Leucocyanidin: Synthesis and properties of (2R,3S,4R)-(+)-3,4,5,7,3′,4′-hexahydroxyflavan

An isomer of leucocyanidin, (2R,3S,4R)-(+)-3,4,5,7,3′,4′-hexahydroxyflavan has been synthesized from (+)-taxifolin, isolated in its phe     

Synthesis of glycos-3-yl-α,γ-diamino acids. Synthesis of four diastereomeric spiro-3,4′-(R and S)-3-deoxy-1,2:5,6-di-O-isopropylidene-α-d-ribo-hexofuranose)-3′-(R and S)-acetamido-2′-pyrrolidinones

Treatment of (Z)-3-deoxy-1,2:5,6-di-O-isopropylidine-3-C-(methoxycarbonyl)-methylene-α-d-ribo-hexofuranose (1) with diazomethane in ether afforded the unstable Δ¹- and Δ²-pyrazolines 2 and 2a. High-pressure hydrogenation of the latter compounds over Raney nickel afforded a mixture of amines 3, 5, 7, and 9 (in 80% yield), which were separated by chromatography. Acetylation of these compounds yielded the N-acetyl derivatives 4, 6, 8, and 10. X-Ray analysis of compounds 8 and 10 showed them to be spiro-3,4′-(R)-(3-deoxy-1,2:5,6-di-O-isopropylidine-α-d-ribo-hexofuranose)-3′-(R)-[and 3′-(S)]-acetamido-2′-pyrrolidinone, respectively. The structures of compounds 4 and 6 (determined by chemical means) were the corresponding spiro-3,4′-(S)-3′-(R)-acetamido-2′-pyrrolidinone and 3′-(S)-acetamido-2′-pyrrolidinone, respectively.     

Synthesis of (±)-7,3′- and 7,4′-di-O-methyleriodictyol and of velutin and pilloin

Synthetic 2′-hydroxy-3,4′,6′-trimethoxy-4-benzyloxychalcone (I) affords (±)-7,3′-di-O-methyleriodictyol (II) and 7,3′-di-O-methylluteolin (or velutin, VII) identical with natural samples. Similarly synthetic 2′-hydroxy-4,4′,6′-trimethoxy-3-benzyloxychalcone (X) gives natural (±)-7,4′-di-O-methyleriodictyol (XI) and 7,4′-di-O-methylluteolin (or pilloin, IX). However, attempts to partially etherify II with one mole of prenyl bromide to obtain the natural prenyl ether failed; only the corresponding diprenyloxychalcone (IV) was obtained.     

R-(-)-β-O-methylsynephrine, a natural product, inhibits VEGF-induced angiogenesis in vitro and in vivo

R-(-)-β-O-methylsynephrine (OMe-Syn) is an active compound isolated from a plant of the Rutaceae family. We conducted cell proliferation assays on various cell lines and found that OMe-Syn more strongly inhibited the growth of human umbilical vein endothelial cells (HUVECs) than that of other normal and cancer cell lines tested. In angiogenesis assays, it inhibited vascular endothelial growth factor (VEGF)-induced invasion and tube formation of HUVECs with no toxicity. The anti-angiogenic activity of OMe-Syn was also validated in vivo using the chorioallantonic membrane (CAM) assay in growing chick embryos. Expression of the growth factors VEGF, hepatocyte growth factor, and basic fibroblast growth factor was suppressed by OMe-Syn in a dose-dependent manner. Taken together, our results indicate that this compound could be a novel basis for a small molecule targeting angiogenesis.     

5′-Monohydroxyphylloquinone from Anacystis and Euglena

The monohydroxy analogue of phylloquinone found in Anacystis nidulans and Euglena gracilis has been characterized as 5′-monohydroxyphylloquinone by MS analysis.     

Definitive Solution Structures for the 6-Formylated Versions of 1-(βD-Ribofuranosyl)-, 1-(2′-Deoxy-β-D-Ribofuranosyl)-, and 1-β-D-Arabinofuranosyluracil,and of Thymidine

Abstract

ROESY and NOESY NMR spectroscopic analyses of the ribofuranosyl (1a), 2′-deoxyribofuranosyl (1b), and arabinofuranosyl (1c) derivatives of 6-formyluracil in (CD₃)₂SO and D₂O solutions have established that each exclusive 7,05′-cyclic hemiacetal diastereomer of 1a,b and the major 7,O2′-cyclic hemiacetal diastereomer of 1c possess the 7R configuration. In addition, (7R)-1c has been shown to be thermodynamically more stable than (7S)-1c, contrary to our previous indication. A new, higher yielding synthetic route to 1a has been developed, 1b has been obtained for the first time in crystalline form, the route to 1c has been modified to better accommodate large scale preparations, and a new, fourth member of this class, 6-formylthymidine (1d), has been synthesized and its solution structures in (CD₃)₂SO, D₂O, and CD₃OD have been determined. Antitumor and antiviral evaluations of 1a-c have revealed no significant levels of activity.     

