Synthesis and pharmacology of novel analogues of oxytocin and deaminooxytocin: Directed methods for the construction of disulfide and trisulfide bridges in peptides

Journal of Medicinal Chemistry

Volumn 40, Issue 6, 1997, Pages 864-876

  Chen, Lin ^a   Zoulíková, Ivana ^b   Slaninová, Jiřina ^b   Barany, George ^a,c  

^a University of Minnesota   (United States)

^b INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY   (Czech Republic)

^c UNIVERSITY OF MINNESOTA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 MERCAPTOPROPIONIC ACID; ARGIPRESSIN; CYSTEINE; DEMOXYTOCIN; DISULFIDE; MACROGOL; MEMBRANE RECEPTOR; NEUROHYPOPHYSIS HORMONE; NONAPEPTIDE; OXYTOCIN DERIVATIVE; UTEROTONIC AGENT;

ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; CYCLIZATION; DISULFIDE BOND; DRUG ACTIVITY; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; NONHUMAN; PEPTIDE SYNTHESIS; PRESSOR RESPONSE; RAT; RECEPTOR AFFINITY; UTERUS CONTRACTION;

ANIMALS; CYSTEINE; DISULFIDES; DRUG STABILITY; FEMALE; MAGNETIC RESONANCE SPECTROSCOPY; OLIGOPEPTIDES; OXYTOCIN; PEPTIDES, CYCLIC; RATS; RATS, WISTAR; SULFHYDRYL COMPOUNDS; SULFIDES; UTERINE CONTRACTION;

EID: 0030939626     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9607156     Document Type: Article

References (76)

