Synthesis of the deuterated thymidine-d9 and deuterated oligonucleotides

The efficient synthesis of the highly-deuterated thymidine-d₉ by the glycosylation reaction between a deuterated nucleobase and deuterated sugar is described. It is also incorporated into the oligonucleotides using a DNA synthesizer. Using this approach, it is possible to make highly-deuterated oligonucleotides for biological studies and structural analyses.     

Synthesis and crystal structure of mixed-cation salt of trans-hydroxotetranitronitrosoruthenium(II) complex, KNa[Ru(NO)(NO2)4(OH)]·H2O

The mixed-cation complex salt KNa[Ru(NO)(NO₂)₄(OH)]·H₂O has been synthesized and studied with methods of IR-spectroscopy, X-ray phase and X-ray structural analysis. The crystallographic data for H₃KN₅NaO₁₁Ru are: a = 7.389(1) Å, b = 14.196(2) Å, c = 21.507(5) Å; V = 2256.0(7) ų, Z = 8, d _calc = 2.427 g/cm³, space group is P2₁2₁2₁. The structure is chiral and its absolute structural parameter equals 0.04. General motif of the arrangement of complex anions was determined by the translation sublattice method. Geometric characteristics for coordinate NO₂-groups in structurally characterized nitro complexes of ruthenium(II) have been analyzed.     

Preparation of highly deuterated zeaxanthin, lycopene, and β-carotene from fully deuterated mevalonate using engineered Escherichia coli

Carotenoids are important natural pigments produced by various microorganisms and plants. Specific deuterium-labeling of these compounds is invaluable in biochemical and physiochemical research. In this paper, preparation of highly deuterated zeaxanthin, lycopene, and β-carotene using engineered Escherichia coli with fully deuterated mevalonate is described. Also described are physico-chemical properties of the obtained deuterated carotenoids.     

The use of deuterated solvents in high-performance liquid chromatography-Fourier transform infrared spectrometry

Summary Deuterated compounds have been used as mobile phases for microcolumn high-performance liquid chromatography (HPLC) employing flow-cell Fourier transform infrared spectroscopy for detection. Separations were carried out on adsorption, reversed-phase, non-aqueous size-exclusion and aqueous size-exclusion chromatographic columns. Due to the IR transparency of deuterated compounds in a C–H stretching region they represent nearly ideal eluents in terms of universal detection. In addition, due to the shift in the absorption wavenumber following deuteration, deuterated solvents allow FTIR detection of solutes in other regions, where otherwise it would be prohibited, or sensitivity sacrified by interfering solvent absorption.     

Flow chemistry approach for partial deuteration of alkynes: synthesis of deuterated taxol side chain

The partial deuteration of alkynes proceeds via a flow chemistry approach under Lindlar’s heterogeneous catalysis to provide cis-dideuterated olefins in good yields. Further, dideuterated olefin has been successfully utilized for Sharpless asymmetric dihydroxylation followed by Mitsunobu reaction for the synthesis of deuterated taxol side chain.     

Development of a universal Raman detector for microchromatography

Summary A detector for microchromatography in which Raman spectroscopy is used to identify the eluted species has been developed. The detector is designed to be applicable to a wide range of compounds without requiring the presence of a chromophore. Its use is illustrated in the analysis of nitro compounds on a 250 μm i.d. column. Raman spectra of each of the compounds could be identified as they passed the detector. The advatages of the use of fully deuterated solvents are demonstrated by the analysis of nitrobenzenes in methanol/water mobile phases. The detection limit for nitrobenzene using the Raman line at 1342 cm⁻¹ was 75ng.     

