinical activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5100. doi:10.1158/1538-7445.AM2017-5100
- Published
- 2017
18. Design and synthesis of novel 5,6-disubstituted uracil derivatives as potent inhibitors of thymidine phosphorylase
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Radim Nencka, Květa Horská, Eva Tloušt’ová, Hubert Hřebabecký, Ivan Votruba, Antonín Holý, and Milena Masojídková
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Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,medicine.disease_cause ,Biochemistry ,Chemical synthesis ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Glycosyltransferase ,Escherichia coli ,medicine ,Humans ,heterocyclic compounds ,Amines ,Enzyme Inhibitors ,Thymidine phosphorylase ,Uracil ,Molecular Biology ,chemistry.chemical_classification ,Thymidine Phosphorylase ,Molecular Structure ,biology ,Organic Chemistry ,biology.organism_classification ,Enterobacteriaceae ,Enzyme ,chemistry ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine - Abstract
We report on a series of novel 5,6-disubstituted uracils with significant inhibitory activity against human and Escherichia coli thymidine phosphorylases. Bis-uracil conjugates were identified as the most potent inhibitors of TPs in this study.
- Published
- 2006
19. Amidate prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine as inhibitors of adenylate cyclase toxin from Bordetella pertussis
- Author
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Markéta Šmídková, Zlatko Janeba, Michal Česnek, Alexandra Dvořáková, Eva Tloušt’ová, and Helena Mertlíková-Kaiserová
- Subjects
Bordetella pertussis ,Stereochemistry ,Cell Survival ,Organophosphonates ,Microbial Sensitivity Tests ,Inhibitory Concentration 50 ,Mice ,In vivo ,Cell Line, Tumor ,Animals ,Humans ,Pharmacology (medical) ,Prodrugs ,Experimental Therapeutics ,IC50 ,Active metabolite ,Pharmacology ,biology ,Chemistry ,Adenine ,Macrophages ,Prodrug ,biology.organism_classification ,Anti-Bacterial Agents ,Infectious Diseases ,Biochemistry ,Cell culture ,Adenylate Cyclase Toxin ,Lipophilicity ,Caco-2 Cells - Abstract
Adenylate cyclase toxin (ACT) is the key virulence factor of Bordetella pertussis that facilitates its invasion into the mammalian body. 9-[2-(Phosphonomethoxy)ethyl]adenine diphosphate (PMEApp), the active metabolite of the antiviral drug bis(POM)PMEA (adefovir dipivoxil), has been shown to inhibit ACT. The objective of this study was to evaluate six novel amidate prodrugs of PMEA, both phenyloxy phosphonamidates and phosphonodiamidates, for their ability to inhibit ACT activity in the J774A.1 macrophage cell line. The two phenyloxy phosphonamidate prodrugs exhibited greater inhibitory activity (50% inhibitory concentration [IC 50 ] = 22 and 46 nM) than the phosphonodiamidates (IC 50 = 84 to 3,960 nM). The inhibitory activity of the prodrugs correlated with their lipophilicity and the degree of their hydrolysis into free PMEA in J774A.1 cells. Although the prodrugs did not inhibit ACT as effectively as bis(POM)PMEA (IC 50 = 6 nM), they were significantly less cytotoxic. Moreover, they all reduced apoptotic effects of ACT and prevented an ACT-induced elevation of intracellular [Ca 2+ ]i. The amidate prodrugs were less susceptible to degradation in Caco-2 cells compared to bis(POM)PMEA, while they exerted good transepithelial permeability in this assay. As a consequence, a large amount of intact amidate prodrug is expected to be available to target macrophages in vivo . This feature makes nontoxic amidate prodrugs attractive candidates for further investigation as novel antimicrobial agents.
- Published
- 2013
20. ChemInform Abstract: Synthesis and Cytostatic Activity of N-[2-(Phosphonomethoxy)alkyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds
- Author
-
Antonin Holy, Ivan Votruba, Eva Tloušt’ová, and Milena Masojidkova
- Subjects
chemistry.chemical_classification ,Chemistry ,Stereochemistry ,Nucleic acid ,Organic chemistry ,General Medicine ,Alkyl - Published
- 2010
21. Inhibition of human telomerase by diphosphates of acyclic nucleoside phosphonates
- Author
-
Eva Tloušt’ová, Naděžda Matulová, Miroslav Hájek, Ivan Votruba, and Antonín Holý
- Subjects
Pharmacology ,chemistry.chemical_classification ,Telomerase ,Base Sequence ,Guanine ,Organophosphonates ,HL-60 Cells ,Biology ,Nucleotidyltransferase ,Biochemistry ,Molecular biology ,Telomere ,chemistry.chemical_compound ,Enzyme ,chemistry ,Humans ,Nucleotide ,Telomerase reverse transcriptase ,IC50 ,DNA Primers - Abstract
Diphosphates of the antiviral acyclic nucleoside phosphonates (ANPs) were evaluated in telomeric repeat amplification protocol (TRAP) for their ability to inhibit the extension of telomeres by human telomerase. Extracts from human leukaemia HL-60 cells were used as a source of the enzyme. Data show that the most effective compound studied was the guanine derivative PMEGpp (IC50 12.7+/-0.5 micromolL(-1) at 125 micromolL(-1) deoxynucleoside triphosphates (dNTPs)). The inhibitory effects of other PME, PMP and HPMP diphosphates on telomerase reverse transcriptase decreased in the order: (R)-PMPGpp>(R)-HPMPGpp>PMEDAPpp>(S)-PMPGpp>(S)-HPMPApp>PMEO-DAPypp>(R)-6-cyprPMPDAPpp>(R)-PMPApp>(R)-PMPDAPpp> or =PMEApp> or =PMECpp>PMETpp>(S)-PMPApp approximately 6-Me2PMEDAPpp. These results are consistent with the observed antineoplastic activities of the parental guanine (PMEG) and 2,6-diaminopurine (PMEDAP) PME-derivatives. Moreover, structure-activity relationship indicates enantioselectivity of some of these human telomerase inhibitors: (R)-isomers of the PMP-derivatives possess stronger inhibitory potency towards the enzyme than (S)-isomers. The data may contribute to the rational design of telomerase inhibitors based on the structure of acyclic nucleotide analogues.
- Published
- 2005
22. Discovery of 5-Substituted-6-chlorouracils as Efficient Inhibitors of Human Thymidine Phosphorylase.
- Author
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Radim Nencka, Ivan Votruba, Hubert Hebabecký, Petr Jansa, Eva Tloušt'ová, Kvta Horská, Milena Masojídková, and Antonín Holý
- Published
- 2007
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