Totalsynthese von Humaninsulin unter gezielter Bildung der Disulfidbindungen. Vorläufige Mitteilung

Abstract

A preliminary account is given of a total synthesis of human insulin involving directed formation of the three disulfide bonds a t different stages of the fragment-condensation approach. The synthesis was facilitated by the application of two new methods for the selective removal of protecting groups. I n the first, two S-Trt-protected cysteine residues are converted to the disulfide without affecting S-Acm-protected cysteine residues. The second new method consists in a very mild, pH-controllcd, acidolysis of N(a)-Trt, leaving intact N(a)-Bpoc and other acid-labile protecting groups. The last step of the synthesis was the formation of the disulfide bridge between the Acm-protected cysteine residues A7 and B7 by iodine. Extensive countercurrent distribution yielded the synthetic hormone in pure form. It was compared and found to be identical with natural human insulin. Identification was achieved by means of thinlayer chromatography and electrophoretic procedures, as well as by comparing the pattern of breakdown by enzymes (finger-printing). The natural and synthetic hormones were crystallized under identical conditions. The synthetic human insulin was found to possess full biological activity in an in vitvo system.

Schutzgruppenstrategien in der organischen Synthese

“…Zunachst konnte der Tritylrest in Gegen-Schema 35. Verwendung saurelabiler Schutzgruppen mit abgestufter Labilitit in der Synthese des Humaninsulins nach P. Sieber et al[71]. Vorgehensweise sehr erfolgreich sein kann, hat sie sich in der Peptidchemie wegeii der Gefahr des Verlusts weiterhin benotigter Schutzgruppen nicht durchsetzen konnen.…”

Advanced Approaches in Insulin Delivery

“…A and B chains are then combined by air oxidation to produce human insulin. This insulin is described as chain recombinant bacterial (crb) [26][27][28][29][30].…”

My journey from wool research to insulin

“…The exhibit consists of written explanations, plots of the structure of insulin, small samples of some of the larger A and B chain peptides and the laboratory diary of Bremer with handwritten entries on all steps of his synthesis of the complete A chain, the combination with the synthetic B chain of Schnabel and Meienhofer and the data on the biological activity [56]. Strictly speaking, the first insulin syntheses were already outdated in 1974 when Rittel and his associates published their total synthesis of human insulin involving directed formation of the three disulfide bonds at different stages of the fragment-condensation approach [57].…”