Tandem mass spectrometry study of C-phenyl-N-tert-butyl nitrone spin adducts from in vitro rat liver microsomal metabolism of bromotrichloromethane and carbon tetrachloride

Electron ionization and thermospray were used in conjunction with tandem mass spectrometry methods to identify trichloromethyl/C-phenyl-N-tert-butyl nitrone (PBN) spin adducts produced in rat liver microsomal dispersions that had been treated with reduced nicotinamide adenine dinucleotide phosphate (NADPH)-generating system and BrCCl₃ (or CCl₄). In the identification of PBN spin adducts, a scan of precursors of m / z 57 was utilized to confirm the presence of PBN spin adducts, because PBN spin adducts produce m / z 57 from tert-butyl as a characteristic fragment. Use of deuterated PBN (PBN-d₉ deuterated at tert-butyl; PBN-d ₁₄ deuterated at both phenyl and tert-butyl) improved the recognition of PBN adducts in mixtures by precursor ion scans, because m / z 66 (which corresponds to the deuterated tert-butyl group) is characteristic and, unlike m / z 57, it is not a common fragment for any other compounds. Two new PBN spin adducts that were not detected before by electron paramagnetic resonance or mass spectrometry were identified by these methods for the first time.     

Quantitative analysis of deuterium using the isotopic effect on quaternary C NMR chemical shifts

Quantitative analysis of specifically deuterated compounds can be achieved by a number of conventional methods, such as mass spectroscopy, or by quantifying the residual ¹H NMR signals compared to signals from internal standards. However, site specific quantification using these methods becomes challenging when dealing with non-specifically or randomly deuterated compounds that are produced by metal catalyzed hydrothermal reactions in D₂O, one of the most convenient deuteration methods. In this study, deuterium-induced NMR isotope shifts of quaternary ¹³C resonances neighboring deuterated sites have been utilized to quantify the degree of isotope labeling of molecular sites in non-specifically deuterated molecules. By probing ¹³C NMR signals while decoupling both proton and deuterium nuclei, it is possible to resolve ¹³C resonances of the different isotopologues based on the isotopic shifts and the degree of deuteration of the carbon atoms. We demonstrate that in different isotopologues, the same quaternary carbon, neighboring partially deuterated carbon atoms, are affected to an equal extent by relaxation. Decoupling both nuclei (¹H, ²H) resolves closely separated quaternary ¹³C signals of the different isotopologues, and allows their accurate integration and quantification under short relaxation delays (D1 = 1 s) and hence fast accumulative spectral acquisition. We have performed a number of approaches to quantify the deuterium content at different specific sites to demonstrate a convenient and generic analysis method for use in randomly deuterated molecules, or in cases of specifically deuterated molecules where back-exchange processes may take place during work up.     

Quinoline-pyrimidine hybrid compounds from 3-acetyl-4-hydroxy-1-methylquinolin-2(1H)-one: Study on synthesis,cytotoxicity, ADMET and molecular docking

Some novel 2-amino-6-aryl-4-(4′-hydroxy-N-methylquinolin-2′-on-3′-yl)pyrimidines have been synthesized from α,β-unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one by reaction of corresponding α,β-unsaturated ketones with guanidine hydrochloride. The purity and structure of the obtained products have been confirmed by thin layer chromatography, IR, ¹H NMR, ¹³C NMR, HSQC, HMBC and MS spectra. All the synthesized of 3-(2-amino-6-arylpyrimidin-4-yl)-4-hydroxy-1-methylquinolin-2(1H)-ones 6a-i were screened for their in vitro cytotoxic activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines. Compounds 6b and 6e had the best activity in the series, with IC₅₀ values equal to 1.33 μM. Compounds 6a-g exhibited weak or insignificant activity with liver cancer cell lines HepG2, while compounds 6a and 6g had more powerful activity in this sequence, with IC₅₀ values equal to 47.99 and 89.38 μM, respectively. ADMET properties showed that compounds 6b, 6e, and 6f possessed the drug-likeness behavior. Cross-docking results indicated that two hydrogen bonding interactions in the binding pocket, as potential ligand binding hot-spot residues for compounds 6b and 6e, may be one of the mechanisms of action responsible for the higher cytotoxic effect on HepG2 and KB cells.     

