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Through an Amino Acid Side Chain: [8-Lysine]-Vasopressin

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Through an Amino Acid Side Chain: [8-Lysine]-Vasopressin Proc. Nat. Acad. Sci. USA Vol. 68, No. 5, pp. 1006-1009, May 1971 Solid-Phase Synthesis with Attachment of Peptide to Resin through an Amino Acid Side Chain: [8-Lysine]-Vasopressin JOHANNES MEIENHOFER AND ARNOLD TRZECIAK The Children's Cancer Research Foundation and Department of Biological Chemistry, Harvard Medical School, Boston, Massachusetts 02115 Communicated by Hans T. Clarke, March 1, 1971 ABSTRACT It is proposed that the scope of solid-phase of amino acids or peptides (2). We wish to suggest that attach- peptide synthesis could be considerably broadened by attaching peptides to the solid-phase through functional ment to a solid-phase through functional groups in side- side-chain groups rather than through the commonly chains of amino acids could, (a) considerably broaden the used a-carboxyl groups. Side-chain attachment offers the chemical scope of such investigations, and (b) eliminate any use of a large variety of chemical linkages to solid sup- danger of partial racemization of the amino acid residue ports. Attachment through the e-amino group of the serving as link to the solid phase, lysine residue to a polystyrene resin has been applied to a and thereby remove solid-phase synthesis of lysine-vasopressin. Na-tert-butyl- certain restrictions on reaction conditions during the attach- oxycarbonyl-L-lysyl-glycinamide was condensed with ment. chloroformoxymethyl polystyrene-2% divinylbenzene We have investigated the attachment of lysine-containing resin. After removal of the Na-protecting tert-butyloxycar- peptides to a solid-phase through the e-amino group of the bonyl group, the peptide chain was elongated by standard Merrifield procedures to give Tos-Cys(Bzl)-Tyr-Phe-Glu- lysine residue. For this purpose chloroformoxymethyl poly- (NH2) - Asp(NH2) - Cys(Bzl) - Pro - Lys(Z - resin) - Gly- styrene-2% divinylbenzene 1 (8) was prepared from the NH2. Cleavage from the resin with HBr in dioxane or tri- standard Merrifield resin (chloromethyl polystyrene-2% fluoroacetic acid gave a partially protected nonapeptide hydrobromide. For purification, it was converted into a (-CH2-CH-)n (2% crosslinked) fully protected peptide by treatment with benzyl p-nitro- phenyl carbonate and crystallized. Deprotection by sodium in liquid ammonia, oxidative cyclization, IRC-50 0 desalting, and ion-exchange chromatography gave lysine- vasopressin with high potency in a rat-pressor assay. CH2-O-C-Cl The solid-phase method of peptide synthesis, developed by 1 Merrifield (1, 2), makes possible the chemical syntheses of divinylbenzene) via acetoxymethyl and hydroxymethyl proteins. Synthetic achievements to date include syntheses of intermediates (17). Treatment of 1 with carboxyl-protected bovine insulin (3) in 1966, an analog of horse heart cytochrome Na-tert-butyloxycarbonyl-lysine derivatives gave resin-bound c (4) and bovine pancreatic ribonuclease A (5) in 1969, and N6-benzyloxycarbonyl-type derivatives, 4. human growth hormone (6) in 1970. The advantages of the solid-phase method lie in (a) unprecedented speed, (b) sim- R-(J~-CH2-O-C=IO plicity of operation, (c) elimination of solubility problems, (d) minimal danger of racemization, and (e) possibility for NH automation. However, at its present state of development, the (CH2)4 procedure suffers from several serious shortcomings. In- complete peptide-bond formation (a), potentially occurring in Boc-NH-CH-CO--R' each peptide-coupling step, results in so-called failure se- quences and truncated sequences (7). The reagents (b) that R, (-CH2-CHt),X -2 (2% crosslinked) must be used to remove the final product from the solid sup- R', 0-alkyl, peptide port often give incomplete cleavage and (or) partial degrada- 4 tion of the peptide. Analytical methods (c) sensitive enough to accurately monitor the process and to assess the purity of Side-chain attachment allows the use of the proven strategy the products are not yet available. of stepwise chain elongation, in the direction from the C- Some of the many efforts to improve the solid-phase method terminal toward the N-terminal*, by adding one N-protected have focused on variations of the solid-phase (1, 8-16), or on amino acid at a time. Completed peptides were detached from facilitating formation of the commonly used benzyl-ester bond (17-19) between the starting C-terminal amino acid and the standard resin (chloromethyl polystyrene-2% divinyl- *A solid-phase synthesis of a dipeptide in opposite direction the to the (starting from the N-terminal amino acid) on resin (1) was re- benzene). In all of these investigations, attachment ported by Letsinger and collaborators (8). To prepare larger pep- solid-phase has been made through the a functional groups tides, a completely racemization-free method would be required for peptide bond formation. The use of the azide method for Abbreviations follow the rules of the IUPAC-IUB Commission this reversed solid-phase procedure was studied recently by Felix on Biochemical Nomenclature, in Biochemistry, 5, 1445, 2485 and Merrifield (8) and was judged inadequate because of mar- (1966); 6, 362 (1967); J. Biol. Chem., 241, 2491 (1966). ginal yields. 