Conformation-based design of two cyclic physalaemin analogues.

Two new cyclic analogues of physalaemin were designed on the basis of the conformation found in DMSO solution. Glp-Ala-cyclo(-Asp-Pro-Asn-Lys-)-Phe-Tyr-Gly-Leu-Met-NH2 (1) was synthesized by cyclization of physalaemin. In 2 the Asp residue was replaced by Glu. The linear analogue of 2 was synthesized by the solid phase method and subsequently cyclized. Two-dimensional nmr methods were employed to assign the proton and carbon resonances. Proton-proton distances were extracted from rotating frame nuclear Overhauser effect spectra and used as restraints in the molecular dynamics calculations. Analogue 1 was found to have a similar conformation as physalaemin, whereas 2 did not form intramolecular hydrogen bonds. The pharmacological evaluation revealed that both peptides have similar potencies as physalaemin in the dog carotid artery (NK-1 receptor). Therefore, the charged side chains of physalaemin appear not essential for NK-1 activation. However, the other tachykinin receptors show good sensitivity to the cyclic peptides. It is concluded that the replacement of a salt bridge by an amide bond connecting the side chains of natural residues might provide useful information about the biological significance of some charged side chains of neurokinins.

Synthesis, conformational studies, and molecular dynamics calculations of two cyclic tetrapeptides with 17- and 18-membered rings.

Two cyclic tetrapeptides [Boc-cyclo(-Xxx-Pro-Asn-Lys-)OMe (Xxx = Asp or Glu)] were synthesized and investigated by NMR spectroscopy. They were designed in order to mimic the salt bridge found in physalaemin. Isomers of the urethane bond were observed in DMSO solution. The ROESY spectrum allowed the assignment of many signals of the minor isomer of both compounds. Conformational studies based on the temperature gradients of the NH chemical shifts, coupling constants, and ROEs revealed a similar conformation for the Asp analogue as proposed for physalaemin. A beta I turn with Pro and Asn in the corner positions was found for the major isomer. No hydrogen bonds were detected for the major isomer of the cyclic Glu analogue. Molecular dynamics calculations, using the NMR based initial structures, yielded sets of conformations in agreement with the experimental data. It is concluded that the salt bridge in physalaemin is best approximated by a lactam formed from the original amino acids.

pH dependent conformation of physalaemin.

The undecapeptide physalaemin was investigated by n.m.r. spectroscopy in DMSO solution under acidic and neutral conditions. Large changes of the NH chemical shifts and the temperature gradients of the NH protons occurred on going from pH 3.5 to pH 7.0 for residues around the charged amino acids Asp and Lys. At pH 3.5 the data are in accord with a flexible conformation of the peptide. The results at neutral pH are interpreted in terms of a folded structure having two interresidue and one intraresidue hydrogen bond. They include a beta turn with proline in position i + 1 and asparagine in position i + 2.

[Nitrefazole, a 4-nitroimidazole derivative with a marked inhibitory effect on aldehyde dehydrogenase. Synthesis and structural assignment]. / Nitrefazol, ein 4-Nitroimidazol-Derivat mit starker Hemmwirkung auf die Aldehyddehydrogenase. Synthese und Strukturzuordnung.

2-Methyl-4-nitro-1-(4-nitrophenyl)imidazole (nitrefazole) is a drug which causes a strong and long lasting inhibition of aldehyde dehydrogenase, an enzyme involved in the metabolism of alcohol. The synthesis of this compound as well as that of the isomeric 5-nitro analogue are described. It can be shown by means of detailed 1H- and 13C-NMR studies of both isomers and some other structurally related compounds that the nitro group in nitrefazole is in position 4 of the imidazole ring, whereas the other pharmacologically active nitroimidazoles like metronidazole are mainly substituted in position 5 (or in exceptional cases in position 2).

Further compounds from the pedal gland of the bontebok (Damaliscus dorcas dorcas).

The identification of four further major constituents of the pedal gland exudate of the bontebok, Damaliscus dorcas dorcas, viz. alpha-terpineol, 2-n-heptylpyridine, m-cresol and (A)-6-dodecen-4-olide and the investigation of the stereochemistry of the double bond in (Z)-6-dodecen-4-olide by means of iterative computer analysis are described. An improved synthesis of this compound is outlined.