Solid-phase synthesis of MEN 11270, a new cyclic peptide kinin B-2 receptor antagonist

An efficient synthesis of the cyclic decapeptide MEN 11270 [H-DArg(1)-Arg(2 )-Pro(3)-Hyp(4)-Gly(5)-Thi(6)-Dab(7)-DTic(8)-Oic(9)-Arg(10) c(7 gamma -10x) ] was developed. Two three-dimensional orthogonal strategies were applied a nd compared: Fmoc/Tos/Boc (procedure A) and Fmoc/Pmc/Dde (procedure B), Bot h resulted in a 23-step strategy comprising the stepwise solid-phase chain assembly of the linear protected peptide, partial deprotection, solution-ph ase cyclization and final full deprotection. The stepwise assembly of the l inear peptide was optimized by double coupling and acylation time prolongat ion for critical residues (Tic, Dab, Thi, Pro). O-(7-azabenzotriazol-1-yl)- N,N.N',N'-tetramethyluronium (HATU) was preferred as coupling reagent for D ab. In the cyclization step, the partial racemization of Arg(10) (31% using 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide/1-hydroxybenzotriazole (ED C/HOBt) as activation system) was reduced to 3% with HATU. The final deprot ection was performed in the presence of dimethylsulfide (procedure A) and t hiocresol (procedure B) as scavengers, to avoid the sulfation of Hyp side c hain. The final compound and the main by-products were characterized by mas s spectroscopy (MS), nuclear magnetic resonance (NMR) and racemization test . Procedure B produced operationally simpler and more efficient results tha n A (28% overall yield versus 4%). Copyright (C) 2000 European Peptide Soci ety and John Wiley & Sons, Ltd.