Publications by authors named "Māris Turks"

41 Publications

Metal-free glycosylation with glycosyl fluorides in liquid SO.

Beilstein J Org Chem 2021 29;17:964-976. Epub 2021 Apr 29.

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena str. 3, Riga, LV-1048, Latvia.

Liquid SO is a polar solvent that dissolves both covalent and ionic compounds. Sulfur dioxide possesses also Lewis acid properties, including the ability to covalently bind Lewis basic fluoride ions in a relatively stable fluorosulfite anion (FSO). Herein we report the application of liquid SO as a promoting solvent for glycosylation with glycosyl fluorides without any external additive. By using various temperature regimes, the method is applied for both armed and disarmed glucose and mannose-derived glycosyl fluorides in moderate to excellent yields. A series of pivaloyl-protected - and -mannosides, as well as one example of a -mannoside, are synthesized to demonstrate the scope of the glycosyl acceptors. The formation of the fluorosulfite species during the glycosylation with glycosyl fluorides in liquid SO is proved by F NMR spectroscopy. A sulfur dioxide-assisted glycosylation mechanism that proceeds via solvent separated ion pairs is proposed, whereas the observed α,β-selectivity is substrate-controlled and depends on the thermodynamic equilibrium.
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http://dx.doi.org/10.3762/bjoc.17.78DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093551PMC
April 2021

Anticancer Potential of Betulonic Acid Derivatives.

Int J Mol Sci 2021 Apr 1;22(7). Epub 2021 Apr 1.

Department of Pharmacognosy, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania.

Clinical trials have evidenced that several natural compounds, belonging to the phytochemical classes of alkaloids, terpenes, phenols and flavonoids, are effective for the management of various types of cancer. Latest research has proven that natural products and their semisynthetic variants may serve as a starting point for new drug candidates with a diversity of biological and pharmacological activities, designed to improve bioavailability, overcome cellular resistance, and enhance therapeutic efficacy. This review was designed to bring an update regarding the anticancer potential of betulonic acid and its semisynthetic derivatives. Chemical derivative structures of betulonic acid including amide, thiol, and piperidine groups, exert an amplification of the in vitro anticancer potential of betulonic acid. With the need for more mechanistic and in vivo data, some derivatives of betulonic acids may represent promising anticancer agents.
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http://dx.doi.org/10.3390/ijms22073676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037575PMC
April 2021

1,2,3-Triazoles as leaving groups: SAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles.

Beilstein J Org Chem 2021 11;17:410-419. Epub 2021 Feb 11.

Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, LV-1048 Riga, Latvia.

A new approach was designed for the synthesis of C6-substituted 2-triazolylpurine derivatives. A series of substituted products was obtained in SAr reactions between 2,6-bistriazolylpurine derivatives and O- and C-nucleophiles under mild conditions. The products were isolated in yields up to 87%. The developed C-O and C-C bond forming reactions clearly show the ability of the 1,2,3-triazolyl ring at the C6 position of purine to act as leaving group.
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http://dx.doi.org/10.3762/bjoc.17.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884883PMC
February 2021

1,2,3-Triazoles as leaving groups in SAr-Arbuzov reactions: synthesis of C6-phosphonated purine derivatives.

Beilstein J Org Chem 2021 20;17:193-202. Epub 2021 Jan 20.

Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, LV-1048 Riga, Latvia.

A new method for C-N bond transformations into C-P bonds was developed using 1,2,3-triazoles as leaving groups in SAr-Arbuzov reactions. A series of C6-phosphonated 2-triazolylpurine derivatives was synthesized for the first time, with the isolated yields reaching up to 82% in the C-P-bond-forming event. The SAr-Arbuzov reaction of 2,6-bistriazolylpurines follows the general regioselectivity pattern of the C6-position being more reactive towards substitution, which was unambiguously proved by X-ray analysis of diethyl (9-heptyl-2-(4-phenyl-1-1,2,3-triazol-1-yl)-9-purin-6-yl)phosphonate.
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http://dx.doi.org/10.3762/bjoc.17.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849246PMC
January 2021

Proof of principle of a purine D-A-D' ligand based ratiometric chemical sensor harnessing complexation induced intermolecular PET.

Phys Chem Chem Phys 2020 Nov;22(45):26502-26508

Institute of Photonics and Nanotechnology, Faculty of Physics, Vilnius University, Sauletekis Av. 3, LT-10222 Vilnius, Lithuania.

