AbstractPreviously reported studies of the iodine oxidation of S‐trityl‐cysteine peptides and S‐acetamidomethyl‐cysteine peptides, leading directly to cystine peptides, have been extended. Detailed investigations have been made of the reactivities of the S‐trityl and the S‐acetamidomethyl group towards iodine in various solvents. In chloroform, methylene chloride, trifluoroethanol, and hexafluoroisopropyl alcohol the differences in the reaction rates of the two groups have been found to be extremely large, allowing the selective conversion of the tritylthio groups to disulfides in the presence of the S‐acetamidomethyl derivatives. In a second group of solvents, consisting of methanol, acetic acid, dioxane, and mixtures of these solvents with water, simultaneous iodine oxidation of S‐trityl‐ and S‐acetamidomethyl‐cysteine peptides leads to a preferential combination of these two residues, resulting in predominantly asymmetrical cystine derivatives. ‐ The suitability of the two sulfur‐protecting groups in the synthesis of cyclic cystine peptides has been assessed. ‐ Possible reaction mechanisms are discussed. ‐ The scope and limitations of iodine oxidation in peptide synthesis have been studied.The applicability of the method has been demonstrated in the preparation of the open‐chain asymmetrical cystine peptide 5, the protected somatostatin derivative 17, and the A(1–13) segment 19 of human insulin, previously employed in the total synthesis of this hormone.

We synthesized seventeen analogues of human insulin, applying the principle of stepwise, selective formation of the disulphide bonds. Most of these analogues only differ from human insulin in the replacement of a single amino acid in positions 2, 5, 6, 7, 8 and 11 of the A chain and 5, 7, 13 and 16 of the B-chain. The influence of these modifications on the physicochemical properties of the analogues is discussed. Eight analogues could be crystallized. All the analogues produce the same biological effects as insulin, but differ markedly in their potency. In isolated fat cells in vitro, [HisA8]insulin showed a relative potency of 2.46 in stimulating glucose oxidation (human insulin = 1), whereas [D-CysA6,A11]insulin had a potency of only 0.00027. Very low potency was observed when IleA2 or the half-cystines A6, A7, A11 or B7 were modified. Replacement of the invariant GlnA5 by alanine only reduced potency slightly. All the analogues are full agonists. The effects of the analogues on glucose oxidation and lipolysis are correlated, supporting the view that they are mediated by a common receptor on the fat-cell membrane. Hypoglycaemic potencies in the rat were similar to potencies in vitro. As expected, no correlation was demonstrable between antiserum binding--measured in the radioimmunoassay--and biological activity. Several results of this investigation are difficult to reconcile with the current view regarding the structure-activity relationship of insulin which appears to require further refinement.

Five analogs of human insulin with d -Cys in different positions (A 6 , A 7 , A 11 , A 6+11 , B 7 ) have been synthesized by the fragment condensation approach, combined with selective disulfide formation. All of them have physicochemical properties noticeably different from those of human insulin. They possess very low biological activity (0.03−1.2%, glucose oxidation in rat fat cells). In contrast, the potency for antibody binding ranges from 7 to 70% of that of insulin. The two analogs with d -Cys in positions A 6 and A 7 have been obtained in crystalline form.

Chemischer InformationsdienstVolume 7, Issue 41 Natural Products ChemInform Abstract: SYNTHESIS OF HUMAN INSULIN. II. PREPARATION OF THE A(1-13) CYCLIC FRAGMENT PETER SIEBER, PETER SIEBERSearch for more papers by this authorBRUNO KAMBER, BRUNO KAMBERSearch for more papers by this authorKAREL EISLER, KAREL EISLERSearch for more papers by this authorALBERT HARTMANN, ALBERT HARTMANNSearch for more papers by this authorBERNHARD RINIKER, BERNHARD RINIKERSearch for more papers by this authorWERNER RITTEL, WERNER RITTELSearch for more papers by this author PETER SIEBER, PETER SIEBERSearch for more papers by this authorBRUNO KAMBER, BRUNO KAMBERSearch for more papers by this authorKAREL EISLER, KAREL EISLERSearch for more papers by this authorALBERT HARTMANN, ALBERT HARTMANNSearch for more papers by this authorBERNHARD RINIKER, BERNHARD RINIKERSearch for more papers by this authorWERNER RITTEL, WERNER RITTELSearch for more papers by this author First published: October 12, 1976 https://doi.org/10.1002/chin.197641351AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume7, Issue41October 12, 1976 RelatedInformation

Synthesis of human insulin. II. Preparation of the A(1–13) fragment.The present report gives a detailed account of the synthesis of the protected tridecapeptide A(1–13), BocGlyIleValGlu(OBut)Gln Ser(But)LeuOH (20), an essential intermediate in the recently published total synthesis of human insulin [1]. The main feature in the synthesis of 20 was the specific formation of a disulfide bond between A6 and A11 in the presence of an additional cysteine residue (A7). The selective ring closure was accomplished with the segment A(6–13), HCys(Trt)Cys(Acm)Thr(But)Ser(But)IleCys(Trt)Ser(But)LeuOH (18), which was obtained by way of conventional synthesis routes. Treatment of 18 with iodine in trifluoroethanol formed the desired disulfide bridge from the two S‐trityl‐cysteine residues without affecting the S‐acetamidomethyl‐protected cysteine A7. A final azide coupling with the N‐terminal derivative A(1–5) (3) provided the tridecapeptide fragment 20 as a crystalline compound.