Māris Turks

Synthesis of novel 3-deoxy-3-C-triazolylmethyl-allose derivatives and evaluation of their biological activity

AbstractRecently, monosaccharide-triazole conjugates have proved to possess a large variety of useful biological activities. This paper describes synthesis of a new series of 3-deoxy-3-C-triazolylmethyl-allose derivatives. These new compounds are obtained from acetonide-protected 3-deoxy-3-azidomethyl allose and commercial alkynes via Cu(I) catalyzed 1,3-dipolar cycloaddition. The obtained molecular scaffolds differ from those described earlier by the presence of a methylene linker (-CH2-) between the C(3) of allose and the triazole moiety. It was demonstrated that acetonide-protected monosaccharide, 3-deoxy-3-C-(4-phenyl-1H-1,2,3-triazol-1-yl)methyl-1,2:5,6-di-O-isopropylidene-α-d-allofuranose, inhibited α-L-fucosidase for 26% at 0.1 mM concentration, but a deprotected analog, 3-deoxy-3-C-(4-(4-tert-butylphenyl)-1H-1,2,3-triazol-1-yl)methyl-β-d-allofuranose, showed 15% inhibition of β-glucosidase at 1 mM concentration.

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

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.

On Moffatt dehydration of glucose-derived nitro alcohols

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.

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

Abstract 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.

Non-activated aziridines as building blocks for the synthesis of aza-heterocycles (microreview)

This microreview deals with ring opening reactions of non-activated aziridines and their applications in heterocycle synthesis. Only recent methods published in the last five years are discussed.

Synthesis of 1,2,3-triazole-linked glycohybrids in the gluco-, gulo-, and allopyranose series

Ketone derived from diacetone-α-D-glucose is a suitable starting material for the synthesis of 3-C-linked glycohybrids containing 1,2,3-triazole moiety as an intersugar linkage. The pyranose tautomers of 3-deoxy-3-(1,2,3-1H-triazol-1-yl)glucose, 3-C-[(1,2,3-1Htriazol-1-yl)methyl]allose and 3-C-[(1,2,3-1H-triazol-1-yl)methyl]gulose moieties are released upon the acidic hydrolysis of the corresponding O-isopropylidene-protected furanosyl-type synthetic intermediates. Some of the title compounds show a rare property of activating β-galactosidase from Escherichia coli.

ON DIFFERENCES BETWEEN RACEMIC AND ENANTIOMERICALLY PURE FORMS OF AZIRIDINE-2-CARBOXAMIDE*

Synthesis, X-ray, and cytotoxicity studies of (S)- and (R)-aziridine-2-carboxamide (Leakadine) are described. X-ray data for the enantiomerically pure form are compared with those for racemic aziridine-2-carboxamide in order to explain the 21°C large melting point difference between both series. It was found that despite their overall low cytotoxicity (S)-aziridine-2-carboxamide is slightly more cytotoxic than (R)-aziridine-2-carboxamide.

User Friendly Synthesis of Vogel’S Silyl Sulfinate and its Application in Quantitative Gc–Ms Analysis

GRAPHICAL ABSTRACT Abstract The synthesis of trimethylsilyl 2-methylprop-2-ene-1-sulfinate (Vogels silyl sulfinate) from methallyltrimethylsilane and SO2 in the presence of Tf2NTMS was developed. The title compound silylates carbohydrates and other polyhydroxylated compounds by producing SO2 and isobutene as gaseous side products. This silylation procedure is perfectly suitable for derivatization and subsequent GC–MS quantitative analysis of ribose and malic acid as representatives of organic polyhydroxylated compounds.

Synthesis of monomeric methylene-linked 1,2,3-triazole glycoconjugates from allo- and glucofuranoses

Carbohydrate–triazole conjugates proved themselves as valuable enzyme activity-modifying agents. Recent exploration of nontrivial conjugates in which the bonding is formed not at the glycosidic or terminal carbons of the carbohydrates, but at C-3 position showed a potential of this type of structures as the ligands for various glycosidases and galectins. Here, we report synthesis of protected monomeric 3-C-(triazolylmethyl)-substituted gluco- and alloconjugates. Diastereomeric azides are synthesized from common intermediate, 3-deoxy-1,2:5,6-di-O-isopropylidene-3-oxo-α-D-allofuranose, and used in Cu-catalyzed azide–alkyne cycloaddition (CuAAC) reactions with commercial alkynes. The yields of the cycloaddition reactions are good to excellent under different catalytic conditions.

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

Graphical abstract Figure. No Caption available. HighlightsNovel lupane triterpenoid‐indazolone hybrids with oxime linkage are obtained.This is the first report on oxime esters derived from betulonic and betulinic acid at their C(28).X‐ray structure of the hybrid molecule is reported.Purification procedure for betulonic acid via its cyclohexylammonium salt is developed. Abstract 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 NaBH4 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.