A comprehensive photophysical study of a series of purines, doubly decorated at C2 and C6 positions with identical fragments ranging from electron acceptor to donor groups of different strengths, is presented. The asymmetry of substitutions creates a unique molecular D-A-D' structure possessing two independent electronic charge transfer (CT) systems attributed to each fragment and exhibiting dual-band fluorescence. Moreover, the inherent property of coordination of metal ions by purines was enriched due to a presence of nearby triazoles used as spacers for donor or acceptor fragments. New molecules present a bidentate coordination mode, which makes the assembly of several ligands with one metal cation possible. This property was exploited to create a new concept of a ratiometric chemical fluorescence sensor involving the photoinduced electron transfer between branches of different ligands as a mechanism of fluorescence modulation.
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http://dx.doi.org/10.1039/d0cp04091fDOI Listing
November 2020

Synthesis and cytotoxicity of hybrids of 1,3,4- or 1,2,5-oxadiazoles tethered from ursane and lupane core with 1,2,3-triazole.

Steroids 2020 10 17;162:108698. Epub 2020 Jul 17.

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, Riga LV-1048, Latvia.

Ursane and lupane type (1-((5-aryl-1,3,4-oxadiazol-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl and (1-((4-methyl-2-oxido-1,2,5-oxadiazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl hybrids were prepared by 1,3-cycloaddition reactions of azole-derived azides with alkyne esters connected to positions C-3 and C-28 of triterpene core and tested for cytotoxicity. Hybrid compounds of 1,3,4-oxadiazoles attached at positions 3- and 28- of triterpenoid frame via triazole spacer and combinations of 1,2,5-oxadiazole or 1,3,4-oxadiazole, tethered with succinate linker and 1,2,3-triazole at the position 3- of the ursane backbone, were inactive in relation to all the cancer cells tested. Eventually, combinations of furoxan fragment and 1,2,3-triazole linked to C-28 position of triterpene backbone demonstrated marked cytotoxic activity towards MCF-7 and HepG2 cells. The most active ester of ursolic acid with (1-((4-methyl-2-oxido-1,2,5-oxadiazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl substituent and 3-O-acetyl group was superior in activity and selectivity over doxorubicin and ursolic acid on MCF-7 cells. The length of the carbon spacer group may be of crucial importance for cytotoxicity. The introduction of the additional ester linker between the C-28 of triterpenoid and triazole or changing triazole spacer between furoxan moiety and triterpenoid core resulted in activity decrease against all the tested cells. In accordance with molecular modeling results, the activity of new derivatives may be explained in terms of the interaction of the new hybrid molecules and Mdm2 binding sites.
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http://dx.doi.org/10.1016/j.steroids.2020.108698DOI Listing
October 2020

Metal- and Reagent-Free Electrochemical Synthesis of Alkyl Arylsulfonates in a Multi-Component Reaction.

Chemistry 2020 Jul 22;26(38):8358-8362. Epub 2020 Jun 22.

Department of Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany.

This work presents the first electrochemical preparation of alkyl arylsulfonates by direct anodic oxidation of electron-rich arenes. The reaction mechanism features a multi-component reaction consisting of electron-rich arenes, an alcohol of choice and excess SO in an acetonitrile-HFIP reaction mixture. In-situ formed monoalkyl sulfites are considered as key intermediates with bifunctional purpose. Firstly, this species functions as nucleophile and secondly, excellent conductivity is provided. Several primary and secondary alcohols and electron-rich arenes are implemented in this reaction to form the alkyl arylsulfonates in yields up to 73 % with exquisite selectivity. Boron-doped diamond electrodes (BDD) are employed in divided cells, separated by a simple commercially available glass frit.
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http://dx.doi.org/10.1002/chem.202001180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383810PMC
July 2020

Sulfonyl Group Dance: A Tool for the Synthesis of 6-Azido-2-sulfonylpurine Derivatives.

J Org Chem 2020 04 13;85(7):4753-4771. Epub 2020 Mar 13.

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, Paula Valdena Str. 3, Riga LV-1048, Latvia.

9-Substituted 2-chloro-6-sulfonylpurines provide 6-azido-2-sulfonylpurine derivatives with 61-83% yields when treated with sodium azide. Under optimized reaction conditions, the title compounds are obtained in a one-pot process, which involves a sequential treatment of 2,6-dichloropurines with a selected sodium sulfinate and sodium azide. Such a sulfonyl group dance (functional group swap) results from a cascade of SAr reactions, which are facilitated by azidoazomethine-tetrazole (azide-tetrazole) tautomeric equilibrium. The formation of Meisenheimer-type intermediates as tetrazolopurine tautomers was supported by various spectroscopic methods, including N NMR.
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http://dx.doi.org/10.1021/acs.joc.9b03518DOI Listing
April 2020

Marine Natural Products with High Anticancer Activities.

