Synthesis of substance P via its sulfoxide by the repetitive excess mixed anhydride (REMA) method

Abstract

AbstractThe N‐protected heptapeptide sulfoxide corresponding to positions 5 to 11 inclusive of substance P, Boc‐Gln‐Gln‐Phe‐Phe‐Gly‐Leu‐Met(O)‐NH2 (VII), was synthesized by the repetitive excess mixed anhydride (REMA) method (Scheme). Consecutive mixed anhydride coupling to N‐deprotected VII of the dipeptides Boc‐Lys(Z)‐Pro‐OH (VIII) and Z‐Arg(NO2)‐Pro‐OH (X) yielded protected substance P sulfoxide, XI. From XI both Z groups and the NO2 group were removed with liquid hydrogen fluoride, yielding substance P sulfoxide.Substance P sulfoxide was conveniently reduced to substance P with the aid of iodide ions in strongly acid olution. Preliminary results are given on the scope of this method, i.e. peptides containing ‐ besides methionine ‐ tyrosine, where the method worked well, or tryptophan, where the method failed.REMA‐synthesized substance P, after gel filtration, was found to be chemically pure and to possess the same biological activity as a substance P standard (Beckman), according to two tests (sialagogic assay and guinea pig ileum contraction).