Synthesis and Biological-activity of Some Linear and Cyclic Kinin Analogs

Syntheses are described of some linear and cyclic kinin analogues. Cyclization, by the diphenyl-phosphorazide method, of linear peptides prepared by the solid-phase procedure based on Fmoc chemistry, was used for preparing cyclo-bradykinin and cyclo-kallidin (cyclo-Lys-bradykinin). Removal of the protecting group from the lysine side chain of cyclo-kallidin followed by acylation with the N-terminal sequence of vespulakinin 1 (VSK 1), Fmoc-Thr(tBu)-Ala-Thr(tBu)-Thr(tBu)-Arg(Pmc)-Arg(Pmc)-Arg(Pmc)-Gly-OH, by the Bop-HOBt procedure, yielded the protected N-epsilon-(1-8 VSK 1)-cyclo-N-alpha-kallidin, which was deblocked by acid treatment and purified by semi-preparative HPLC. The diglycosylated 1-8 VSK 1 sequence Boc-Thr(tBu)-Ala-(Gal beta)Thr-(Gal beta)Thr-Arg(Pmc)-Arg(Pmc)-Agr(Pmc)-Gly-OH was also synthesized by the solid-phase procedure and used to prepare the N-epsilon-[(Gal beta)Thr(3), (Gal beta)Thr(4), 1-8 VSK 1]-cyclo-N-alpha-kallidin. Peptides and glycopeptides were characterized by amino acid analysis, optical rotation, analytical HPLC and FAB-MS. Preliminary pharmacological experiments showed that the cyclic kinin analogues are much less potent than bradykinin but still show specific bradykinin-like actions that support the hypothesis of the presence of a pharmacophore in the centre of the (brady)kinin molecule. (C) Munksgaard 1994.