Curr Med Chem 2020 ;27(8):1243-1307

Department of Biotechnology, University of Rijeka, Radmile Matejcic 2, 51000 Rijeka, Croatia.

This review covers recent literature from 2012-2019 concerning 170 marine natural products and their semisynthetic analogues with strong anticancer biological activities. Reports that shed light on cellular and molecular mechanisms and biological functions of these compounds, thus advancing the understanding in cancer biology are also included. Biosynthetic studies and total syntheses, which have provided access to derivatives and have contributed to the proper structure or stereochemistry elucidation or revision are mentioned. The natural compounds isolated from marine organisms are divided into nine groups, namely: alkaloids, sterols and steroids, glycosides, terpenes and terpenoids, macrolides, polypeptides, quinones, phenols and polyphenols, and miscellaneous products. An emphasis is placed on several drugs originating from marine natural products that have already been marketed or are currently in clinical trials.
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http://dx.doi.org/10.2174/0929867327666200113154115DOI Listing
May 2020

Synthesis of cytotoxic urs-12-ene- and 28-norurs-12-ene- type conjugates with amino- and mercapto-1,3,4-oxadiazoles and mercapto-1,2,4-triazoles.

Steroids 2020 01 14;153:108524. Epub 2019 Oct 14.

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, Riga LV-1048, Latvia.

A small library of 2-mercapto-1,3,4-oxadiazoles, 2-amino-1,3,4-oxadiazoles, and 3-mercapto-1,2,4-triazoles attached to the urs-12-ene- and 28-nor-urs-12-ene skeleton has been obtained. Ursolic acid derived hydrazides have been identified as useful starting materials for the developed synthesis. Ursolic acid hydrazide provided access to oxadiazoles attached directly to C-17 of the ursane core, but synthesis of structurally related 3-mercapto-1,2,4-triazoles was not possible in this way due to steric hindrance of the triterpenoid. Ester- and amide-linked hydrazides arising from ethoxycarbonylmethyl ursolate and ursolic acid amide with methyl β-alaninate served as key starting materials for the remotely connected mercapto-and amino-azoles. Antioxidant activities (DPPH method) of the newly obtained compounds are mediocre. However, excellent cytotoxicity and selectivity against MCF7 cell line were found for 28-nor-urs-12-ene 2-amino-1,3,4-oxadiazole conjugate. Also some other library members exceeded the cytotoxicity values of natural ursolic acid. The novel hybrid heterocycles with amino and mercapto substituents possess a great potential for further derivatization and are prospective scaffolds for the synthesis of triterpenoid analogs with chemopreventive and cytotoxic properties.
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http://dx.doi.org/10.1016/j.steroids.2019.108524DOI Listing
January 2020

Lupane-type conjugates with aminoacids, 1,3,4- oxadiazole and 1,2,5-oxadiazole-2-oxide derivatives: Synthesis, anti-inflammatory activity and in silico evaluation of target affinity.

Steroids 2019 10 8;150:108443. Epub 2019 Jul 8.

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, Riga LV-1048, Latvia.

With the purpose to improve anti-inflammatory activity, the impact of introduction of 1,2,5- and 1,3,4-oxadiazole fragments to betulonic acid core as well as hybrids tethered with short ω-amino acids has been studied. The anti-inflammatory activity of synthesized compounds was tested in vivo using models of inflammation induced by concanavalin A and histamine. The majority of new compounds demonstrated higher anti-inflammatory activity compared with starting betulonic acid. To confirm the molecular targets of new derivatives in NRf2 and NFκB pathways the docking at Kelch and BTB active sites of Keap1 as well as IKK was done. The novelty of the present work is the development of new class of low toxic anti-inflammatory substances consisting of amino acid-linked betulonic acid - oxadiazole conjugates. These compounds can be considered as prospective chemopreventive agents.
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http://dx.doi.org/10.1016/j.steroids.2019.108443DOI Listing
October 2019

Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines.

Beilstein J Org Chem 2019 15;15:474-489. Epub 2019 Feb 15.

Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, LV-1048 Riga, Latvia.