Unsymmetrical 1,1′-disubstituted Ferrocenes: Synthesis of Co(ii), Cu(ii), Ni(ii) and Zn(ii) Chelates of Ferrocenyl -1-thiadiazolo-1′-tetrazole, -1-thiadiazolo-1′-triazole and -1-tetrazolo-1′-triazole with Antimicrobial Properties

Condensation reactions of 1,1"-diacetylferrocene with different heteroaromatic amines such as, 2-amino-1,3,4-thiadiazole, 5-aminotetrazole and 3-amino-1,2,4-triazole to form unsymmetrically 1,1′-disubstituted ferrocenes have been studied. The obtained compounds have been further investigated for their liganding and biological properties upon chelation with Co(II), Cu(II), Ni(II) and Zn(II) metal ions. The synthesized compounds have been characterized by physical, spectral and analytical data and have been screened against pathogenic bacterial strains e.g., Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus, showing moderate activity as antibacterials in vitro.     

Study of the inclusion of the (R)- and (S)-camphor enantiomers in α-cyclodextrin by X-ray crystallography and molecular dynamics

The inclusion of (R)- and (S)-camphor compounds in α-cyclodextrin has been studied by X-ray crystallography. The crystal structures of the complexes reveal that one guest molecule is accommodated inside the cavity formed by a head-to-head cyclodextrin dimer. In the crystal lattice, the dimers form layers which are successively shifted by half a dimer. In both (R)- and (S)-cases, the camphor molecule exhibits disorder and occupies three major sites with orientations that can be described as either ‘polar’ or ‘equatorial’. Molecular dynamics simulations performed for the observed complexes indicate that although the carbonyl oxygen of both (R)- and (S)-camphor switches between different hydrogen bonding partners, it maintains the observed mode of ‘polar’ or ‘equatorial’ alignment.     

Synthesis of Two 3-(7′-Theophyllyl)glycals, 3-Deoxy-3-(7′-theophyllyl)-d-xylo-hex-1-enopyranose and Methyl 3-Deoxy-3-(7′-theophyllyl)-d-xylo-hex-1-enopyranuronate,and their Derivatives

Two 3-(7′-theophyllyl)glycals, (IV) and (V), were synthesized by fusion of theophylline and the appropriate glycals in the presence of p-toluenesulfonic acid. The structure and stereochemistry of the glycals were determined mainly from NMR analysis of their dihydro and 1,6-anhydro derivatives.     

Stereocontrolled Facile Synthesis and Biological Evaluation of (3′S) and (3′R)-3′-Amino (and Azido)-3′-Deoxy Pyranonucleosides

This article describes the synthesis of (3 ′S) and (3 ′R)-3 ′-amino-3 ′-deoxy pyranonucleosides and their precursors (3 ′S) and (3 ′R)-3 ′-azido-3 ′-deoxy pyranonucleosides. Azidation of 1,2:5,6-di-O-isopropylidene-3-O-toluenesulfonyl-α-D-allofuranose followed by hydrolysis and subsequent acetylation afforded 3-azido-3-deoxy-1,2,4,6-tetra-O-acetyl-D-glucopyranose, which upon coupling with the proper silylated bases, deacetylation, and catalytic hydrogenation, obtained the target 3 ′-amino-3 ′-deoxy-β-D-glucopyranonucleosides. The desired 1-(3 ′-amino-3 ′-deoxy-β-D-allopyranosyl)5-fluorouracil was readily prepared from the suitable imidazylate sugar after azidation followed by a protection/deprotection sequence and reduction of the unprotected azido precursor. No antiviral activity was observed for the novel nucleosides. Moderate cytostatic activity was recorded for the 5-fluorouracil derivatives.     

Comparison of mutagenicity and chemical properties of N-methyl-N′-alkyl-N-nitrosoureas

Thed mutagenic activities of 11 N-methyl-N′-alkyl-N-nitrosoureas were tested on Samonellatyphimurium TA1535 and compared with chemical properties (alkylating activity and decompostion rate). In their relative mutagenicities the N-nitrosoureas that had a cyclic N′-alkyl group showed far more mutagenic activity than those having a chain N′-alkyl group. M(1-A)NU and M(2-A)NU, which had the most bulky N′-alkyl group in this series, exhibited lethal effects at high concentrations. The mutagenicity showed a small positive correlation with decomposition rates but not with alkylating activities on 4-(p-nitrobenzyl_prridine. The highest mutagenicity in this series was observed in N-methyl-N′-cyclobutyl-N-nitrosourea.These results suggest that, in this series of N-methyl-M′-alkyl-N-nitrosoureas, structural differences in the N′-alkyl groups had great significance in mutagenicity.     

