SOLID-PHASE SYNTHESIS OF CIONIN, A PROTOCHORDATE-DERIVED OCTAPEPTIDE RELATED TO THE GASTRIN CHOLECYSTOKININ FAMILY OF PEPTIDES, AND ITS MONO-TYROSINE-SULFATE-CONTAINING DERIVATIVES/

Cionin, a protochordate-derived octapeptide amide related to the gastr in/cholecystokinin family of peptides, contains two consecutive tyrosi ne sulfate residues. In order to gain insight into the role of the res pective tyrosine sulfate residue in biological activity, cionin and it s derivatives in which one of the two tyrosine sulfate residues was re placed by tyrosine, were prepared by two Fmoc-based solid-phase approa ches. In approach (1) Fmoc-Tyr(SO3Na)-OH was employed as a building bl ock to assemble the Tyr(SO3Na)-containing peptide-resin, and a global deprotection/cleavage was conducted with 90% aqueous TFA in the presen ce of m-cresol and 2-methylindole at 4 degrees C. In approach (2) the Tyr(Msib) [Msib =p-(methylsulfinyl)benzyl] derivative was used for the peptide-chain assembly to achieve sulfation on the selective Tyr resi due. Partially protected peptide with the Msib/Msz protecting groups [ Msib =p-(methylsulfinyl)benzyloxycarbonyl], obtained after peptide-res in cleavage, was treated with DMF-SO3 complex in the presence of ethan edithiol to achieve the sulfation of free Tyr residue and the reductio n of the Msib/Msz groups to TFA-labile Mtb/Mtz groups [Mtb =p-(methylt hio)benzyl, Mtz =p-(methylthio)benzyloxycarbonyl]. Final deprotection of the Mtb/Mtz Mtz groups with 90% aqueous TFA in the presence of m-cr esol and 2-methylindole gave the desired cionin derivative, which cont ains the tyrosine sulfate residue al the selective position. Yields ob tained with approach (2) were considerably higher than those obtained with approach (1). Cionin and mono-Tyr(SO3H)-containing derivatives we re assayed on exocrine pancreas in dogs. (C) Munksgaard 1994.