The synthesis of novel fluorescent N(9)-alkylated 2-amino-6-triazolylpurine and 7-deazapurine derivatives is described. A new C(2)-regioselectivity in the nucleophilic aromatic substitution reactions of 9-alkylated-2,6-diazidopurines and 7-deazapurines with secondary amines has been disclosed. The obtained intermediates, 9-alkylated-2-amino-6-azido-(7-deaza)purines, were transformed into the title compounds by CuAAC reaction. The designed compounds belong to the push-pull systems and possess promising fluorescence properties with quantum yields in the range from 28% to 60% in acetonitrile solution. Due to electron-withdrawing properties of purine and 7-deazapurine heterocycles, which were additionally extended by triazole moieties, the compounds with electron-donating groups showed intramolecular charge transfer character (ICT/TICT) of the excited states which was proved by solvatochromic dynamics and supported by DFT calculations. In the 7-deazapurine series this led to increased fluorescence quantum yield (74%) in THF solution. The compounds exhibit low cytotoxicity and as such are useful for the cell labelling studies in the future.
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http://dx.doi.org/10.3762/bjoc.15.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404417PMC
February 2019

Delivery Systems for Birch-bark Triterpenoids and their Derivatives in Anticancer Research.

Curr Med Chem 2020 ;27(8):1308-1336

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, Riga, Latvia.

Birch-bark triterpenoids and their semi-synthetic derivatives possess a wide range of biological activities including cytotoxic effects on various tumor cell lines. However, due to the low solubility and bioavailability, their medicinal applications are rather limited. The use of various nanotechnology-based drug delivery systems is a rapidly developing approach to the solubilization of insufficiently bioavailable pharmaceuticals. Herein, the drug delivery systems deemed to be applicable for birch-bark triterpenoid structures are reviewed. The aforementioned disadvantages of birch-bark triterpenoids and their semi-synthetic derivatives can be overcome through their incorporation into organic nanoparticles, which include various dendrimeric systems, as well as embedding the active compounds into polymer matrices or complexation with carbohydrate nanoparticles without covalent bonding. Some of the known triterpenoid delivery systems consist of nanoparticles featuring inorganic cores covered with carbohydrates or other polymers. Methods for delivering the title compounds through encapsulation and emulsification into lipophilic media are also suitable. Besides, the birch-bark triterpenoids can form self-assembling systems with increased bio-availability. Even more, the self-assembling systems are used as carriers for delivering other chemotherapeutic agents. Another advantage besides increased bioavailability and anticancer activity is the reduced overall systemic toxicity in most of the cases, when triterpenoids are delivered with any of the carriers.
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http://dx.doi.org/10.2174/0929867325666180530095657DOI Listing
May 2020

Crystal structure of 3,6,6-trimethyl-4-oxo-1-(pyridin-2-yl)-4,5,6,7-tetra-hydro-1-indazol-7-aminium chloride and its monohydrate.

Acta Crystallogr E Crystallogr Commun 2017 Dec 24;73(Pt 12):1931-1936. Epub 2017 Nov 24.

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, Riga LV-1048, Latvia.

The title compounds, CHNO·Cl and CHNO·Cl·HO, obtained in attempts to synthesize metal complexes using tetra-hydro-indazole as a ligand, were characterized by NMR, IR and X-ray diffraction techniques. The partially saturated ring in the tetra-hydro-indazole core adopts a sofa conformation. An intra-molecular N-H⋯N hydrogen bond formed by the protonated amino group and the N atom of the pyridyl substituent is found in the first structure. In the hydro-chloride, the organic moieties are linked by two N-H⋯Cl hydrogen bonds, forming a (4) graph-set. In the hydrate crystal, a Cl anion and a water mol-ecule assemble the moieties into infinite bands showing hydrogen-bond patterns with graph sets (6), (12) and (8). Organic moieties form π-π stacked supra-molecular structures running along the axis in both structures.
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http://dx.doi.org/10.1107/S205698901701667XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730255PMC
December 2017

Synthesis and Immunological Evaluation of Virus-Like Particle-Milbemycin A₃/A₄ Conjugates.

Antibiotics (Basel) 2017 Sep 11;6(3). Epub 2017 Sep 11.

PharmIdea Ltd., Rupnicu 4, Olaine, Riga District, LV-2114 Olaine, Latvia.

Milbemycins are macrolide antibiotics with a broad spectrum of nematocidal, insecticidal, and acaricidal activity. To obtain milbemycin A₃/A₄ derivatives suitable for chemical conjugation to protein carriers (milbemycin haptens), succinate linker and a novel 17-atom-long linker containing a terminal carboxylic acid group were attached to the milbemycin core in a protecting group-free synthesis. The obtained milbemycin A₃/A₄ derivatives were coupled to Potato virus Y-like nanoparticles by the activated ester method. The reaction products were characterized and used in mice immunization experiments. It was found that the mice developed weak specific immune responses toward all tested milbemycin haptens.
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http://dx.doi.org/10.3390/antibiotics6030018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617982PMC
September 2017

Synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage.

