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79 results on '"Zubriene, A."'

3. Exploration and optimisation of structure-activity relationships of new triazole-based C-terminal Hsp90 inhibitors towards in vivo anticancer potency

Author

Dernovšek, Jaka, Zajec, Živa, Poje, Goran, Urbančič, Dunja, Sturtzel, Caterina, Goričan, Tjaša, Grissenberger, Sarah, Ciura, Krzesimir, Woziński, Mateusz, Gedgaudas, Marius, Zubrienė, Asta, Grdadolnik, Simona Golič, Mlinarič-Raščan, Irena, Rajić, Zrinka, Cotman, Andrej Emanuel, Zidar, Nace, Distel, Martin, and Tomašič, Tihomir

Published
2024
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7. Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

Author

Virginija Jakubkiene, Gabrielius Ernis Valiulis, Markus Schweipert, Asta Zubriene, Daumantas Matulis, Franz-Josef Meyer-Almes, and Sigitas Tumkevicius

Subjects
alkylation, aminolysis, hdac inhibitors, hydroxamic acid, pyrimidine, Science, Organic chemistry, QD241-441
Abstract

Histone deacetylases (HDACs) play an essential role in the transcriptional regulation of cells through the deacetylation of nuclear histone and non-histone proteins and are promising therapeutic targets for the treatment of various diseases. Here, the synthesis of new compounds in which a hydroxamic acid residue is attached to differently substituted pyrimidine rings via a methylene group bridge of varying length as potential HDAC inhibitors is described. The target compounds were obtained by alkylation of 2-(alkylthio)pyrimidin-4(3H)-ones with ethyl 2-bromoethanoate, ethyl 4-bromobutanoate, or methyl 6-bromohexanoate followed by aminolysis of the obtained esters with hydroxylamine. Oxidation of the 2-methylthio group to the methylsulfonyl group and following treatment with amines resulted in the formation of the corresponding 2-amino-substituted derivatives, the ester group of which reacted with hydroxylamine to give the corresponding hydroxamic acids. The synthesized hydroxamic acids were tested as inhibitors of the HDAC4 and HDAC8 isoforms. Among the synthesized pyrimidine-based hydroxamic acids N-hydroxy-6-[6-methyl-2-(methylthio)-5-propylpyrimidin-4-yloxy]hexanamide was found to be the most potent inhibitor of both the HDAC4 and HDAC8 isoforms, with an IC50 of 16.6 µM and 1.2 µM, respectively.

Published
2022
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9. PLBD: protein-ligand binding database of thermodynamic and kinetic intrinsic parameters.

Author

Darius Linge, Marius Gedgaudas, Andrius Merkys, Vytautas Petrauskas, Antanas Vaitkus, Algirdas Grybauskas, Vaida Paketuryte, Asta Zubriene, Audrius Zaksauskas, Aurelija Mickeviciute, Joana Smirnoviene, Lina Baranauskiene, Edita Capkauskaite, Virginija Dudutiene, Ernestas Urniezius, Aleksandras Konovalovas, Egidijus Kazlauskas, Kirill Shubin, Helgi B. Schiöth, Wen-Yih Chen, John E. Ladbury, Saulius Grazulis, and Daumantas Matulis

Published
2023
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18. Synthesis and histone deacetylases inhibitory activity of pyrimidine‐based 1,3,4‐oxadiazoles.

Author

Jakubkiene, V., Labalaukyte, I., Schweipert, M., Zubriene, A., Meyer‐Almes, F.‐J., Matulis, D., and Tumkevicius, S.

Subjects
MANNICH reaction, PROPYL group, CHEMICAL synthesis, METHYL groups, GROUP rings, PYRIMIDINES
Abstract

