Raivis Zalubovskis - Academia.edu (original) (raw)

Papers by Raivis Zalubovskis

Research paper thumbnail of Quantum Chemical Investigation of the Interaction between Thiocyanate and the Human Carbonic Anhydrase II

Research paper thumbnail of Inhibitors of Selected Bacterial Metalloenzymes

Current Medicinal Chemistry, 2019

The utilization of bacterial metalloenzymes, especially ones not having mammalian (human) counter... more The utilization of bacterial metalloenzymes, especially ones not having mammalian (human) counterparts, has drawn attention to develop novel antibacterial agents to overcome drug resistance and especially multidrug resistance. In this review, we focus on the recent achievements on the development of inhibitors of bacterial enzymes peptide deformylase (PDF), metallo-β-lactamase (MBL), methionine aminopeptidase (MetAP) and UDP-3-O-acyl- N-acetylglucosamine deacetylase (LpxC). The state of the art of the design and investigation of inhibitors of bacterial metalloenzymes is presented, and challenges are outlined and discussed.

Research paper thumbnail of 3H-1,2-benzoxathiepine 2,2-dioxides: a new class of isoform-selective carbonic anhydrase inhibitors

Journal of enzyme inhibition and medicinal chemistry, 2017

A new chemotype with carbonic anhydrase (CA, EC 4.2.1.1) inhibitory action has been discovered, t... more A new chemotype with carbonic anhydrase (CA, EC 4.2.1.1) inhibitory action has been discovered, the homo-sulfocoumarins (3H-1,2-benzoxathiepine 2,2-dioxides) which have been designed considering the (sulfo)coumarins as lead molecules. An original synthetic strategy of a panel of such derivatives led to compounds with a unique inhibitory profile and very high selectivity for the inhibition of the tumour associated (CA IX/XII) over the cytosolic (CA I/II) isoforms. Although the CA inhibition mechanism with these new compounds is unknown for the moment, we hypothesize that it may be similar to that of the sulfocoumarins, i.e. hydrolysis to the corresponding sulfonic acids which thereafter anchor to the zinc-coordinated water molecule within the enzyme active site.

Research paper thumbnail of Enantio- and regioselectivity in Palladium- and Molybdenum-Catalyzed Allylic Alkylations

Latvian Journal of Chemistry, 2004

Research paper thumbnail of ChemInform Abstract: Synthesis of an 8-Membered Heterocycle (III) from Saccharin and Leakadine

Research paper thumbnail of Three dimensional structure of human carbonic anhydrase II in complex with 2-(Pentylsulfamoyl)-4-sulfamoylbenzoic acid

Research paper thumbnail of An Efficient Expression and Crystallization System of the Cancer Asociated Carbonic Anhydrase Isoform IX

Journal of medicinal chemistry, Jan 31, 2015

Human carbonic anhydrase IX (CA IX) is overexpressed in a number of solid tumors and is considere... more Human carbonic anhydrase IX (CA IX) is overexpressed in a number of solid tumors and is considered as a marker for cellular hypoxia, while it is not produced in most of the normal tis-sue. CA IX contributes to acidification of extracellular matrix, which in turn favors growth and metastasis of tumor. Therefore, CA IX is considered a promising anti-cancer drug target. How-ever, specific targeting of CA IX is challenging due to the fact that human genome encodes 15 different isoforms of carbonic anhydrases with a high degree of homology. Furthermore, struc-ture-based drug design of CA IX inhibitors so far has been largely unsuccessful due to technical difficulties in expression and crystallization of enzyme. Currently, only one baculovirus pro-duced CA IX structure in complex with unspecific CA inhibitor acetazolamide is available in Protein Data Bank. We have developed an efficient production system of the catalytic domain of CA IX in methylotrophic yeast Pichia pastoris. The produce...

Research paper thumbnail of X-ray crystallography-promoted drug design of carbonic anhydrase inhibitors

Chemical communications (Cambridge, England), Jan 27, 2015

1-N-Alkylated-6-sulfamoyl saccharin derivatives were prepared and assayed as carbonic anhydrase i... more 1-N-Alkylated-6-sulfamoyl saccharin derivatives were prepared and assayed as carbonic anhydrase inhibitors (CAIs). During X-ray crystallographic experiments an unexpected hydrolysis of the isothiazole ring was evidenced which allowed us to prepare highly potent enzyme inhibitors with selectivity for some isoforms with medical applications.

Research paper thumbnail of Synthesis of 6-aryl-substituted sulfocoumarins and investigation of their carbonic anhydrase inhibitory action

Bioorganic & Medicinal Chemistry, 2015

Research paper thumbnail of X-ray crystallographic and kinetic investigations of 6-sulfamoyl-saccharin as a carbonic anhydrase inhibitor

Organic & Biomolecular Chemistry, 2015

Sulfamoylated saccharin binds to human carbonic anhydrase II through the SO2NH2and not CONHSO2moi... more Sulfamoylated saccharin binds to human carbonic anhydrase II through the SO2NH2and not CONHSO2moiety.

