Interaction of L-gamma-glutamyl-alpha,beta-dehydroamino acids with gamma-glutamyl transpeptidase.

Three gamma-glutamyl alpha,beta-dehydroamino acids: L-gamma-glutamyl-dehydroalanine, L-gamma-glutamyl-(Z)-dehydrobutyrine and L-gamma-glutamyl-(E)-dehydrobutyrine have been prepared as potential ligands (inhibitors or substrates) for gamma-glutamyl transpeptidase (GGT). Both isomers of gamma-glutamyl-dehydrobutyrines proved to be inhibitors of GGT, slightly better than the saturated analogue, L-gamma-glutamyl-L-butyrine. However, their solvolysis catalysed by the enzyme is slower than that of the latter. L-gamma-Glutamyl-(E)-dehydrobutyrine seems to be a more active compound in both enzymatic tests. L-gamma-Glutamyl-dehydroalanine elicited only low inhibitory activity and, moreover, was unstable under conditions of the solvolysis test.

Synthesis of peptides with alpha,beta-dehydroamino acids. XIII photoisomerization of Ac-(Z)-delta Phe-NHMe: Ac-(E)-delta Phe-NHMe.

Easily accessible Ac-(Z)-delta Phe-NHMe was photoisomerized to so far unknown Ac-(E)-delta Phe-NHMe. Some parameters of the process leading to a diastereomeric mixture of ratio 90(Z):10(E) have been tested and the photoisomerization has been carried out on a preparative milligram scale. The isomers were separated via crystallization followed by preparative HPLC.

[Evaluation of drug utilization from positive lists]. / Hodnocení spotreby léku pri zavádení pozitivních listu.

BACKGROUND: The introduction of positive drug lists (positive lists) is part of the regulating mechanisms which try to reduce the increasing expenditure on drugs. An essential part of these provisions is at present an analysis of the trend of drug consumption. The objective of the work was to introduce and evaluate the method DU 90% which in analyses of drug consumption uses a 90% ratio of preparations of their total consumption. METHODS AND RESULTS: The analysis was focused on prescriptions in medical clinics of the General Faculty Hospital Classification of drugs according to anatomical, therapeutic and chemical groups and the use of defined daily doses made it possible to calculate DU 90% and to prepare a consecutive list of drugs according to costs in different departments. The number of drugs with a defined daily dose was within the range of 280-316. In the interval DU 90% were 116-142 drugs. In all departments there was a practically identical ratio of drugs which were part of the positive list. The greatest expenditure were anti-infectious drugs for systemic use and drugs with an effect an blood and haematopoietic organs. CONCLUSIONS: The advantages of the method DU 90% is its easy application, low cost and possibility to identify controversial lields. This facilitates further qualitative and quantitative evaluation of the standard of pharmacotherapy.

Conformational investigation of alpha,beta-dehydropeptides. VII. Conformation of Ac-Pro-deltaAla-NHCH3 and Ac-Pro-(E)-deltaAbu-NHCH3: comparison with (Z)-substituted alpha,beta-dehydropeptides.

The crystal structure and solution conformation of Ac-Pro-deltaAla-NHCH3 and the solution conformation of Ac-Pro-(E)-deltaAbu-NHCH3 were investigated by X-ray diffraction method and NMR, FTIR and CD spectroscopies. Ac-Pro-deltaAla-NHCH3 adopts an extended-coil conformation in the crystalline state, with all-trans peptide bonds and the deltaAla residue being in a C5 form, phi(1)=-71.4(4), psi(1)=-16.8(4), phi(2)= -178.4(3) and psi(2)= 172.4(3) degrees. In inert solvents the peptide also assumes the C5 conformation, but a gamma-turn on the Pro residue cannot be ruled out. In these solvents Ac-Pro-(E)-deltaAbu-NHCH3 accommodates a beta(II)-turn, but a minor conformer with a nearly planar disposition of the CO-NH and C=C bonds (phi(2) approximately 0 degrees) is also present. Previous spectroscopic studies of the (Z)-substituted dehydropeptides Ac-Pro-(Z)-deltaAbu-NHCH3 and Ac-Pro-deltaVal-NHCH3 reveal that both peptides prefer a beta(II)-turn in solution. Comparison of conformations in the family of four Ac-Pro-deltaXaa-NHCH3 peptides let us formulate the following order of their tendency to adopt a beta-turn in solution: (Z)-deltaAbu > (E)-deltaAbu > deltaVal; deltaAla does not. None of the folded structures formed by the four compounds is stable in strongly solvating media.

Conformational investigation of alpha,beta-dehydropeptides. Part. IV. Beta-turn in saturated and alpha,beta-unsaturated peptides Ac-Pro-Xaa-NHCH3: NMR and IR studies.

Solution conformations of three series of model peptides, homochiral Ac-Pro-L-Xaa-NHCH3 and heterochiral Ac-Pro-D-Xaa-NHCH3 (Xaa = Val, Phe, Leu, Abu, Ala) as well as alpha,beta-unsaturated Ac-Pro-delta Xaa-NHCH3 [delta Xaa = delta Val, (Z)-delta Phe, (Z)-delta Leu, (Z)-delta Abu] were investigated in CDCl3 and CH2Cl2 by 1H-, 13C-NMR, and FTIR spectroscopy. NH stretching absorption spectra, solvent shifts delta delta for NH (Xaa) and NHCH3 on going from CDCl3 to (CD3)2SO, diagnostic interresidue proton NOEs, and trans-cis isomer ratios were examined. These studies performed showed the essential difference in conformational propensities between homochiral peptides (L-Xaa) on the one hand and heterochiral (D-Xaa) and alpha,beta-dehydropeptides (delta Xaa) on the other. Former compounds are conformationally flexible with an inverse gamma-bend, a beta-turn, and open forms in an equilibrium depending on the nature of the Xaa side chain. Conformational preferences of heterochiral and alpha,beta-dehydropeptides are very similar, with the type-II beta-turn as the dominating structure. There is no apparent correlation between conformational properties and the nature of the Xaa side chain within the two groups. The beta-turn formation propensity seems to be somewhat greater in alpha,beta-unsaturated than in heterochiral peptides, but an estimation of beta-folded conformers is risky.