The histone deacetylases (HDACs) are being explored as a promising therapeutic target for the treatment of various diseases. Here, the synthesis of a series of pyrimidine‐based 1,3,4‐oxadiazoles, in which the oxadiazole scaffold is attached to the pyrimidine ring via a methyleneoxy spacer, is described and their HDAC inhibitory activity studied. The target compounds were synthesized by sequence of reactions involving O‐alkylation of 2‐(methylthio)pyrimidin‐4(3H)‐ones with ethyl 2‐bromoethanoate followed by oxidation of the 2‐methylthio group, displacement of the obtained 2‐methylsulfonyl group with amines, hydrazinolysis of the obtained ethyl (2‐amino‐substituted pyrimidin‐4‐yloxy)acetates to give the corresponding hydrazides and their cyclization under the treatment with ethyl O‐ethyl xanthate or carbonyldiimidazole to 1,3,4‐oxadiazole‐2(3H)‐thiones and 1,3,4‐oxadiazol‐2(3H)‐one, correspondingly. In addition, two 1,3,4‐oxadiazole‐2(3H)‐thiones were converted into (N3)‐morpholinomethyl derivatives by the Mannich reaction with formaldehyde and morpholine. The yields of intermediates and target compounds ranged from moderate to excellent. The synthesized compounds were characterized by 1H and 13C NMR spectra and HRMS data, their purity was controlled by TLC. The synthesized pyrimidine‐based 1,3,4‐oxadiazoles (18 compounds) were tested as inhibitors of the HDAC4 and HDAC8 isoforms and their inhibitory activity was compared with that of Vorinostat. Most of the oxadiazolethiones containing methyl group at the position 6 of the pyrimidine moiety were found to be more selective towards HDAC8, while oxadiazolethiones with propyl group in the pyrimidine ring were active against HDAC4. Among the tested compounds, 5‐((2‐(dibutylamino)‐6‐propylpyrimidin‐4‐yloxy)methyl)‐1,3,4‐oxadiazole‐2(3H)‐thione (48) was found to have the strongest inhibitory activity for HDAC4 isoform (IC50 = 4.2 μM vs. IC50 = 59 μM for Vorinostat) while 5‐((2‐(cyclopentylamino)‐6‐propylpyrimidin‐4‐yloxy)methyl)‐1,3,4‐oxadiazole‐2(3H)‐thione (50) was the most potent HDAC8 inhibitor (IC50 = 6.8 μM). [ABSTRACT FROM AUTHOR]

Published
2024
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22. PLBD : protein-ligand binding database of thermodynamic and kinetic intrinsic parameters

Author

Linge, Darius, Gedgaudas, Marius, Merkys, Andrius, Petrauskas, Vytautas, Vaitkus, Antanas, Grybauskas, Algirdas, Paketuryte, Vaida, Zubriene, Asta, Zaksauskas, Audrius, Mickeviciute, Aurelija, Smirnoviene, Joana, Baranauskiene, Lina, Capkauskaite, Edita, Dudutiene, Virginija, Urniezius, Ernestas, Konovalovas, Aleksandras, Kazlauskas, Egidijus, Shubin, Kirill, Schiöth, Helgi B., Chen, Wen-Yih, Ladbury, John E., Grazulis, Saulius, Matulis, Daumantas, Linge, Darius, Gedgaudas, Marius, Merkys, Andrius, Petrauskas, Vytautas, Vaitkus, Antanas, Grybauskas, Algirdas, Paketuryte, Vaida, Zubriene, Asta, Zaksauskas, Audrius, Mickeviciute, Aurelija, Smirnoviene, Joana, Baranauskiene, Lina, Capkauskaite, Edita, Dudutiene, Virginija, Urniezius, Ernestas, Konovalovas, Aleksandras, Kazlauskas, Egidijus, Shubin, Kirill, Schiöth, Helgi B., Chen, Wen-Yih, Ladbury, John E., Grazulis, Saulius, and Matulis, Daumantas

Abstract

We introduce a protein-ligand binding database (PLBD) that presents thermodynamic and kinetic data of reversible protein interactions with small molecule compounds. The manually curated binding data are linked to protein-ligand crystal structures, enabling structure-thermodynamics correlations to be determined. The database contains over 5500 binding datasets of 556 sulfonamide compound interactions with the 12 catalytically active human carbonic anhydrase isozymes defined by fluorescent thermal shift assay, isothermal titration calorimetry, inhibition of enzymatic activity and surface plasmon resonance. In the PLBD, the intrinsic thermodynamic parameters of interactions are provided, which account for the binding-linked protonation reactions. In addition to the protein-ligand binding affinities, the database provides calorimetrically measured binding enthalpies, providing additional mechanistic understanding. The PLBD can be applied to investigations of protein-ligand recognition and could be integrated into small molecule drug design.

