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Solid‐phase synthesis of MEN 11270, a new cyclic peptide kinin B 2 receptor antagonist 1 2
Author(s) -
Anichini Beatrice,
Ricci Renzo,
Fabbri Gaetano,
Balacco Giuseppe,
Mauro Sandro,
Triolo Antonio,
Altamura Maria,
Maggi Carlo Alberto,
Quartara Laura
Publication year - 2000
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/1099-1387(200012)6:12<612::aid-psc291>3.0.co;2-k
Subject(s) - chemistry , racemization , peptide synthesis , yield (engineering) , carbodiimide , solid phase synthesis , combinatorial chemistry , acylation , peptide bond , peptide , reagent , protecting group , stereochemistry , nuclear magnetic resonance spectroscopy , organic chemistry , biochemistry , catalysis , materials science , alkyl , metallurgy
An efficient synthesis of the cyclic decapeptide MEN 11270 [H‐Arg 1 ‐Arg 2 ‐Pro 3 ‐Hyp 4 ‐Gly 5 ‐Thi 6 ‐Dab 7 ‐Tic 8 ‐Oic 9 ‐Arg 10 c(7γ–10α)] was developed. Two three‐dimensional orthogonal strategies were applied and compared: Fmoc/Tos/Boc (procedure A) and Fmoc/Pmc/Dde (procedure B). Both resulted in a 23‐step strategy comprising the stepwise solid‐phase chain assembly of the linear protected peptide, partial deprotection, solution‐phase cyclization and final full deprotection. The stepwise assembly of the linear peptide was optimized by double coupling and acylation time prolongation for critical residues (Tic, Dab, Thi, Pro). O‐(7‐azabenzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium (HATU) was preferred as coupling reagent for Dab. In the cyclization step, the partial racemization of Arg 10 (31% using 1‐ethyl‐3‐(3′‐dimethylaminopropyl)‐carbodiimide/1‐hydroxybenzotriazole (EDC/HOBt) as activation system) was reduced to 3% with HATU. The final deprotection was performed in the presence of dimethylsulfide (procedure A) and thiocresol (procedure B) as scavengers, to avoid the sulfation of Hyp side chain. The final compound and the main by‐products were characterized by mass spectroscopy (MS), nuclear magnetic resonance (NMR) and racemization test. Procedure B produced operationally simpler and more efficient results than A (28% overall yield versus 4%). Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.