1006 Downloaded by guest on October 1, 2021 Proc. Nat. Acad. Sci. USA 68 (1971) Solid-phase Synthesis by Side-Chain-Link 1007 the resin support of type 4 under somewhat milder conditions C6H4OH C6H5 I I than those required for the cleavage of the standard benzyl NIl2 0 CtH2 0 OH2 estei bonding (20,21). HBr in dioxane gave good results, as did HBr in trifluoroacetic acid (20), which cleaved such bonds CH2-QH--C-NH-CH-C-NH-CH I 1 2 3 within one-half of the commonly required time. S C=° To examine the practical usefulness of this type of side- S 0 O NH chain attachment to the solid phase, the neurohypophyseal 1 6 11 114 1 hormone [8-lysinel-vasopressin (Fig. 1) was synthesized. CH2-CH-NH-C-CH-NH-C-CH-(CH)-CONH2 The C-terminal dipeptide derivative, Na-tert-butyloxycar- I I C= OH2 bonyl-NE-benzyloxycarbonyl-ilysyl-glycinamide (3) was cat- alytically hydrogenated to yield the free e-amino group and CH2-N 0 CONH2 0 \7 11 8 1 9 condensed with 1. For chain elongation, the general proce- CH-C-NH-CH-C-NH-CH2-OONH2 dure (22) for solid-phase synthesis was used execpt that (23) the reaction times were generally longer and the N-protecting CH2-CH2 CH2 groups were removed from the asparagine and glutamine components by treatment with anhydrous trifluoroacetic acid CH2CH2CH2NH, (24). Dicyclohexylcarbodiimide (25) was used as the cou- Fig. 1. The structure of [8-Lysine]-vasopresin. pling reagent for tert-butyloxycarbonyl-iproline (26, 27), tert- butyloxycarbonyl-i4phenylalanine (26, 27), tert-butyloxy- bonding to the solid phase, which would allow the removal of carbonyl-ityrosine (26, 27), and S-benzyl-N-tosyl-icysteine the completed peptide by milder treatments than the acido- (28, 29). The remaining amino acid residues were introduced lytic reactions presently used, is strikingly apparent in the into the growing peptide chain via active esters, i.e., S-benzyl- very recent solid-phase synthesis of human growth hormone N-tert-butyloxycarbonyl-L-cysteine p-nitrophenyl ester (30), (6), in which considerable activity was lost at this penultimate tert-butyloxycarbonyl-i>asparagine p-nitrophenyl ester (31), step of a total of 190 operational stages. The type of bonding and tert-butyloxycarbonyl-L-glutamine p-nitrophenyl ester used in this work allowed somewhat milder cleavage condi- (32). HBr in dioxane or in trifluoroacetic acid (21) was used tions compared with the standard Merrifield benzyl ester for cleavage of the completed peptide (5) from the solid sup- cleavage, but acidolytic treatment was still required. However, port to give the hydrobromide of S-benzyl-N-tosyl-L-cys- side-chain attachment offers other potential alternatives, e.g., teinyl-L-tyrosyl - L- phenylalanyl- iglutaminyl-iasparaginyl- disulfide bonding through cysteine residues, or utilization of S-benzyl-iocysteinyl-i-prolyl-i1lysyl-glycinamide (6), which the hydroxyl functions in serine, threonine, or tyrosine resi- was purified by repeated washing and reprecipitating. Total dues (37). yields, based on the dipeptide content of the starting resin, EXPERIMENTAL were 20-25% in several syntheses. These yields were similar to those obtained in a standard solid-phase synthesis The methods used in this work have been recently de- of lysine-vasopressin (33). The hormone, prepared from 6 by scribed in detail (23). deprotection and oxidative cyclization, possessed 40-130 Chloroformoxymethyl polystyrene- units/mg of activity by a rat-pressor assay for different 2% divinylbenzene resin (1) batches purification gave synthesized. Chromatographic Chloromethyl (70 g) (1) lysine-vasopressin with iat-pressor potencies of 180-190 polystyrene-2%divinylbenzene containing 2.14 meq of Cl/g, was converted into the acetoxy- the activity remained constant on repeated chro- units/mg; methyl polymer (77.4 g) [IR (KCl) 1735 (C=0)] bytreatment To obtain highly active hormone from 6, we took matography. with potassium acetate (147 g) in for advantage of the demonstrated efficacy (34) of crystallization benzyl alcohol (500 ml) 50 hr at 80°C (17). The product was saponified by refluxing a of protected nonapeptides from organic solvents to remove suspension in benzyl alcohol (300 ml) for 5.5 hr with 6 N impurities, previously exploited in the solid-phase syntheses of methanolic NaOH (300 ml) to give hydroxymethyl poly- lysine-vasopressin (33) and arginine-vasopressin (23). 6 was styrene-2% divinylbenzene [72.4 g; IR (KCl) no absorption converted into a fully protected derivative by treatment with at 1735] (17). Treatment (50 g) with 20% phosgene in benzyl p-nitrophenyl carbonate (35). The eamino group of the benzene (370 ml) for 5.5 hr at 20°C, followed by washing with lysine residue and the hydroxyl group of the tyrosine residue dry benzene and ether, gave 1, 54.1 g, containing 1.27 meq of were both acylated to give S-benzyl-N-tosyl-icysteinyl-O- Cl/g, IR (KCl) 1735 (C=0).
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