Steroids 2017 01 5;117:77-89. Epub 2016 Aug 5.

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, Riga LV-1048, Latvia. Electronic address:

An efficient protocol for the synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage has been developed from naturally accessible precursor betulin. For the first time a series of betulonic acid-indazolone hybrids have been synthesized via an acylation of corresponding 6,7-dihydro-1H-indazol-4(5H)-one oximes with betulonic acid chloride. Diastereoselective reduction of the obtained betulonic acid conjugates with NaBH resulted in a formation of betulinic acid-indazolone hybrids in excellent yields. The configuration of the key compounds has been fully established by X-ray and 2D NMR analysis.
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http://dx.doi.org/10.1016/j.steroids.2016.08.002DOI Listing
January 2017

Crystal structure of 3-O-benzyl-4(R)-C-(1-benzyl-1H-1,2,3-triazol-4-yl)-1,2-O-iso-propyl-idene-α-d-erythro-furan-ose.

Acta Crystallogr E Crystallogr Commun 2015 Dec 28;71(Pt 12):1542-4. Epub 2015 Nov 28.

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena 3/7, Riga, LV-1048, Latvia.

The title compound, C23H25N3O4, {systematic name: 1-benzyl-4-[(3aR,5R,6R,6aR)-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl]-1H-1,2,3-triazole}, consists of a substituted 2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxole. The furan-ose ring adopts an envelope conformation close to C 3-exo, where the C atom substituted by the benz-yloxy group is the flap. The fused dioxolane ring also adopts an envelope conformation, with the methyl-ene C atom as the flap. In the crystal, mol-ecules are linked by weak C-H⋯O hydrogen bonds, forming zigzag chains along [010].
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http://dx.doi.org/10.1107/S2056989015022434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719834PMC
December 2015

Synthesis and Applications of Silyl 2-Methylprop-2-ene-1-sulfinates in Preparative Silylation and GC-Derivatization Reactions of Polyols and Carbohydrates.

Chemistry 2016 Mar 11;22(12):4196-205. Epub 2016 Feb 11.

Laboratoire de glycochimie et de synthèse asymétrique, Swiss Federal Institute of Technology of Lausanne (EPFL), Lausanne, 1015, Switzerland), Fax: (+41) 21-693-93-55.

Trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl 2-methylprop-2-ene-1-sulfinates were prepared through (CuOTf)2⋅C6H6-catalyzed sila-ene reactions of the corresponding methallylsilanes with SO2 at 50 °C. Sterically hindered, epimerizable, and base-sensitive alcohols gave the corresponding silyl ethers in high yields and purities at room temperature and under neutral conditions. As the byproducts of the silylation reaction (SO2 +isobutylene) are volatile, the workup was simplified to solvent evaporation. The developed method can be employed for the chemo- and regioselective semiprotection of polyols and glycosides and for the silylation of unstable aldols. The high reactivity of the developed reagents is shown by the synthesis of sterically hindered per-O-tert-butyldimethylsilyl-α-D-glucopyranose, the X-ray crystallographic analysis of which is the first for a per-O-silylated hexopyranose. The per-O-silylation of polyols, hydroxy carboxylic acids, and carbohydrates with trimethylsilyl 2-methylprop-2-ene-1-sulfinate was coupled with the GC analysis of nonvolatile polyhydroxy compounds both qualitatively and quantitatively.
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http://dx.doi.org/10.1002/chem.201504380DOI Listing
March 2016

Structural characterization of cevimeline and its trans-impurity by single crystal XRD.

J Pharm Biomed Anal 2016 Jan 14;118:404-409. Epub 2015 Nov 14.

Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena 3, Riga LV-1048, Latvia. Electronic address:

Cevimeline is muscarinic receptor agonist which increases secretion of exocrine glands. Cevimeline base is a liquid (m.p. 20-25 °C) at ambient conditions, therefore its pharmaceutical formulation as a solid hydrochloride hemihydrate has been developed. The synthesis of cevimeline yields its cis- and trans-isomers and only the cis-isomer is recognized as the API and used in the finished formulation. In this study structural and physicochemical investigations of hydrochloride hemihydrates of cis- and trans-cevimelines have been performed. Single crystal X-ray analyses of both cis- and trans-isomers of cevimeline are reported here for the first time. It was found that the cis-isomer, the API, has less dense crystal packing, lower melting point and higher solubility in comparison to the trans-isomer.
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http://dx.doi.org/10.1016/j.jpba.2015.11.006DOI Listing
January 2016

Crystal structure of 3-C-(N-benzyl-oxy-carbon-yl)amino-methyl-3-de-oxy-1,2:5,6-di-O-iso-propyl-idene-α-d-allo-furan-ose.