Research paper thumbnail of Hydrophobic Substituents of the Phenylmethylsulfamide Moiety Can Be Used for the Development of New Selective Carbonic Anhydrase Inhibitors

BioMed Research International, 2014

A new series of compounds containing a sulfamide moiety as zinc-binding group (ZBG) has been synt... more 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 su...

Research paper thumbnail of 5-Membered cyclic hydroxamic acids as HDAC inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry, 2014

Research paper thumbnail of Chiral Metal Complexes in Asymmetric Catalysis

Research paper thumbnail of Glyoxalase 1 and 2 Enzyme Inhibitory Activity of 6-Sulfamoylsaccharin and Sulfocoumarin Derivates

Letters in Drug Design & Discovery, 2013

Research paper thumbnail of Synthesis of 2-Hydroxyimino-1,2,3,4-tetrahydropyrimidines

Chemistry of Heterocyclic Compounds, 2013

Research paper thumbnail of Self-Adaptable Catalysts:  Substrate-Dependent Ligand Configuration

Journal of the American Chemical Society, 2008

Research paper thumbnail of Enantioselective silicon–boron additions to cyclic 1,3-dienes catalyzed by the platinum group metal complexes

Journal of Organometallic Chemistry, 2008

Silaborations of 1,3-cyclohexadiene and 1,3-cycloheptadiene were achieved using catalysts prepare... more Silaborations of 1,3-cyclohexadiene and 1,3-cycloheptadiene were achieved using catalysts prepared from different combinations of phosphorus ligands and group 10 metal compounds. For the six-membered compound, 1,4-adducts with up to 82% ee were obtained employing Pt(0) and phosphoramidite ligands. For the seven-membered diene optimal conditions were found using catalysts based on Ni(0), but the highest selectivity observed was merely 22% ee.

Research paper thumbnail of Influence of Steric Symmetry and Electronic Dissymmetry on the Enantioselectivity in Palladium-Catalyzed Allylic Substitutions

The Journal of Organic Chemistry, 2003

Research paper thumbnail of Sulfocoumarins (1,2-Benzoxathiine-2,2-dioxides): A Class of Potent and Isoform-Selective Inhibitors of Tumor-Associated Carbonic Anhydrases

Journal of Medicinal Chemistry, 2013

Coumarins were recently shown to constitute a novel class of mechanism-based carbonic anhydrase (... more Coumarins were recently shown to constitute a novel class of mechanism-based carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. We demonstrate that sulfocoumarins (1,2-benzoxathiine 2,2-dioxides) possess a similar mechanism of action, acting as effective CA inhibitors. The sulfocoumarins were hydrolyzed by the esterase CA activity to 2-hydroxyphenyl-vinylsulfonic acids, which thereafter bind to the enzyme in a region rarely occupied by other classes of inhibitors. The X-ray structure of one of these compounds in adduct with a modified CA II enzyme possessing two amino acid residues from the CA IX active site, allowed us to decipher the inhibition mechanism. The sulfonic acid was observed anchored to the zinc-coordinated water molecule, making favorable interactions with Thr200 and Pro201. Some other sulfocoumarins incorporating substituted-1,2,3-triazole moieties were prepared by using click chemistry and showed low nanomolar inhibitory action against the tumor-associated isoforms CA IX and XII, being less effective against the cytosolic CA I and II.

Research paper thumbnail of Stereochemical Control of Chirally Flexible Phosphepines

European Journal of Organic Chemistry, 2007

The barriers to interconversion of the two enantiomeric atropisomers of 6‐methoxy‐6,7‐dihydro‐5H‐... more The barriers to interconversion of the two enantiomeric atropisomers of 6‐methoxy‐6,7‐dihydro‐5H‐dibenzo[c,e]phosphepine and that of the diastereomeric forms of 6‐(–)‐menthoxy‐6,7‐dihydro‐3H‐dibenzo[c,e]phosphepine were determined by NMR spectroscopical methods to be 19.3 and 18.5 kcal mol–1, respectively, at 298 K. The ratio of the atropisomers was shown to depend on the group bound to phosphorus. Only complexes with two homochiral ligands bound to the each metal center were obtained upon reaction with [Rh(COD)2]+ BF4–. The Rh complexes catalyzed the hydrogenation of α‐acetamidocinnamate. The major isomer of6‐(–)‐menthoxy‐6,7‐dihydro‐5H‐dibenzo[c,e]phosphepinewas found to exhibit higher activity but to afford a product with lower ee than its diastereomer. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Research paper thumbnail of Quantum Chemical Investigation of the Interaction between Thiocyanate and the Human Carbonic Anhydrase II