Visual learning and memory of Drosophila melanogaster wild type CS and the mutants dunce1, amnesiac, turnip and rutabaga

Dunce¹, amnesiac, turnip and rutabaga, mutants of Drosophila melanogaster deficient in olfactory learning and/or memory, were tested for visual learning ability and memory. All these mutants are able to learn conditioned visual information, but not as well as the corresponding wildtype CS. Memory of all four mutants is reduced during the first 30 min after training, but indistinguishable from that of the wildtype two hours after conditioning.     

Synthesis, characterisation and crystal structure of hydroxylamido-κN,O(iodo)[tris(3,5-dimethylpyrazol-1-yl)borato]nitrosylmolybdenum(II)

The unusual 18e seven-coordinate Mo(II) complex [Mo(NO)(H₂NO-κ²N,O)(Tp^Me2)I] (1; [Tp^Me2]⁻ is hydrotris(3,5-dimethylpyrazol-1-yl)borate) has been synthesised and characterised by IR, ¹H NMR and ESI-MS spectroscopies and by a single crystal X-ray diffraction study. The complex has a distorted pentagonal bipyramid structure with equatorial κ²-NH₂O⁻ ligand (d_N-O = 1.387 Å, d_Mo-N and d_Mo-O equal 2.049 and 2.092 Å, respectively). In the solid state 1 exists as a dimer (the point group C_i) due to the formation of two NH?O hydrogen bonds (d_N-H?O = 2.064 Å) between the adjacent NH₂O⁻ ligands, whilst in solution at/or above RT it resolves itself giving a monomer, which readily isomerises to more thermodynamically stable diastereoisomer.     

Isolation of 1-(1′-2′ S-Nornicotino)-1-deoxy-β-d-fructofuranose and Its Formation in Flue-curing Process of Tobacco Leaves

1-(1′-2′ S-Nornicotino)-1-deoxy-β-d-fructofuranose was first isolated from flue-cured leaves of Cherry Red tobacco, Nicotiana tabacum, cv. Bright Yellow. Its structure was established spectrometrically and synthetically. This substance was shown to be formed from nornicotine during flue-curing. Its smoking effect was mild.     

The effect of hydrogen bonding in two crystal modifications of aquabis(N,N-dimethylglycinato-κN,κO)copper(II): Experimental and theoretical study

From the crystals of trans aquabis(N,N-dimethylglycinato-κN,κO)copper(II) dihydrate (compound 1, space group P2₁2₁2₁) novel crystal structure of trans aquabis(N,N-dimethylglycinato-κN,κO)copper(II) (compound 2, space group Pbca) was obtained and analysed by X-ray diffraction. In the crystal structure 1, the O-H?O hydrogen bonds form three-dimensional network. In the crystal structure 2, two-dimensional layers stacking to each other are formed, with non-polar N,N-dimethyl groups placed on the opposite sides of the layers, and with the polar part in the middle forming CO?O-H and C-H?O hydrogen bonds. Different hydrogen bonding patterns in 1 and 2 do not pronouncedly affect molecular geometry of the title compound. Molecular mechanics force field suited for studying the properties of bis(amino acidato)copper(II) complexes in the solid state can follow the differences between the experimental molecular structures in the two diverse crystalline surroundings. To make possible direct comparison between crystal lattices, the force field was applied to predict unit cell packing of supposed anhydrous bis(N,N-dimethylglycinato)copper(II) in space group Pbca. Relative intermolecular energies of hypothetic anhydrous crystal and simulated 1 and 2 crystals are discussed. On the basis of experimental and theoretical results we conclude that the main effect of two water molecules of crystallisation in 1 is to stabilise the crystal packing via hydrogen bonding, whilst similar pyramidal copper(II) coordination geometry in 1 and 2 is due to axially coordinated water molecule and its intermolecular interactions.     