Acta Crystallogr E Crystallogr Commun 2015 Oct 26;71(Pt 10):1212-5. Epub 2015 Sep 26.

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena 3/7, Riga, LV-1048, Latvia.

The title compound, C21H29NO7 (1) [systematic name: benzyl ({(3aR,5S,6R,6aR)-5-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-di-methyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-yl}meth-yl)carbamate], consists of a substituted 2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxolane skeleton. The furan-ose ring adopts an envelope conformation close to C 3-exo, where the C atom substituted by the benzyl carbamate group is the flap. The fused dioxolane ring also adopts an envelope conformation, as does the terminal dioxolane ring, with in each case an O atom as the flap. In the crystal, mol-ecules are linked by N-H⋯O and C-H⋯O hydrogen bonds, forming chains propagating along the b-axis direction.
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http://dx.doi.org/10.1107/S2056989015017582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647424PMC
October 2015

Crystal structures of two (±)-exo-N-isobornyl-acetamides.

Acta Crystallogr E Crystallogr Commun 2015 Oct 12;71(Pt 10):1117-20. Epub 2015 Sep 12.

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena 3/7, Riga, LV-1048, Latvia.

The title compounds consist of a bornane skeleton with attached acetamide, C12H21NO (±)-(1) {systematic name: (±)-N-[(1RS,2RS,4RS)-1,7,7-tri-methylbi-cyclo-[2.2.1]heptan-2-yl]acetamide}, and chloro-acetamide, C12H20ClNO (±)-(2) {systematic name: (±)-2-chloro-N-[(1RS,2RS,4RS)-1,7,7-tri-methylbi-cyclo-[2.2.1]heptan-2-yl]-acetamide}, functionalities to the 2-exo-position. The crystal structure of the first monoclinic polymorph of (±)-(1) has been reported previously [Ung et al. (2014 ▸). Monatsh. Chem. 145, 983-992]. Compound (±)-(1) crystallizes in the space group P21/n with two independent mol-ecules in the asymmetric unit, in contrast to the above-mentioned polymorph which crystallized in the space group C2/c with one mol-ecule in the asymmetric unit. In the title compounds, the bicyclic bornane moieties have normal geometries. In the crystals of both compounds, mol-ecules are linked by N-H⋯O hydrogen bonds, reinforced by C-H⋯O contacts, forming trans-amide chains propagating along the a-axis direction. In the case of compound (±)-(1), neighbouring chains are linked by further C-H⋯O contacts, forming double-chain ribbons along [100].
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http://dx.doi.org/10.1107/S2056989015015984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647407PMC
October 2015

The isolation and synthesis of neodolastane diterpenoids.

Nat Prod Rep 2015 Feb;32(2):230-55

Laboratoire de Pharmacognosie de Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, U.M.R./C.N.R.S. 8638, 4, Avenue de l'Observatoire, 75006 Paris, France.

The neodolastane diterpenoids comprise a group of 44 compounds including guanacastepenes, heptemerones, plicatilisins, radianspenes, 2,15-epoxy-5,13-dihydroxyneodolast-3-en-14-one and sphaerostanol. These fungal and marine natural products are characterized by a tricyclic neodolastane skeleton that consists of fused five-, seven- and six-membered rings. Their reported antibiotic activities against antibiotic-resistant bacteria together with strong antifungal and anticancer activities and their novel structures render these compounds interesting synthetic targets. The aim of this account is to summarise the progress in the isolation, characterisation and synthesis of these diterpenoids as well as to review their biogenetic origins and diverse biological activities since their discovery in 2000.
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http://dx.doi.org/10.1039/c4np00077cDOI Listing
February 2015

Discovery and structure-activity relationship studies of irreversible benzisothiazolinone-based inhibitors against Staphylococcus aureus sortase A transpeptidase.

Bioorg Med Chem 2014 Nov 16;22(21):5988-6003. Epub 2014 Sep 16.

Latvian Biomedical Research and Study Centre, Ratsupites 1, Riga LV-1067, Latvia.