A novel general method for the synthesis of nitrones by reaction of nitroso compounds with anions of aliphatic nitro compounds

Anions of aliphatic nitro compounds R¹R²C=NO₂ ^– react with nitroso compounds RNO to give nitrones R¹R₂C=N(O)R. Salts of nitro compounds with metals and Et₃N, as well as trimethylsilyl nitronates in the presence of F^–, can serve as the sources of the anions. The structure of the nitrones was established by NMR spectroscopy. 1,3-Dipolar cycloaddition of a series of the nitrones obtained to olefins was investigated.For a brief communication see Ref. 1Translated from IzvestiyaAkademii Nauk. Seriya Khimicheskaya, No. 4, pp. 901–907, April, 1996.     

Iridium-catalysed labelling of anilines, benzylamines and nitrogen heterocycles using deuterium gas and cycloocta-1,5-dienyliridium(I) 1,1,1,5,5,5-hexafluoropentane-2,4-dionate

A wide range of variously substituted anilines, benzylamines, and nitrogen heterocycles may be conveniently deuterated by exchange with deuterium gas and cycloocta-1,5-dienyliridium(I) 1,1,1,5,5,5-hexafluoropentane-2,4-dionate. The isotopic exchange can be carried out efficiently in dimethylformamide or dimethylacetamide, hence it is directly applicable to the deuteration of polar compounds such as pharmaceuticals. Isotope incorporation is rapid and yields ortho-regiospecificity.     

Deuterated dimethyl sulfoxide as a good NMR solvent for the characterization of alkali metal cyclopentadienides, amides, alkoxides and phenoxides

A series of alkali metal cyclopentadienides, amides, alkoxides and phenoxides was characterized using NMR spectroscopy in deuterated dimethyl sulfoxide. Deuterated dimethyl sulfoxide showed very good stability and solubility for these compounds. Very nice and well resolved spectra were obtained for most compounds tested. The low cost of the solvent makes it possible to use it for the routine characterization of these alkali salts as the ligands in organometallic synthesis.     

Preparation of 3-substituted and 2,3-disubstituted-4,4,4-trifluoro-2-butenoic acids—Perkin condensation of activated aromatic ketones

The Perkin reaction of the activated aromatic ketones (2,2,2-trifluoroacetophenone and its 4′-phenyl-derivative) with various condensing agents (acetic anhydride, propionic anhydride, phenylacetic acid/acetic anhydride) gives the title compounds in good or moderate yields, and high E-stereoselectivity. For some derivatives an appreciable amount of the Z isomer was also formed. Several of the resulting butenoic acids and their methyl esters are synthesised and characterised for the first time.     

Vibrational assignment of acetylacetone

The infrared and Raman spectra of acetylacetone and its deuterated analogues have been analyzed by the aid of ab initio calculations at post Hartree-Fock level and considering the spectral behavior upon deuteration. By deconvolution of the infrared spectra of acetylacetone and d6-acetylacetone at 1600 cm(-1) region a broad and strong band is found and correlated with the strong Raman lines observed for these compounds in this region. The broadness of this infrared band at room temperature and it's splitting at low temperature is attributed to free rotation of methyl group attached to carbonyl group at room temperature. Furthermore it is found that all ring modes in 1200-1600 cm(-1) region more or less are mixed with the OH in plane bending motion.     

Reactions of enaminones and related compounds with N,N-dimethylacetamide dimethyl acetal. A simple one-pot metal-free synthesis of polysubstituted benzene derivatives

Herein a simple one-pot metal-free synthesis of alkyl-, aryl-, heteroaryl- and alkoxycarbonyl substituted 1,3-bis(dimethylamino)benzene derivatives is described. The products were prepared from the corresponding methyl ketones or compounds with an α-methylene group in regard to the carbonyl group, using N,N-dimethylacetamide dimethyl acetal (DMADMA) as the reagent.     