Published
2023
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38. Novel fluorinated carbonic anhydrase IX inhibitors reduce hypoxia-induced acidification and clonogenic survival of cancer cells

Author

Reinhard Zeidler, Lina Baranauskiene, Jurgita Matuliene, Asta Zubriene, Virginija Dudutiene, Raymon Niemans, Gabor Gondi, Janis Leitans, Daumantas Matulis, Holger M. Becker, Philippe Lambin, Ala Yaromina, Ludwig Dubois, Justina Kazokaite, Kaspars Tars, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Promovendi ODB, and Radiotherapie

Subjects
0301 basic medicine, A549 cell, biology, Active site, Lyase, biology.organism_classification, Molecular biology, law.invention, HeLa, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, Oncology, chemistry, law, Carbonic anhydrase, Cancer cell, biology.protein, Recombinant DNA, Lead compound, Cancer, Carbonic anhydrase IX, Drug design, Hypoxia, Sulfonamide
Abstract

Human carbonic anhydrase (CA) IX has emerged as a promising anticancertarget and a diagnostic biomarker for solid hypoxic tumors. Novel fluorinated CAIX inhibitors exhibited up to 50 pM affinity towards the recombinant human CA IX,selectivity over other CAs, and direct binding to Zn(II) in the active site of CA IXinducing novel conformational changes as determined by X-ray crystallography. Massspectrometric gas-analysis confirmed the CA IX-based mechanism of the inhibitors ina CRISPR/Cas9-mediated CA IX knockout in HeLa cells. Hypoxia-induced extracellularacidification was significantly reduced in HeLa, H460, MDA-MB-231, and A549 cellsexposed to the compounds, with the IC50 values up to 1.29 nM. A decreased clonogenicsurvival was observed when hypoxic H460 3D spheroids were incubated with ourlead compound. These novel compounds are therefore promising agents for CA IXspecifictherapy.

Published
2018

39. Novel fluorinated carbonic anhydrase IX inhibitors reduce hypoxia-induced acidification and clonogenic survival of cancer cells

Author

Kazokaite, J., Kazokaite, J., Niemans, Raymon, Dudutiene, V., Becker, Holger M., Leitans, J., Zubriene, A., Baranauskiene, L., Gondi, Gabor, Zeidler, Reinhard, Matuliene, J., Tars, K., Yaromina, Ala, Lambin, Philippe, Dubois, Ludwig, Matulis, D., Kazokaite, J., Kazokaite, J., Niemans, Raymon, Dudutiene, V., Becker, Holger M., Leitans, J., Zubriene, A., Baranauskiene, L., Gondi, Gabor, Zeidler, Reinhard, Matuliene, J., Tars, K., Yaromina, Ala, Lambin, Philippe, Dubois, Ludwig, and Matulis, D.

Abstract

Human carbonic anhydrase (CA) IX has emerged as a promising anticancer target and a diagnostic biomarker for solid hypoxic tumors. Novel fluorinated CA IX inhibitors exhibited up to 50 pM affinity towards the recombinant human CA IX, selectivity over other CAs, and direct binding to Zn(II) in the active site of CA IX inducing novel conformational changes as determined by X-ray crystallography. Mass spectrometric gas-analysis confirmed the CA IX-based mechanism of the inhibitors in a CRISPR/Cas9-mediated CA IX knockout in HeLa cells. Hypoxia-induced extracellular acidification was significantly reduced in HeLa, H460, MDA-MB-231, and A549 cells exposed to the compounds, with the IC50 values up to 1.29 nM. A decreased clonogenic survival was observed when hypoxic H460 3D spheroids were incubated with our lead compound. These novel compounds are therefore promising agents for CA IXspecific therapy.

Published
2018

40. Immobilized Alkaline Phosphatase for Molecular Cloning

Author

Gervydas Dienys, Saulute Budriene, Asta Zubriene, and Judita Lubiene

Subjects
chemistry.chemical_classification, Phosphoric monoester hydrolases, Immobilized enzyme, Molecular cloning, Biochemistry, Catalysis, Dephosphorylation, Chitosan, chemistry.chemical_compound, Enzyme, chemistry, Alkaline phosphatase, Cellulose, Biotechnology
Abstract

Alkaline phosphatase from E. coli was immobilized on Sepharose-4B, macroporous cellulose and chitosan-based carriers. The yields of immobilization were over 60% in most cases. It was shown that immobilized alkaline phosphatase can be used for dephosphorylation of DNA 5'-termini.

