Ralph F. Hirschmann

A super active cyclic hexapeptide analog of somatostatin

The cyclic hexapeptide, cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe), I, has been shown to have the biological properties of somatostatin. We now report structure-activity studies which optimize the potency of this cyclic hexapeptide series with the synthesis of cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), II, which is 50-100 times more potent than somatostatin for the inhibition of insulin, glucagon and growth hormone release. The hydroxyl group of tyrosine is seen to lend a 10-fold enhancement to the potency. Potency also is found to be correlated with hydrophobicity. II is found to improve the control of postprandial hyperglycemia in diabetic animals when given in combination with insulin. The analog is found to be quite stable in the blood and in the gastrointestinal tract, but the bioavailability after oral administration is only 1-3%. The biological properties and long duration of II should allow clinical evaluation of the inhibition of glucagon release as an adjunct to insulin in the treatment of patients with diabetes.

Synthesis of a proposed growth hormone releasing factor.

Abstract The synthesis of Val-His-Leu-Ser-Ala-Glu-Glu-Lys-Glu-Ala, isolated by Schally, et al. from porcine hypothalamus and reported by him to possess growth hormone releasing activity, is described. Similarities between this decapeptide and the amino-terminal sequence of the β-chain of porcine hemoglobin are pointed out. The syntheses of two analogs including the amino-terminal decapeptide of the β-chain of human hemoglobin are also described.

Tactics for Minimal Protection in Peptide Synthesis

Viel allgemeinerer Anwendung fahig ist, wie wir im folgenden zeigen, der Rest C6H5·CH2·O·CO der Benzylester-kohlensaure, kurz Carbobenzoxy-Rest (Cbzo) gennant; denn er lasst sich mit Hilfe des leicht zuganglichen Chlorids C6H5·CH2O·CO·Cl unschwer in Amino-sauren der verschiedensten Art einfuhren… und—was das Wesentliche ist—durch einfache katalytische Hydrierung im offenen Gefass in Form von Toluol und Kohlendioxyd wieder abspalten. (Max Bergmann and Leonidas Zervas, Chem. Ber. 65:1192, 1932)