Biosynthesis of α-spinasterol from (2- 14C (4R)-4-3H1) mevalonic acid by Spinacea oleracea and Medicago sativa

Leaves of Spinacea oleracea and Medicago sativa were incubated with (2-¹⁴C, (4R)-4³H₁ mevalonic acid and the sterols isolated. Cycloartenol had a ³H: ¹⁴C atomic ratio of 6:6 whilst oxidation to cycloartenone resulted in a ratio of 5:6 showing that tritium was present in the 3α-position and that the cycloartenol was symmetrically labelled. Separation of the 4-demethyl sterols gave α-spinasterol and a mixture of stigmast-7-enol and 24-methylcholest-7-enol, which had ³H: ¹⁴C atomic ratios of 3:5. Ozonolysis of α-spinastery] acetate gave the terminal side chain fragment as 2-ethyl-3-methyl butanoic acid. The acid contained ¹⁴C but no tritium thus showing that the C-24 hydrogen of cycloartenol is lost during the alkylation reactions leading to the C-24 ethyl group of α-spinasterol.     

Selective synthesis of cerebrosides: (2S, 3R, 4E)-1-O-β-d-galactopyranosyl-N-(2′R and 2′S)-2′-hydroxytetracosanoyl-sphingenine

The cerebrosides were first isolated by Thudicum in 1874 and the structures were established by Carteret al. in 1950 (for review, see [2]). In 1961 Shapiro and Flowers [3] reported the first total synthesis of a cerebroside1 (Fig. 1) which was identified with the natural sample, only through comparison of their i.r. data. In order to confirm the absolute configuration at C-2 of natural cerebroside1, we describe here an unambiguous synthesis of two stereoisomeric cerebrosides1 and2, and found that the¹H-NMR spectra of the synthetic1 (Fig. 2) was completely identical with that of the natural cerebroside reported recently by Dabrowskiet al. [4].In planning the synthetic route, the target structures1 and2 were disconnected at the dotted lines to give three key synthetic intermediates3, 4 and5 or6 (Fig. 1).Abbreviations Bu butyl - Ph phenyl - t-BuPh₂SiCl t-butyldiphenylsilyl chloride - MTPA -methoxy--trifluoromethylphenylacetic acid - THF tetrahydrofuran Part 36 in the series Synthetic Studies on Cell-surface Glycans, for part 35, see [1]     

Structural, magnetic and spectroscopic characterization of two unusual end-on bis(μ-acetato/μ-nitrato) bridged copper(II) complexes with N′-[phenyl(pyridin-2-yl)methylidene]furan-2-carbohydrazide and (2E,4Z)-N,2-dimethylhepta-2,4,6-trienamide-1-phenyl-1-pyridin-2-ylmethanimine (1:1) as capping ligands

Two new binuclear end-on bis(μ-acetato/μ-nitrato) bridged complexes with two NNO donor ligands, viz., [(L¹)Cu(μ-CH₃COO)₂Cu(L¹)]·4,4-bipy 1 and [(L²)Cu(μ-NO₃)₂Cu(L²)] 2 where [L¹ = N′-[phenyl(pyridin-2-yl)methylidene]furan-2-carbohydrazide, L² = (2E,4Z)-N,2-dimethylhepta-2,4,6-trienamide-1-phenyl-1-pyridin-2-ylmethanimine (1:1) μ-CH₃COO⁻ = μ-acetato and μ-NO₃⁻ = μ-nitrato) have been prepared and physiochemically characterized. These complexes are structurally characterized by X-ray crystallography. In both complexes, the two copper centers are linked by two acetate or two nitrate groups in end-on bonding fashion. The copper-copper separation is 3.279 Å for 1 and 3.459 Å for 2. The copper ions are pentacoordinated in both complexes. The coordination geometry may be described as close to square pyramidal (SP) stereochemistry with slight distortion to trigonal bipyramidal (TBP) stereochemistry. The polycrystalline epr spectra of these two complexes exhibit the properties commensurate with S = 1 systems. The magnetic moment (μ_eff) for these complexes are below the theoretical value suggesting antiferromagnetic exchange between the copper(II) ions. The cyclic voltammograms (CV) of the two complexes have been investigated. Superoxide dismutase (SOD) activity of these complexes has also been measured. These complexes can catalyze the dismutation of superoxide.     

Syntheses and antitumor activities of N′1,N′3-dialkyl-N′1,N′3-di-(alkylcarbonothioyl) malonohydrazide: The discovery of elesclomol

A series of N′¹,N′³-dialkyl-N′¹,N′³-di(alkylcarbonothioyl) malonohydrazides have been designed and synthesized as anticancer agents by targeting oxidative stress and Hsp70 induction. Structure–activity relationship (SAR) studies lead to the discovery of STA-4783 (elesclomol), a novel small molecule that has been evaluated in a number of clinical trials as an anticancer agent in combination with Taxol.