Facile synthesis of α,β-acetylenic ketones and 2,5-disubstituted furans: consecutive activation of triple and double bond with ZnBr2 toward the synthesis of furan ring

α,β-Acetylenic ketones were synthesized from the reaction of acid chlorides and acetylenic compounds in the presence of ZnBr₂ and DIEA in acetonitrile. From the acetylenic ketones having nearby methylene unit, 2,5-disubstituted furan derivatives could be synthesized under the same reaction conditions.     

Vibrational spectra and normal coordinate calculations for dimethyltelluride-d0, -d6 and dimethyltellurium difluoride-d0, -d6

The i.r. (4000-30 cm⁻¹) and Raman (4000-O cm⁻¹) spectra of dimethyltelluride, dimethyltellurium difluoride and their deuterated analogs have been obtained. All the active fundamentals of these compounds except methyl torsions were assigned, assuming a C_2υ molecular symmetry for both the tellurides. Normal coordinate calculations have been made in order to confirm the proposed assignments. The skeletal bond strength of the tellurides together with that of TeF₄ are discussed, using the valence stretching force constants.     

Electroreduction of Nitriles: The Reduction of Furfurylidene- and Benzylidenemalonodinitriles and Esters of Substituted 1-Cyanoacrylic Acids

The electrochemical reduction of compounds with a common formula R¹(H)C=C(CN)R², where R¹ is C₆H₅, n-CH₃OC₆H₄, n-FC₆H₄, or -furyl; and R² is CN or COOC₂H₅ is studied. The reduction of these compounds at a zinc cathode in the water–acetonitrile KH₂PO₄ solution yields both cyclic and linear hydrodimers. The relative yield of the linear hydrodimer increases with lowering the temperature and acetonitrile content in the catholyte. The obtained data well correlate with the suggestion that the cyclic products form in the catholyte bulk from linear hydrodimers.     

Gas-phase thermolysis of benzotriazole derivatives. Part 2: Synthesis of benzimidazo[1,2-b]cinnolines, a novel heterocyclic ring system, by pyrolysis of benzotriazole derivatives. Kinetic and mechanistic study

Gas-phase pyrolysis of benzotriazolyl ketones and their arylhydrazones gave indole, benzimidazole and benzimidazo[1,2-b]cinnoline derivatives via interesting novel routes. The homogeneous first-order gas-phase pyrolysis of 10 arylhydrazono derivatives of α-benzotriazol-1-yl ketones was investigated over the temperature range 420-530 K. Five of these substrates were 2-(arylhydrazono)-2-(benzotriazol-1-yl)-1-phenylethanone derivatives (Series 1), and the remaining five were the corresponding acetone analogues (Series 2). The values of the Arrhenius frequency factor (log A/s⁻¹) for the pyrolysis of the compounds of Series 1 and 2 were, respectively, 12.27±1.44 and 9.07±1.20, while the values of the Arrhenius activation energy (E_a/kJ mol⁻¹) were 132.8±8.4 and 123.2±23.0, respectively. Besides, reaction pathways are offered to rationalize the kinetic results and to account for the products of pyrolysis of the substrates under study, namely: (i) extrusion of N₂ and formation of a 1,3-biradical reactive intermediate leading to substituted imidazoles (Series 1); (ii) intramolecular nucleophilic addition, cyclization and subsequent fragmentation with or without loss of H₂O/N₂ fragments (Series 1 and 2).     

Synthesis of novel deuterium labelled derivatives of N-alkylated polyamines

Novel di-, tetra- and octadeuterated derivatives of mono-N-alkylated diaminopropanes, spermidines, spermines, symmetrically bis-N-alkylated spermines and unsymmetrically bis-N-alkylated spermines were synthesized. Deuterium labels were introduced into the RHNCH₂CH₂CN intermediate either by exchanging the protons next to the nitrile group under basic conditions with D₂O-EtOD mixture or/and by reducing the nitrile group to a CD₂-NH₂ fragment with LiAlD₄.