@osi.lv
Latvian institute of Organic synthesis
2018 - Dr. chem. in Medicinal chemistry, Riga Technical university, Riga, Latvia.
Chemistry, Organic Chemistry
Scopus Publications
Jekateri̅na Ivanova, Alessio Nocentini, Kaspars Ta̅rs, Ja̅nis Leita̅ns, Elviss Dvinskis, Andris Kazaks, Ilona Domračeva, Claudiu T. Supuran, and Raivis Žalubovskis
American Chemical Society (ACS)
Here, we report for the first time a series of sulfonamide derivatives with scaffolds bearing flexible moieties, namely, rotamers or tropoisomers capable of adapting their geometry in the active center of enzymes thus being effective and selective carbonic anhydrase (CAs, EC 4.2.1.1) enzyme inhibitors. All compounds exhibited effective in vitro inhibition activity toward the main hCA isoforms related to cancer (i.e., hCA II, hCA IX, and hCA XII with KI values in the low nanomolar range). Three selected compounds showed a great cytotoxic effect on cancer cell lines ex vivo. X-ray crystallographic experiments assessed the binding modes of compound 35 with active centers of hCA IX and hCA XII.
Janis Leitans, Andris Kazaks, Janis Bogans, Claudiu T. Supuran, Inara Akopjana, Jekaterina Ivanova, Raivis Zalubovskis, and Kaspars Tars
Wiley
AbstractThis study explores the binding mechanisms of saccharin derivatives with human carbonic anhydrase IX (hCA IX), an antitumor drug target, with the aim of facilitating the design of potent and selective inhibitors. Through the use of crystallographic analysis, we investigate the structures of hCA IX‐saccharin derivative complexes, unveiling their unique binding modes that exhibit both similarities to sulfonamides and distinct orientations of the ligand tail. Our comprehensive structural insights provide information regarding the crucial interactions between the ligands and the protein, shedding light on interactions that dictate inhibitor binding and selectivity. Through a comparative analysis of the binding modes observed in hCA II and hCA IX, isoform‐specific interactions are identified, offering promising strategies for the development of isoform‐selective inhibitors that specifically target tumor‐associated hCA IX. The findings of this study significantly deepen our understanding of the binding mechanisms of hCA inhibitors, laying a solid foundation for the rational design of more effective inhibitors.
Jekaterīna Ivanova, Morteza Abdoli, Alessio Nocentini, Raivis Žalubovskis, and Claudiu T. Supuran
Informa UK Limited
Abstract A series of 4-methyl-1,2,3-benzoxathiazine-2,2-dioxides with various substituents in 5, 6 or 7 positions was obtained from corresponding 2’-hydroxyacetophenones in their reaction with sulphamoyl chloride. 6- and 7-aryl substituted 4-methyl-1,2,3-benzoxathiazine-2,2-dioxides were obtained from aryl substituted 2’-hydroxyacetophenonesprepared from 4- or 5-bromo-2’-hydroxyacetophenones via two-step protocol. 4-Methyl-1,2,3-benzoxathiazine-2,2-dioxides were investigated as inhibitors of four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, off-target cytosolic hCA I and II, and target transmembrane, tumour-associated hCA IX and XII. Twenty derivatives of 4-methyl-1,2,3-benzoxathiazine 2,2-dioxide were obtained. With one exception (compound2a), they mostly act as nanomolar inhibitors of target hCA IX and XII. Basically, all screened compounds express none or low inhibitory properties towards off-target hCA I. hCA II is inhibited in micromolar range. Overwhelming majority of 4-methyl-1,2,3-benzoxathiazine 2,2-dioxides express excellent selectivity towards CA IX/XII over hCA I as well as very good selectivity towards CA IX/XII over hCA II.
Jekaterina Ivanova, Morteza Abdoli, Alessio Nocentini, Raivis Žalubovskis, and Claudiu T. Supuran
Informa UK Limited
Abstract A series of 1,2,3-benzoxathiazine-2,2-dioxides possessing various substituents in the 5, 7, or 8 position was obtained from corresponding 2-hydroxybenzaldehydes in their reaction with sulfamoyl chloride. 5-, 7-, and 8-aryl substituted 1,2,3-benzoxathiazine-2,2-dioxides were prepared from aryl substituted 2-hydroxybenzaldehydes obtained from 3-, 4-, or 6-bromo-2-hydroxybenzaldehydes via two-step protocol. 1,2,3-Benzoxathiazine-2,2-dioxides were investigated for the inhibition of four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, cytosolic hCA I and II and tumour-associated transmembrane hCA IX and XII. Twenty four derivatives of 1,2,3-benzoxathiazine 2,2-dioxide were obtained. Most of them act as nanomolar inhibitors of hCA IX and XII. Almost all compounds except 2d and 5a-e also express nanomolar inhibitory activity for hCA II. hCA I is poorly inhibited or not inhibited by 1,2,3-benzoxathiazine 2,2-dioxides. Some of the new derivatives exhibit promising selectivity towards CA IX/XII over hCA I, although none of the compounds are selective towards CA IX/XII over both hCA I and II.