Gram-positive bacteria, in general, and staphylococci, in particular, are the widespread cause of nosocomial and community-acquired infections. The rapid evolvement of strains resistant to antibiotics currently in use is a serious challenge. Novel antimicrobial compounds have to be developed to fight these resistant bacteria, and sortase A, a bacterial cell wall enzyme, is a promising target for novel therapies. As a transpeptidase that covalently attaches various virulence factors to the cell surface, this enzyme plays a crucial role in the ability of bacteria to invade the host's tissues and to escape the immune response. In this study we have screened a small molecule library against recombinant Staphylococcus aureus sortase A using an in vitro FRET-based assay. The selected hits were validated by NMR methods in order to exclude false positives and to analyze the reversibility of inhibition. Further structural and functional analysis of the best hit allowed the identification of a novel class of benzisothiazolinone-based compounds as potent and promising sortase inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2014.09.011DOI Listing
November 2014

Betulin 3,28-di-O-tosyl-ate.

Acta Crystallogr Sect E Struct Rep Online 2014 Aug 23;70(Pt 8):o879-80. Epub 2014 Jul 23.

Department of Material Science and Applied Chemistry, Riga Technical University, 3 P. Valdena Str., Riga LV-1007, Latvia.

The title compound, C44H62O6S2 {systematic name: (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-penta-methyl-1-(prop-1-en-2-yl)-3a-[(tos-yloxy)meth-yl]icosa-hydro-1H-cyclo-penta-[a]chrysen-9-yl 4-methyl-benzene-sulfonate}, was obtained by tosyl-ation of naturally occurring betulin. All the cyclo-hexane rings adopt chair conformations and the cyclo-pentane ring adopts a twisted envelope conformation, with the C atom bearing the tosyl-methyl substituent forming the flap. In the crystal, mol-ecules form a three-dimensional network through multiple weak C-H⋯O hydrogen bonds.
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http://dx.doi.org/10.1107/S1600536814016602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158509PMC
August 2014

{(3aR,5S,6R,6aR)-5-[(R)-1,2-Di-hydroxy-eth-yl]-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-6-yl}methyl methane-sulfonate.

Acta Crystallogr Sect E Struct Rep Online 2014 May 5;70(Pt 5):o524-5. Epub 2014 Apr 5.

Faculty of Material Science and Applied Chemistry, Riga Technical University, 3 P. Valdena Street, Riga, LV-1007, Latvia.

In the title compound, C11H20O8S, the furan-ose ring has a pseudorotation phase angle equal to 31.3° and assumes a (3) T 4 conformation, with deviations of 0.297 (4) and -0.152 (4) Å for the corresponding C atoms. The dioxolane ring adopts an envelope conformation. One of the O atoms is at the flap and deviates from the least-squares plane formed by the other four ring atoms by 0.405 (2) Å. The dihedral angle between the planar fragments of the rings is 63.53 (8)°. In the crystal, mol-ecules are associated into sheets perpendiculer to the b axis by means of O-H⋯O hydrogen bonds. A few weak C-H⋯O inter-actions are also observed.
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http://dx.doi.org/10.1107/S1600536814007387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011227PMC
May 2014

Synthesis and X-ray studies of novel 3-C-nitromethyl-hexofuranoses.

Carbohydr Res 2014 Jun 12;391:82-8. Epub 2014 Mar 12.

Department of Biotechnology, University of Rijeka, Trg braće Mažuranića 10, 51000 Rijeka, Croatia.

A practical method for the synthesis of three novel 3-C-nitromethyl-hexofuranoses is reported. The Henry reaction on a 1,2:5,6-di-O-isopropylidene-α-d-gulofuranose-derived ketone provided a 3-C-branched gulo-isomer as the sole reaction product. The dehydration-rehydration of the latter yielded an isopropylidene-protected 3-C-nitromethyl-galactofuranose. The reaction sequence can be also used for the synthesis of a 3-deoxy-3-C-nitromethyl-hexofuranose derivative with a gulo-configuration. Two of the newly obtained carbohydrate derivatives were characterized by X-ray crystallography.
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http://dx.doi.org/10.1016/j.carres.2014.03.003DOI Listing
June 2014

2,6-Di-chloro-9-(2',3',5'-tri-O-acetyl-β-d-ribo-furanos-yl)-9H-purine.

Acta Crystallogr Sect E Struct Rep Online 2014 Feb 4;70(Pt 2):o108-9. Epub 2014 Jan 4.

