Prostaglandin D2 synthase and its post-translational modifications in neurological disorders

Prostaglandin D2 synthase (PGDS) (beta-trace protein) is a highly abundant cerebrospinal fluid (CSF) glycoprotein. A number of studies have been performed to determine the potential value of this protein for the diagnosis of various neurological disorders. The measurement of total PGDS levels in CSF has proved marginally useful for this purpose, but promising results were obtained while investigating changes in the posttranslational modifications (PTM) pattern. Using 2-DE analysis, we previously showed that PGDS is differentially expressed in ante- and post mortem CSF samples. In the present study, we examined whether the PGDS isoforms may help to distinguish stroke and neurodegenerative disease patients from healthy subjects. The pattern of PGDS PTM was analyzed in CSF from patients with various neurological disorders (n = 44) using IEF/immunoblotting techniques. Strong alterations of this pattern were detected in patients with different forms of degenerative dementia. These findings are consistent with PGDS being altered in some neurological diseases and provide new opportunities for clinical applications.     

Synthesis of Cannabinoid Model Compounds. Part 3. (6aR, 10aR)-N-ethyl-Δ8-tetrahydrocannabinol-18-amide, (6aR, 10aR, 17 RS)-N-ethyl-17-methyl-Δ8- tetrahydrocannabinol-18-amide and (6aR, 10aR)-17,18-didehydro-Δ8-tetrahydrocannabinol

The novel cannabinoids (6aR, 10aR)-N-ethyl-Δ⁸-tetrahydrocannabinol-18-amide (15) and (6aR, 10aR, 17 RS)-N-ethyl-17-methyl-Δ⁸- tetrahydrocannabinol-18-amide (16) , designed as cannabinoid affinity ligands, were synthesized from the corresponding acids 11 and 12 via the N-hydroxysuccinimide esters. Amide 16 was tested in the rat and was generalized to Δ⁹-tetrahydrocannabinol, being 5 times less potent than the training drug. An improved synthesis of (6aR, 10aR)-17,18-didehydro-Δ⁸-tetrahydrocannabinol (23) is reported. As model reaction for the preparation of a tritiated Δ⁸-tetrahydrocannabinol, compound 23 was selectively deuterated at C(17) and C(18) in benzene/Et₃N using [(C₆H₅)₃P]₃RuCl₂ as catalyst.     

Synthesis and structure of a stabilized 10-membered cyclic enediyne

The synthesis and structure of an acetal protected 10-membered cyclic enediyne-1,2-diol rac-10 is reported. The conformational constrain of the unsaturated macrocycle by the acetal protection group prevents the thermal cyclization reaction of the endiyne during synthesis and purification.     

A liquid chromatography-mass spectrometry method for the quantification of both etoricoxib and valdecoxib in human plasma

A practicable and selective liquid chromatography-mass spectrometry assay for the determination of two cyclooxygenase-2 inhibitors, etoricoxib and valdecoxib, in human plasma is presented. The analytical technique is based on reversed-phase high-performance liquid chromatography (HPLC) coupled to atmospheric pressure chemical ionisation (APCI) mass spectrometry (Finnigan Mat LCQ ion trap). Mass analysis was performed in the positive ion mode. The ion trap was operated in the tandem MS mode (MS2) and the transitions of etoricoxib (m/z 359.2 --> 280.3) and valdecoxib (m/z 315.1 --> 235.1) were followed by selected reaction monitoring. Retention times of etoricoxib and valdecoxib were 1.05 and 1.08 min, respectively. The method was validated over a linear range 10-2500 and 5-1000 microg/L using the other substrate as internal standard. After validation, the method was used to study the pharmacokinetic pro fi le of etoricoxib or valdecoxib in a healthy volunteer after administration of a single oral dose (valdecoxib, 20 mg; etoricoxib, 90 mg). The presented method was suf fi cient to cover more than 90% of the area under the plasma concentration time curve.     

α-Substituierte phosphonate—38: 1-dimethylamino-1-cyano-methanphosphonsäurediethylester,ein neues edukt zur darstellung von carbonsäuren, 1-cyanoenaminen und homoenolaten

Alkylation of 1-dimethylamino-1-cyanomethanephosphonic acid diethyl ester (8), easily obtainable from diethyl phosphite and the 0,N-acetal 9, yields 1-alkyl derivatives 14. Elimination of HCN converts 14 into 1-phosphonoenamines 6. Carbonyl compounds react with 8 to give 1-cyanoenamines 15 which may be hydrolyzed to from the homologous carboxylic acid. Alternatively, deprotonation of 15 yields the homoenolate anions 17 which can be alkylated or hydroxyalkylated, permitting chain extension of carbonyl compounds through introduction of an α-carboxyl and a β-alkyl group. Acid catalyzed hydrolysis of 8 results in cleavage of the PC bond, leading to the corresponding α-dimethylamino alkanoic acids. A phosphonic acid 11 can be obtained from 8 by application of the silylester method. An unambigous assignment of E/Z-isomers of the cyanoenamines 15 has been derived from ¹³C-NMR spectroscopy.     

