Synthesis of thromboxane B2 via ketalization/ring-closing metathesis

Total synthesis of thromboxane B2 using intermolecular ketalization followed by ring-closing metathesis is reported. Other key steps include a Sharpless asymmetric epoxidation to form an oxirane on the endo face of the bicyclic acetal, epoxide opening using lithioacetonitrile, an allylic alcohol 1,3-transposition, and Mitsunobu lactonization.     

Characteristic fragmentation of thromboxane B2 in thermospray high-performance liquid chromatography-mass spectrometry

Cyclo- and lipo-oxygenase metabolites of arachidonic acid have been reported to have very simple thermospray mass spectra. However, thromboxane B2 (TXB) in ammonium acetate-methanol and at interface temperatures below the point of total vaporization shows a mass spectral pattern characterized by abundant ions at low masses. The more abundant TXB fragment ions have been characterized as adducts from four principal fragments with molecular masses of 156, 170, 196 and 326. Positive- and negative-ion mass spectra, and mass spectra obtained with an alternative thermospray buffer (butylammonium acetate) support the molecular masses of these fragments. A tentative assignment of the fragments can be made by comparison of the thermospray mass spectra of TXB, 2,3-dinor-TXB and some of their methyl ester and methyl oxime derivatives. Interface temperature and solvent composition effects on the fragmentation, as well as in the electron-capture processes observed when working in the filament-on mode, are discussed. Fragmentation mechanisms can be related to those observed for monosaccharides, and imply retro-Diels-Alder as well as retroaldolic condensation-type rearrangements.     

Fluorescent derivatives of thromboxane B(2): Synthesis, spectroscopic and immunologic properties

Thromboxane B(2) has been labeled by four fluorescent probes structurally related to coumarin (4-bromomethyl-7-methoxycoumarin, 7-[(chlorocarbonyl) methoxy]-4-methylcoumarin, 4-luminarin) or anthracen (panacyl bromide). The purity of the derivatives determined by liquid chromatography was over 90%. The extinction coefficient, Stokes' shift, quantum yield, life-time and the anisotropy of the emitted fluorescence were determined. Immunorecognition of thromboxane B(2) derivatives was checked by competition immunoassays. Among the derivatives tested, that obtained with 4-luminarin has a suitable Stokes' shift (95 nm), a quantum yield of 0.46, a single value of excited state life-time (9.3 nsec), a well-preserved immunorecognition and a good chemical stability. Preliminary results in competition experiments showed variations in fluorescence anisotropy correlated to thromboxane B(2) concentration.     

Diethylhydrogensilyl-cyclic diethylsilylene derivatives in gas chromatography-mass spectrometry of prostanoids. III. F alpha-prostaglandins and thromboxane B2 derivatives

The gas chromatographic (GC) and GC-mass spectrometric properties of the diethylhydrogensilyl-cyclic diethylsilylene (DEHS-DES) derivatives of prostaglandin (PG) F1 alpha methyl ester, PGF2 alpha methyl ester, 6-keto-PGF1 alpha methyl ester-alkyloxime and thromboxane (TX) B2 methyl ester-alkyloxime and the DES derivative of 13,14-dihydro-15-keto-PGF2 alpha methyl ester-alkyloxime were studied. When the ketonic PGs and TXB2 were converted into their methyloxime derivatives, the methylene unit values of these five prostanoid derivatives were slightly greater than those of the corresponding dimethylethylsilyl ether derivatives. When the ketonic PGs were converted into their corresponding ethyloxime derivatives, baseline separation was achieved in 20 min by use of a methylsilicone cross-linked fused-silica capillary column. The mass spectra of these derivatives were characterized by the ion at m/z 157 for F alpha prostaglandins and m/z 269 for TXB2. The major fragmentations were directed by the DES group, and other fragmentations common to the prostanoid derivatives were losses of an ethyl radical at the silicon atom, C5H11 hydrocarbon fragment, diethylhydrogensilanol and C15-C20 hydrocarbon fragment. The mass fragmentations of these prostanoid derivatives are briefly discussed. GC with high-resolution selected-ion monitoring was carried out for the TXB2 derivative at a resolution of 8000 by monitoring the ion at m/z 269.1573. A 25-pg amount of this derivative showed a well shaped doublet with a signal-to-noise ratio of more than 300:1.     

Electrophile-initiated conversion of a prostaglandin endoperoxide model compound to the thromboxane B skeleton

Reaction of the simplified prostaglandin endoperoxide model (1) with ferric or cupric ion afforded the lactols (2a, b) containing the thromboxane B ring moiety, along with ketol (3) and levulinaldehyde derivatives (4, 5).     

On the structure of thromboxane A2

The reactions of the 2-alkoxyoxetane 5 with sodium azide and methanol yield the α-azidoether 7 and the dimethyl acetal 8, respectively, paralleling reactions reported for TXA₂. The hydrolysis of 5 reported by Bruice to involve general acid catalysis proceeds at a rate similar to that reported for TXA₂. All these cleavage reactions are most likely to proceed by the same mechanism. These findings support structure 1 for TXA₂.     