Published
2002
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41. Discovery and characterization of novel selective inhibitors of carbonic anhydrase IX

Author

J. Smirnoviene, S. Baksyte, A. Mickeviciute, Alexey Smirnov, Saulius Grazulis, V. Petrauskas, Audrius Zakšauskas, G. Milinaviciute, V. Morkunaite, David D. Timm, Povilas Norvaisas, Jelena Jachno, Jurgita Matuliene, Asta Zubriene, Lina Baranauskiene, Virginija Dudutiene, V. Pilipuityte, Vilma Petrikaite, Justina Kazokaite, Elena Manakova, A. Kasiliauskaite, J. Revuckiene, Edita Capkauskaite, John E. Ladbury, P. Gibieza, Vytautas Smirnovas, M. Kisonaite, Visvaldas Kairys, E. Ivanauskaite, V. Juozapaitiene, Daumantas Matulis, Egidijus Kazlauskas, Vilma Michailoviene, and D. Linge

Subjects
Stereochemistry, Protein Conformation, Kinetics, Plasma protein binding, Calorimetry, Crystallography, X-Ray, Catalysis, law.invention, Protein structure, Carbonic Anhydrase IV, law, Catalytic Domain, Neoplasms, Drug Discovery, Humans, Carbonic Anhydrase Inhibitors, Carbonic Anhydrases, Sulfonamides, biology, Chemistry, Active site, Benzene, Carbonic Anhydrase IX, Carbon Dioxide, Hydrogen-Ion Concentration, Recombinant Proteins, Drug Design, biology.protein, Recombinant DNA, Molecular Medicine, Thermodynamics, Selectivity, Crystallization, Protein Binding
Abstract

Human carbonic anhydrase IX (CA IX) is highly expressed in tumor tissues, and its selective inhibition provides a potential target for the treatment of numerous cancers. Development of potent, highly selective inhibitors against this target remains an unmet need in anticancer therapeutics. A series of fluorinated benzenesulfonamides with substituents on the benzene ring was designed and synthesized. Several of these exhibited a highly potent and selective inhibition profile against CA IX. Three fluorine atoms significantly increased the affinity by withdrawing electrons and lowering the pKa of the benzenesulfonamide group. The bulky ortho substituents, such as cyclooctyl or even cyclododecyl groups, fit into the hydrophobic pocket in the active site of CA IX but not CA II, as shown by the compound's co-crystal structure with chimeric CA IX. The strongest inhibitor of recombinant human CA IX's catalytic domain in human cells achieved an affinity of 50 pM. However, the high affinity diminished the selectivity. The most selective compound for CA IX exhibited 10 nM affinity. The compound that showed the best balance between affinity and selectivity bound with 1 nM affinity. The inhibitors described in this work provide the basis for novel anticancer therapeutics targeting CA IX.

Published
2014

42. ChemInform Abstract: Design of [(2-Pyrimidinylthio)acetyl]benzenesulfonamides as Inhibitors of Human Carbonic Anhydrase

Author

Saulius Grazulis, Visvaldas Kairys, Sigitas Tumkevicius, Elena Manakova, Daumantas Matulis, Giedre Tamulaitiene, Asta Zubriene, Lina Baranauskiene, and Edita Capkauskaite

Subjects
chemistry.chemical_compound, biology, Pyrimidine, Chemistry, Stereochemistry, Carbonic anhydrase, biology.protein, General Medicine
Abstract

S-Alkylation of pyrimidine derivatives (I) with ω-bromoacetylbenzenesulfonamides (II) and (IV) affords the title compounds (III) and (V), respectively.

Published
2012
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43. ß-galactosidase from Penicillium canescens. Properties and immobilization

Author

Gervydas Dienys, Natalija Gorochovceva, Saulute Budriene, Asta Zubriene, Aldona Miezeliene, Tatjana Romaskevic, and Lyubov V. Yugova

Subjects
Lactose hydrolysis, Polyurethane foams, General Chemistry, Chitosan, chemistry.chemical_compound, Hydrolysis, chemistry, Penicillium canescens, Biochemistry, Kluyveromyces-fragilis, Yield (chemistry), Materials Chemistry, Bed, Lactose, Polyurethane, Nuclear chemistry
Abstract

ß-galactosidase from Penicillium canescens was immobilized on chitosan, sepharose-4B, foamable polyurethane and some other carriers. The highest yield of immobilization (up to 98 %) was obtained by using chitosan as a carrier. The optimum pH and temperature were not significantly altered by immobilization. High stability of immobilized ß-galactosidase during storage was demonstrated. Efficient lactose saccharification (over 90 %) in whey was achieved by using immobilized ß-galactosidase. (C) Central European Science Journals. All rights reserved.

Published
2005

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