Research paper thumbnail of Inhibitors of Selected Bacterial Metalloenzymes

Current Medicinal Chemistry, 2019

The utilization of bacterial metalloenzymes, especially ones not having mammalian (human) counter... more The utilization of bacterial metalloenzymes, especially ones not having mammalian (human) counterparts, has drawn attention to develop novel antibacterial agents to overcome drug resistance and especially multidrug resistance. In this review, we focus on the recent achievements on the development of inhibitors of bacterial enzymes peptide deformylase (PDF), metallo-β-lactamase (MBL), methionine aminopeptidase (MetAP) and UDP-3-O-acyl- N-acetylglucosamine deacetylase (LpxC). The state of the art of the design and investigation of inhibitors of bacterial metalloenzymes is presented, and challenges are outlined and discussed.

Research paper thumbnail of 3H-1,2-benzoxathiepine 2,2-dioxides: a new class of isoform-selective carbonic anhydrase inhibitors

Journal of enzyme inhibition and medicinal chemistry, 2017

A new chemotype with carbonic anhydrase (CA, EC 4.2.1.1) inhibitory action has been discovered, t... more A new chemotype with carbonic anhydrase (CA, EC 4.2.1.1) inhibitory action has been discovered, the homo-sulfocoumarins (3H-1,2-benzoxathiepine 2,2-dioxides) which have been designed considering the (sulfo)coumarins as lead molecules. An original synthetic strategy of a panel of such derivatives led to compounds with a unique inhibitory profile and very high selectivity for the inhibition of the tumour associated (CA IX/XII) over the cytosolic (CA I/II) isoforms. Although the CA inhibition mechanism with these new compounds is unknown for the moment, we hypothesize that it may be similar to that of the sulfocoumarins, i.e. hydrolysis to the corresponding sulfonic acids which thereafter anchor to the zinc-coordinated water molecule within the enzyme active site.

Research paper thumbnail of Enantio- and regioselectivity in Palladium- and Molybdenum-Catalyzed Allylic Alkylations

Latvian Journal of Chemistry, 2004

Research paper thumbnail of ChemInform Abstract: Synthesis of an 8-Membered Heterocycle (III) from Saccharin and Leakadine

Research paper thumbnail of Three dimensional structure of human carbonic anhydrase II in complex with 2-(Pentylsulfamoyl)-4-sulfamoylbenzoic acid

Research paper thumbnail of An Efficient Expression and Crystallization System of the Cancer Asociated Carbonic Anhydrase Isoform IX

Journal of medicinal chemistry, Jan 31, 2015

Human carbonic anhydrase IX (CA IX) is overexpressed in a number of solid tumors and is considere... more Human carbonic anhydrase IX (CA IX) is overexpressed in a number of solid tumors and is considered as a marker for cellular hypoxia, while it is not produced in most of the normal tis-sue. CA IX contributes to acidification of extracellular matrix, which in turn favors growth and metastasis of tumor. Therefore, CA IX is considered a promising anti-cancer drug target. How-ever, specific targeting of CA IX is challenging due to the fact that human genome encodes 15 different isoforms of carbonic anhydrases with a high degree of homology. Furthermore, struc-ture-based drug design of CA IX inhibitors so far has been largely unsuccessful due to technical difficulties in expression and crystallization of enzyme. Currently, only one baculovirus pro-duced CA IX structure in complex with unspecific CA inhibitor acetazolamide is available in Protein Data Bank. We have developed an efficient production system of the catalytic domain of CA IX in methylotrophic yeast Pichia pastoris. The produce...

Research paper thumbnail of X-ray crystallography-promoted drug design of carbonic anhydrase inhibitors

Chemical communications (Cambridge, England), Jan 27, 2015

1-N-Alkylated-6-sulfamoyl saccharin derivatives were prepared and assayed as carbonic anhydrase i... more 1-N-Alkylated-6-sulfamoyl saccharin derivatives were prepared and assayed as carbonic anhydrase inhibitors (CAIs). During X-ray crystallographic experiments an unexpected hydrolysis of the isothiazole ring was evidenced which allowed us to prepare highly potent enzyme inhibitors with selectivity for some isoforms with medical applications.

Research paper thumbnail of Synthesis of 6-aryl-substituted sulfocoumarins and investigation of their carbonic anhydrase inhibitory action

Bioorganic & Medicinal Chemistry, 2015

Research paper thumbnail of X-ray crystallographic and kinetic investigations of 6-sulfamoyl-saccharin as a carbonic anhydrase inhibitor

Organic & Biomolecular Chemistry, 2015

Sulfamoylated saccharin binds to human carbonic anhydrase II through the SO2NH2and not CONHSO2moi... more Sulfamoylated saccharin binds to human carbonic anhydrase II through the SO2NH2and not CONHSO2moiety.

