Insulin peptides. XVI. The synthesis of a nonapeptide and a dodecapeptide derivative related to the a chain of human insulin (positions 1-9 and 10-21).

Abstract

Syntheses are described of protected peptides related to the N-terminus and C-terminus of the human insulin A chain. Thus the preparation is given of N-carbobenzox yglycyl-L-isoleucyl-L-valyl-7-f-butyl-L-glutamyl- L-glutaminyl-S-benzyl-L-cysteinyl-S-benzyl-L-cysteinyl-L-threonyl-L-serine hydrazide and N-carbobenzoxy-L-iso- leucyl-S-benzyl-L-cysteinyl-L-seryl-L-leucyl-L-tyrosyl-L-glutaminyl-L-leucyl-L-glutamyl- L- asparaginyl- L- tyrosyl - S - benzyl-L-cysteinyl-L-asparagine p-nitrobenzyl ester. The former derivative corresponds to positions 1-9 and the latter to positions 10—21 in the human insulin A chain sequence. R ecent communications3'4 from this laboratory described the synthesis of peptide derivatives related to the N-terminus of the A chain of sheep insulin and the synthesis of a dodecapeptide derivative con­ taining the C-terminal sequence of that chain. An in­ termediate in the construction of the latter peptide fragment, namely, the C-terminal nonapeptide portion, embodies the amino acid sequence found at the carboxyl terminus of the A chain of human insulin. The present report describes the synthesis of a protected nonapep­ tide and a protected dodecapeptide containing the N- terminal and C-terminal amino acid sequence, respec­ tively, of the human insulin A chain. The amino acid sequence of the reduced A chain of human insulin as determined by Nicol and Smith6 is glycylisoleucylvalylglutamylglutaminylcysteinylcyste- inylthreonylserylisoleucylcysteinylserylleucyltyrosylgul- taminylleucylglutamylasparaginyltyrosylcysteinylaspar- agine. An identical sequence was proposed for the reduced A chain of porcine insulin.6 The total synthesis of the human insulin A chain in the S-sul- fonated form is presented in the following paper7 and the preparation of two key intermediates used for that synthesis is described in the present report. One of these intermediates is the hydrazide of N-carboben- zoxyglycyl-L-isoleucyl-L-valyl - 7 - / - butyl -L - glutamyl - L - glutaminyl-S-benzyl-L-cysteinyl-S-benzyl-L-cysteinyl-L- threonyl-L-serine (I), the nonapeptide fragment which contains the amino acid sequence found at the amino terminus of the A chain, and the other intermediate is N - carbobenzoxy - L - isoleucyl - S - benzyl - L - cysteinyl - L - seryl-L - leucyl - L - tyrosyl - L - glutaminyl - L - leucyl - L - glu - tamyl-L-asparaginyl-L - tyrosy 1- S - benzyl - L - cysteinyl -L- asparagine ^-nitrobenzyl ester (XVI), the dodecapeptide