1,2‐Dithioquadratato‐ und 1,2‐Dithiooxalatoindate(III)

Indium(III) chloride forms in water with potassium 1,2‐dithiooxalate (dto) and potassium 1,2‐dithiosquarate (dtsq) stable coordination compounds. Due to the higher bridging ability of the 1,2‐dithiooxalate ligand in all cases only thiooxalate bridged binuclear complexes were found. From 1,2‐dithioquadratate with an identical donor atom set mononuclear trischelates could be isolated. Five crystalline complexes, (BzlMe₃N)₄[(dto)₂In(dto)In(dto)₂] ( 1 ), (BzlPh₃P)₄[(dto)₂In(dto)In(dto)₂] ( 2 ), (BzlMe₃N)₃[In(dtsq)₃] ( 3 ), (Bu₄N)₃[In(dtsq)₃] ( 4 ) and (Ph₄P)[In(dtsq)₂(DMF)₂] ( 5 ), have been isolated and characterized by X‐ray analyses. Due to the type of the complex and the cations involved these compounds crystallize in different space groups with the following parameters: 1 , monoclinic in P2₁/c with a = 14.4035(5) Å, b = 10.8141(5) Å, c = 23.3698(9) Å, β = 124.664(2)°, and Z = 2; 2 , triclinic in P with a = 11.3872(7) Å, b = 13.6669(9) Å, c = 17.4296(10) Å, α = 88.883(5)°, β = 96.763(1)°, γ = 74.587(5)°, and Z = 1; 3 , hexagonal in R3 with a = 20.6501(16) Å, b = 20.6501(16) Å, c = 19.0706(13) Å and Z = 6; 4 , monoclinic in P2₁/c with a = 22.7650(15) Å, b = 20.4656(10) Å, c = 14.4770(9) Å, β = 101.095(5)°, and Z = 4; 5 , triclinic in P with a = 9.2227(6) Å, b = 15.3876(9) Å, c = 15.5298(9) Å, α = 110.526(1)°, β = 100.138(1)°, γ = 101.003(1)°, and Z = 2.     

Collective excitations in solid hydrogen as observed by incoherent neutron scattering

Incoherent neutron scattering experiments are reported at a number of scattering angles for solid H₂ using the time-of-flight technique. The samples had an ortho concentration ofX0.91 and the temperatures were 4.2, 2.2 and 1.2 K. The recorded scattering functions exhibit the elastic line, the ortho-para conversion line, the phonon spectrum on the energy-gain side of the neutrons and finally the phonon spectrum on the energy-loss side. Analysis of the data shows multiple scattering to be very important especially at small scattering angles. Accordingly, the results of an extensive calculation are reported that include up to four-fold scattering. The phonon spectrum that brings calculation and experiment in agreement at all angles is presented. It is concluded from the comparison between the spectra at various temperatures that unexpectedly the samples have always remained in the hexagonal close-packed phase even below the usual transition temperature into the cubic phase. Comparison is made with the spectrum (also in thehcp phase) obtained from coherent neutron scattering. The high-energy phonon tail, to be expected for quantum crystals, is observed and is qualitatively consistent with that in a similar spectral density derived theoretically from ortho-para conversion data under pressure. No evidence of a libron spectrum atT=2.2 K for a sample withX=0.91 could be found, which is consistent with the absence of the cubic orientationally ordered phase in these experiments.Supported in this research by a grant from the National Science Foundation     

Assignment of E/Z isomers in Schiff bases of 3-acyltetramic acids with ethylenediamine by 1H and 13C NMR spectroscopy

The reaction of ethylenediamine with an equivalent mixture of diversely substituted 3-acyltetramic acids leads to Z/Z, Z/E, E/Z and E/E isomers. The E/Z isomerisation is slow in the NMR time scale of the ¹H and ¹³C chemical shifts; therefore at room temperature and in deuterochloroform all isomers of the new synthesized asymmetric compounds N,N′-ethylene-(1-ethyl-5,5-dimethyl-1′,5′,5′-trimethyl-3,3′-acetyltetramic acid) a, N,N′-ethylene-(5,5-dimethyl-1′,5′,5′-trimethyl-3,3′-acetyltetramic acid) b and, N,N′-ethylene-(1,5,5-trimethyl-1′,5′,5′-trimethyl-3-acetyl-3′-formyl-tetramic acid) c could be found in the corresponding spectra. To assign the ¹³C NMR signals we used two-dimensional ¹³C-¹H one-bond (HMQC) and ¹³C-¹H multibond (HMBC) correlated spectroscopy and the empirical rule that CO signals involved in hydrogen bonds are shifted to a lower field. The relative stability of isomers depending on substitution pattern could be estimated from the composition of the equilibria. b crystallizes as Z/Z isomer from ethanolic solution. The X-ray structural analysis of b has shown two CH-O hydrogen bonds. Received: 31 May 1996 / Revised: 26 June 1996 / Accepted: 1 July 1996