Synthesis and biological activity of some linear and cyclic kinin analogues.
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)-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)-Gly-OH was also synthesized by the solid-phase procedure and used to prepare the N epsilon-[(Gal beta)Thr3, (Gal beta)Thr4, 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 then 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.
Gobbo
M
M
Department of Organic Chemistry, University of Padova, Italy.
Biondi
L
L
Filira
F
F
Rocchi
R
R
Piek
T
T
D000595:Amino Acid Sequence; D000818:Animals; D001920:Bradykinin / Q000138:chemical synthesis / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D007609:Kallidin / Q000138:chemical synthesis / Q000494:pharmacology; D007705:Kinins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000187:drug effects
D007705:Kinins; D007609:Kallidin; D001920:Bradykinin