Department of Material Science and Applied Chemistry, Riga Technical University, 14/24 Azenes street, Riga, LV-1007, Latvia.

The title synthetic analog of purine nucleosides, C16H16Cl2N4O7, has its acetyl-ated β-furan-ose ring in a 3'β-envelope conformation, with the corresponding C atom deviating by 0.602 (5) Å from the rest of the ring. The planar part of the furan-ose ring forms a dihedral angle of 65.0 (1)° with the mean plane of the purine bicycle. In the crystal, mol-ecules form a three-dimensional network through multiple C-H⋯O and C-H⋯N hydrogen bonds and C-H⋯π interactions.
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http://dx.doi.org/10.1107/S1600536813034521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998279PMC
February 2014

A novel matrix metalloproteinase-2 inhibitor triazolylmethyl aziridine reduces melanoma cell invasion, angiogenesis and targets ERK1/2 phosphorylation.

J Enzyme Inhib Med Chem 2014 Dec 19;29(6):765-72. Epub 2013 Nov 19.

Latvian Institute of Organic Synthesis , Riga , Latvia and.

A novel matrix metalloproteinase-2 (MMP-2) inhibitor JaZ-30, which belongs to the class of C(2)-monosubstituted aziridine - aryl-1,2,3-triazole conjugates, was developed. MTT and crystal violet assays were used to determine cytotoxicity- IC(50) values of compound JaZ-30 on melanoma cell line B16 4A5. Our study proves the anti-cancer properties of JaZ-30 with a wide spectrum of activities. JaZ-30 was revealed as selective inhibitor of matrix metalloproteinase-2. JaZ-30-mediated decrease of Vascular Endothelial Growth Factor (VEGF) secretion results in inhibition of angiogenesis, performed with the human umbilical vein endothelial cell line (HUVEC-2) on Matrigel. A novel inhibitor decreases invasive properties of melanoma cells measured in Matrigel chambers assay. JaZ-30 downregulates phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in melanoma cells stimulated by phorbol-12-myristate-13-acetate (PMA). Our findings propose a novel MMP-2 inhibitor JaZ-30 as an attractive potential agent for melanoma treatment.
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http://dx.doi.org/10.3109/14756366.2013.855207DOI Listing
December 2014

A practical access to glucose- and allose-based (5+5) 3-spiropseudonucleosides from a common intermediate.

Carbohydr Res 2013 Jun 17;375:5-15. Epub 2013 Apr 17.

Faculty of Material Science and Applied Chemistry, Riga Technical University, Riga, Latvia.

A practical access to glucose-based and allose-based spirooxazolidinones is reported. The synthetic sequence consisting of TEMPO-catalyzed oxidation of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose, Henry reaction, and reduction provides amino alcohol with allo-configuration on a multigram scale. Alternatively, water elimination from Henry products followed by a rehydration gives an access to diastereomerically pure glucose-based nitro alcohol which upon reduction provides complementary amino alcohol with gluco-configuration. The latter amino alcohols are transformed into spirooxazolidinones (3-spiropseudonucleosides) via their N-Cbz or N-phenylcarbamate derivatives. The title compounds easily undergo N-derivatization and give highly crystalline materials. Two of the newly obtained (5+5) 3-spiropseudonucleosides are characterized by X-ray crystallography.
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http://dx.doi.org/10.1016/j.carres.2013.04.008DOI Listing
June 2013

On Moffatt dehydration of glucose-derived nitro alcohols.

Carbohydr Res 2012 Mar 29;350:86-9. Epub 2011 Dec 29.

Faculty of Material Science and Applied Chemistry, Riga Technical University, 14/24 Azenes Str., Riga, Latvia.

Moffatt dehydration of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose derived nitro alcohols with a mixture of Ac(2)O and DMSO was reinvestigated. It was discovered that, regardless of the absolute configuration at C(3) of the sugar moiety, the dehydration provided exclusively the (3Z)-nitromethylene derivative. Slight modification of the workup conditions (pH⩾8, temperature: 25-30°C) gave exclusively a novel product, (3S)-3-deoxy-3-methylthio-3-C-nitromethyl-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose. The latter was obtained by a Michael addition of thiomethylate anion to the previously reported nitromethylene derivative during the aqueous basic workup at ambient or slightly elevated temperature. The putative mechanism leading to the thiomethylate anion includes Pummerer rearrangement of DMSO and basic hydrolysis of thus formed methylsulfanylmethyl acetate.
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http://dx.doi.org/10.1016/j.carres.2011.12.020DOI Listing
March 2012