Research paper thumbnail of Hydrophobic Substituents of the Phenylmethylsulfamide Moiety Can Be Used for the Development of New Selective Carbonic Anhydrase Inhibitors

BioMed Research International, 2014

A new series of compounds containing a sulfamide moiety as zinc-binding group (ZBG) has been synt... more 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 su...

Research paper thumbnail of 5-Membered cyclic hydroxamic acids as HDAC inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry, 2014

Research paper thumbnail of Chiral Metal Complexes in Asymmetric Catalysis

Research paper thumbnail of Glyoxalase 1 and 2 Enzyme Inhibitory Activity of 6-Sulfamoylsaccharin and Sulfocoumarin Derivates

Letters in Drug Design & Discovery, 2013

Research paper thumbnail of Synthesis of 2-Hydroxyimino-1,2,3,4-tetrahydropyrimidines

Chemistry of Heterocyclic Compounds, 2013

Research paper thumbnail of Self-Adaptable Catalysts:  Substrate-Dependent Ligand Configuration

Journal of the American Chemical Society, 2008

Research paper thumbnail of Enantioselective silicon–boron additions to cyclic 1,3-dienes catalyzed by the platinum group metal complexes

Journal of Organometallic Chemistry, 2008

Silaborations of 1,3-cyclohexadiene and 1,3-cycloheptadiene were achieved using catalysts prepare... more Silaborations of 1,3-cyclohexadiene and 1,3-cycloheptadiene were achieved using catalysts prepared from different combinations of phosphorus ligands and group 10 metal compounds. For the six-membered compound, 1,4-adducts with up to 82% ee were obtained employing Pt(0) and phosphoramidite ligands. For the seven-membered diene optimal conditions were found using catalysts based on Ni(0), but the highest selectivity observed was merely 22% ee.

Research paper thumbnail of Influence of Steric Symmetry and Electronic Dissymmetry on the Enantioselectivity in Palladium-Catalyzed Allylic Substitutions

The Journal of Organic Chemistry, 2003

Research paper thumbnail of Sulfocoumarins (1,2-Benzoxathiine-2,2-dioxides): A Class of Potent and Isoform-Selective Inhibitors of Tumor-Associated Carbonic Anhydrases

Journal of Medicinal Chemistry, 2013

Coumarins were recently shown to constitute a novel class of mechanism-based carbonic anhydrase (... more Coumarins were recently shown to constitute a novel class of mechanism-based carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. We demonstrate that sulfocoumarins (1,2-benzoxathiine 2,2-dioxides) possess a similar mechanism of action, acting as effective CA inhibitors. The sulfocoumarins were hydrolyzed by the esterase CA activity to 2-hydroxyphenyl-vinylsulfonic acids, which thereafter bind to the enzyme in a region rarely occupied by other classes of inhibitors. The X-ray structure of one of these compounds in adduct with a modified CA II enzyme possessing two amino acid residues from the CA IX active site, allowed us to decipher the inhibition mechanism. The sulfonic acid was observed anchored to the zinc-coordinated water molecule, making favorable interactions with Thr200 and Pro201. Some other sulfocoumarins incorporating substituted-1,2,3-triazole moieties were prepared by using click chemistry and showed low nanomolar inhibitory action against the tumor-associated isoforms CA IX and XII, being less effective against the cytosolic CA I and II.

Research paper thumbnail of Stereochemical Control of Chirally Flexible Phosphepines

European Journal of Organic Chemistry, 2007

The barriers to interconversion of the two enantiomeric atropisomers of 6‐methoxy‐6,7‐dihydro‐5H‐... more The barriers to interconversion of the two enantiomeric atropisomers of 6‐methoxy‐6,7‐dihydro‐5H‐dibenzo[c,e]phosphepine and that of the diastereomeric forms of 6‐(–)‐menthoxy‐6,7‐dihydro‐3H‐dibenzo[c,e]phosphepine were determined by NMR spectroscopical methods to be 19.3 and 18.5 kcal mol–1, respectively, at 298 K. The ratio of the atropisomers was shown to depend on the group bound to phosphorus. Only complexes with two homochiral ligands bound to the each metal center were obtained upon reaction with [Rh(COD)2]+ BF4–. The Rh complexes catalyzed the hydrogenation of α‐acetamidocinnamate. The major isomer of6‐(–)‐menthoxy‐6,7‐dihydro‐5H‐dibenzo[c,e]phosphepinewas found to exhibit higher activity but to afford a product with lower ee than its diastereomer. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)