Jekaterīna Ivanova, Boriss Štrumfs, and Raivis Žalubovskis
Elsevier BV
Jekaterīna Ivanova, Fabrizio Carta, Daniela Vullo, Janis Leitans, Andris Kazaks, Kaspars Tars, Raivis Žalubovskis, and Claudiu T. Supuran
Elsevier BV
Jekaterīna Ivanova, Agnese Balode, Raivis Žalubovskis, Janis Leitans, Andris Kazaks, Daniela Vullo, Kaspars Tars, and Claudiu T. Supuran
Elsevier BV
Jekaterīna Ivanova and Raivis Žalubovskis
Springer Science and Business Media LLC
Janis Leitans, Andris Kazaks, Agnese Balode, Jekaterina Ivanova, Raivis Zalubovskis, Claudiu T. Supuran, and Kaspars Tars
American Chemical Society (ACS)
Human carbonic anhydrase IX (CA IX) is overexpressed in a number of solid tumors and is considered to be a marker for cellular hypoxia that it is not produced in most normal tissues. CA IX contributes to the acidification of the extracellular matrix, which, in turn, favors tumor growth and metastasis. Therefore, CA IX is considered to be a promising anti-cancer drug target. However, the ability to specifically target CA IX is challenging due to the fact that the human genome encodes 15 different carbonic anhydrase isoforms that have a high degree of homology. Furthermore, structure-based drug design of CA IX inhibitors so far has been largely unsuccessful due to technical difficulties regarding the expression and crystallization of the enzyme. Currently, only one baculovirus-produced CA IX structure in complex with a nonspecific CA inhibitor, acetazolamide, is available in Protein Data Bank. We have developed an efficient system for the production of the catalytic domain of CA IX in methylotrophic yeast Pichia pastoris. The produced protein can be easily crystallized in the presence of inhibitors, as we have demonstrated for several 2-thiophene-sulfonamide compounds. We have also observed significant differences in the binding mode of chemically identical compounds to CA IX and CA II, which can be further exploited in the design of CA IX-specific inhibitors.
Jekaterina Ivanova, Janis Leitans, Muhammet Tanc, Andris Kazaks, Raivis Zalubovskis, Claudiu T. Supuran, and Kaspars Tars
Royal Society of Chemistry (RSC)
The X-ray co-crystallization experiments of saccharin derivative with carbonic anhydrase revealed hydrolysis of isothiazole ring of saccharin and guided design of new inhibitors.
V. Alterio, M. Tanc, J. Ivanova, R. Zalubovskis, I. Vozny, S. M. Monti, A. Di Fiore, G. De Simone, and C. T. Supuran
Royal Society of Chemistry (RSC)
Sulfamoylated saccharin binds to human carbonic anhydrase II through the SO2NH2and not CONHSO2moiety.
R. Aleksis, K. Jaudzems, J. Ivanova, R. Žalubovskis, I. Kalvinsh, and E. Liepinsh
Springer Science and Business Media LLC
Giuseppina De Simone, Ginta Pizika, Simona Maria Monti, Anna Di Fiore, Jekaterina Ivanova, Igor Vozny, Peteris Trapencieris, Raivis Zalubovskis, Claudiu T. Supuran, and Vincenzo Alterio
Hindawi Limited
A new series of compounds containing a sulfamide moiety as zinc-binding group (ZBG) has been synthesized and tested for determining inhibitory properties against four human carbonic anhydrase (hCA) isoforms, namely, CAs I, II, IX, and XII. The X-ray structure of the cytosolic dominant isoform hCA II in complex with the best inhibitor of the series has also been determined providing further insights into sulfamide binding mechanism and confirming that such zinc-binding group, if opportunely derivatized, can be usefully exploited for obtaining new potent and selective CAIs. The analysis of the structure also suggests that for drug design purposes the but-2-yn-1-yloxy moiety tail emerges as a very interesting substituent of the phenylmethylsulfamide moiety due to its capability to establish strong van der Waals interactions with a hydrophobic cleft on the hCA II surface, delimited by residues Phe131, Val135, Pro202, and Leu204. Indeed, the complementarity of this tail with the cleft suggests that different substituents could be used to discriminate between isoforms having clefts with different sizes.
Vaida Morkūnaitė, Lina Baranauskienė, Asta Zubrienė, Visvaldas Kairys, Jekaterina Ivanova, Pēteris Trapencieris, and Daumantas Matulis
Hindawi Limited
A series of modified saccharin sulfonamides have been designed as carbonic anhydrase (CA) inhibitors and synthesized. Their binding to CA isoforms I, II, VII, XII, and XIII was measured by the fluorescent thermal shift assay (FTSA) and isothermal titration calorimetry (ITC). Saccharin bound the CAs weakly, exhibiting the affinities of 1–10 mM for four CAs except CA I where binding could not be detected. Several sulfonamide-bearing saccharines exhibited strong affinities of 1–10 nM towards particular CA isoforms. The functional group binding Gibbs free energy additivity maps are presented which may provide insights into the design of compounds with increased affinity towards selected CAs.
Marina Makrecka, Raivis Zalubovskis, Edijs Vavers, Jekaterina Ivanova, Aiga Grandane, and Maija Dambrova
Bentham Science Publishers Ltd.
G. Kiselev, A. F. Mishnev, E. M. Ivanova, I. V. Vozny, and R. Žalubovskis
Springer Science and Business Media LLC
E. M. Ivanova, E. Yu. Simin, I. V. Vozny, P. Trapencieris, and R. Žalubovskis
Springer Science and Business Media LLC
E. M. Ivanova, D. A. Borovika, I. V. Vozny, P. Trapencieris, and R. Žalubovskis
Springer Science and Business Media LLC