Collect. Czech. Chem. Commun. 2002, 67, 373-392

Synthesis, Bioassay and NMR Study of Methyleneoxy Isosters of Oxytocin and Vasopressin

Jan Mařík, Miloš Buděšínský, Jiřina Slaninová and Jan Hlaváček*

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic


Syntheses of pseudodipeptides H-Tyrψ[CH2O]Ile-OH and H-Tyrψ[CH2O]Phe-OH were carried out using the intramolecular Williamson reaction of O-benzyltyrosinol with ethyl chloroacetate followed by N-protection and aldol reaction of the corresponding morpholin-3-one in position C2 with butanone or benzaldehyde, elimination of the hydroxy group to give derivatives with a double bond either as the E/Z (1 : 1) diastereomeric mixture in the case of the former derivative or as the Z-isomer only in the case of the latter one. Stereoselective hydrogenation and hydrolysis of both the lactams yielded the corresponding pseudodipeptides lacking the carbonyl group as a hydrogen bond donor. The introduction of the pseudodipeptides into positions 2 and 3 of oxytocin and vasopressin caused total absence of all biological activities in the formed analogues. The results of the bioassay and NMR study confirmed the importance of the H-bond between the backbone carbonyl of the Tyr2 and NH proton of the Asn5 residues for stabilization of the β-turn in the cyclic hexapeptide part of both the hormones and for their biological activity.

Keywords: Peptides; Peptidomimetics; Methyleneoxy isosters; Solid phase synthesis; Biological activity; 1H and 13C NMR spectroscopy.

References: 38 live references.