Synthesis of thromboxane A2 analog,dl-(9,11)-methano-(11,12)-amino thromboxane A2

A synthesis of nitrogen containing thromboxane, A₂ analog, $\text{dl}$-(9,11)-methano-(11,12)-amino thromboxane A₂ ($\text{1}$) is described.     

Determination of 6-keto-PGF1 alpha, 2,3-dinor-6-keto-PGF1 alpha, thromboxane B2, 2,3-dinor-thromboxane B2, PGE2, PGD2 and PGF2 alpha in human urine by gas chromatography-negative ion chemical ionization mass spectrometry

A method for quantification of 6-keto-PGF1 alpha, 2,3-dinor-6-keto-PGF1 alpha TXB2, 2,3-dinor TXB2, PGE2, PGD2 and PGF2 alpha in human urine samples, using gas chromatography-negative ion chemical ionization mass spectrometry, is described. Deuterated analogues were used as internal standards. Methoximation was carried out in urine samples which were subsequently applied to phenylboronic acid cartridges, reversed-phase cartridges and thin-layer chromatography. The eluents were further derivatized to pentafluorobenzyl ester trimethylsilyl ethers for final quantification by gas chromatography-mass spectrometry. The overall recovery was 77% for tritiated 6-keto-PGF1 alpha and 55% for tritiated TXB2. Urinary levels of prostanoids were determined in a group of six volunteers before and after intake of the thromboxane synthase inhibitor Ridogrel, and related to creatinine clearance.     

Synthesis of structure analogues of thromboxane A2

Analogues I of thromboxane A₂ (TXA₂) in which the ether linkages are replaced by carbon groupings have been synthesised by elaboration of a commercially available pinene derivative IIb.     

Synthesis of thromboxane A2 analog dl-(9,11),(11,12)-dideoxa-(9,11),(11,12)-dimethylene thromboxane A2

The thromboxane A₂ analog, dl-(9,11),(11,12)-dideoxa-(9,11),(11,12)-dimethylene thromboxane A₂ (TX A₂) has been synthesized; the compound showed high agonist activities on platelet aggregation and the aorta contracting activities.     

Glass capillary column chromatography of mixed derivatives of primary prostaglandins, 6-keto prostaglandin F1α and thromboxane B2

This work describes the use of glass capillary columns (GCC) in the rapid concurrent analysis of primary prostaglandins (PGs) (e. g. PGE₂, PGE₂, PGF_2α) and other functionally significant metabolites of arachidonic acid (AA) such as TXB₂ and 6-keto PGF_1α. The use of a new multistep mixed derivatization approach that generates the methyl esters of n-butylboronate, pentafluorobenzyloxime, trimethylsilyl ether derivatives of these compounds remarkably simplifies the GC profiling of the three main pathways of AA metabolism (PGs, thromboxane, and prostacyclin). Furthermore, isomeric species giving very similar or identical mass spectral patterns can be easily identified by their relative retention times on high efficiency capillary columns.     

A simple synthesis of a stable thromboxane A2 analogue

A simple synthetic route, which appears to have some general utility, has been used to obtain a Bicyclo[2.2.1]heptane analogue of Thromboxane A₂.     

Refined pharmacophore features for virtual screening of human thromboxane A2 receptor antagonists

For a long time, the structural basis of TXA2 receptor is limited due to the lack of crystal structure information, till the release of the crystal structure of TXA2 receptor, which deepens our understanding about ligand recognition and selectivity mechanisms of this physiologically important receptor. In this research, we report the successful implementation in the discovery of an optimal pharmacophore model of human TXA2 receptor antagonists through virtual screening. Structure-based pharmacophore models were generated based on two crystal structures of human TXA2 receptor (PDB entry 6IIU and 6IIV). Docking simulation revealed interaction modes of the virtual screening hits against TXA2 receptor, which was validated through molecular dynamics simulation and binding free energy calculation. ADMET properties were also analyzed to evaluate the toxicity and physio-chemical characteristics of the hits. The research would provide valuable insight into the binding mechanisms of TXA2 receptor antagonists and thus be helpful for designing novel antagonists.     

Superconductivity in the intermetallic borocarbides YPd2B2C,YPt2B2C and LaPt2B2C

We report a detailed study of the thermodynamic properties of the conventional phonon-mediated superconductors YPd₂B₂C, YPt₂B₂C and LaPt₂B₂C. Our calculations conducted within the framework of the Migdal-Eliashberg formalism show that the experimental values of the critical temperature cannot be properly reproduced using commonly accepted value of Coulomb pseudopotential. Moreover, we proved that the values of universal ratios of conventional superconductivity appearing in the Bardeen-Copper-Schrieffer (BCS) theory are inconsistent with our results obtained from the investigated borocarbides. The observed differences are connected with the strong/medium-coupling and retardation effects existing in the studied systems.