1. Chen, L.; Munson, M. C.; Tejbrant, J.; Barany, G. Synthesis of trisulfide-eontaining peptides. Poster P-110; Presented at the Fourteenth American Peptide Symposium, Columbus, OH, June 18-23, 1995.
2. Barany, G.; Chen, L. Recent Progress on the Formation of Sulfur-Sulfur Bridges in Peptides. In Innovations and Perspectives in Solid Phase Synthesis and Combinatorial Chemical Libraries, 1995; Epton, R., Ed.; Mayflower Worldwide; Birmingham, England, 1996; pp 181-186.
3. Review; Field, L. Disulfides and Polysulfides. In Organic Chemistry of Sulfur; Oae, S., Ed.; Plenum: New York, 1977; pp 303-382.
4. Review: Andreu, D.; Albericio, F.; Solé, N. A.; Munson, M. C.; Ferrer, M.; Barany, G. Formation of Disulfide Bonds in Synthetic Peptides and Proteins. In Methods in Molecular Biology: Peptide Synthesis Protocols; Pennington, M. W., Dunn, B. M., Eds.; Humana: Totowa, NJ, 1994; Vol. 35, pp 91-169.
5. Mott, A. W.; Barany, G. A New Method for the Synthesis of Unsymmetrical Trisulfanes. Synthesis 1984, 657-660 and references cited therein.
6. Derbesy, G.; Harpp, D. N. A Simple Method to Prepare Unsymmetrical Di- Tri- and Tetrasulfides. Tetrahedron Lett. 1994, 35, 5381-5384 and references cited therein.
7. For a review of this and related compounds of interest, see: Block, E. The Organosulfur Chemistry of the Genus Allium - Implications for the Organic Chemistry of Sulfur. Angew. Chem., Int. Ed. Engl. 1992, 31, 1135-1178.
8. Sandy, J. D.; Davies, R. C.; Neuberger, A. Control of 5-Amino-laevulinate Synthetase Activity in Rhodopseudomonas spheroides. Biochem. J. 1975, 150, 245-257.
9. Safe, S.; Taylor, A. Sporidesmins. Part X. Synthesis of Polysulphides by Reaction of Dihydrogen Bisulphide with Bisulphides and Thiols. J. Chem. Soc. C 1970, 432-435.
10. Golik, J.; Clardy, J.; Bubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.-i.; Doyle, T. W. Esperamicins, a Novel Class of Potent Antitumor Antibiotics. 2. Structure of Esperamicin X. J. Am. Chem. Soc. 1987, 109, 3462-3464.
11. Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.; Morton, G, O.; McGahren, W. J.; Borders, D. B. Calichemicins, a Novel Family of Antitumor Antibiotics. 1. Chemistry and Partial Structure of Calichemicin. J. Am. Chem. Soc. 1987, 109, 3466-3468.
12. Haseltine, J. N.; Cabal, M. P.; Mantlo, N. B.; Iwasawa, N.; Yamashita, D. S.; Coleman, R. S.; Danishefsky, S. J.; Schulte, G. K. Total Synthesis of Calicheamicinone: New Arrangements for Actuation of the Reductive Cycloaromatization of Aglycon Congeners. J. Am. Chem. Soc. 1991, 113, 3850-3866.
13. 1. Oxidative Functionalization of the 13-Ketobicyclo[7.3.1]tridecenediyne Core Structure: Construction of the Allylic Trisulfide Trigger. J. Am. Chem. Soc. 1992, 114, 2560-2567.
14. 1. J. Am. Chem. Soc. 1993, 115, 7625-7635.
15. Jespersen, A. M.; Christensen, T.; Klausen, N. K.; Nielsen, P. F.; Sørensen, H. H. Characterisation of a trisulphide derivative of biosynthetic human growth hormone produced in Escherichia Coli. Eur. J. Biochem. 1994, 219, 365-373.
16. Andersson, C.; Edlund, P. O.; Gellerfors, P.; Hansson, Y.; Holmberg, E.; Hult, C.; Johansson, S.; Kördel, J.; Lundin, R.; Mendel-Hartvig, I.; Norén, B.; Wehler, T.; Widmalm, G.; Öhman, J. Isolation and characterization of a trisulfide variant of recombinant human growth hormone formed during expression in Escerichia Coli. Int. J. Pept. Protein Res. 1996, 47, 311-321.
17. Fletcher, J. C.; Robson, A. The Occurrence of Bis-(2-Amino-2-Carboxyethyl) Trisulphide in Hydrolysates of Wool and Other Proteins. Biochem. J. 1963, 87, 553-559.
18. Ghadimi, M.; Hill, R. R. Facile Trisulphide Formation in the Thermolysis of N,N′-Diacetyl-L-cystine Bismethylamide, an Excellent Model for Protein-bound Cystine. J. Chem. Soc., Chem. Commun. 1991, 903-904.
19. Parmentier, B.; Moutiez, M.; Tartar, A.; Sergheraert, C. Preparation of Trisulphide Derivatives of Cystine and their Formation as By-products during Peptide Synthesis. Tetrahedron Lett. 1994, 35, 3531-3534.
20. Mott, A. W.; Słomczyńska, U.; Barany, G. Formation of Sulfur-Sulfur Bonds During Solid-Phase Peptide Synthesis: Application to the Synthesis of Oxytocin. In Forum Peptides Le Cap d'Agde 1984; Castro, B., Martinez, J., Eds.; Les Impressions Dohr: Nancy, France, 1986; pp 321-324.
21. Compare to: Lundin, R. H. L.; Norén, B. E.; Edlund, P. O. A Convenient Method for the Synthesis of Peptide Trisulfides. Tetrahedron Lett. 1994, 35, 6339-6342. These authors' method was applied to a partial sequence related to the discovery described in ref 16. To the best of our knowledge, other than our own earlier work (ref 20), this is the only reported synthesis of a peptide trisulfide in the literature.
22. The preliminary assays reported in ref 20 have been extended extensively in the present study. For examples of the greatly reduced potency of oxytocin analogues with 21-membered rings, see refs 23-25.
23. Jarvis, D.; du Vigneaud, V. The Effect of Decreasing the Size of the Ring Present in Deamino-oxytocin by One Methylene Group on Its Biological Properties. J. Biol. Chem. 1967, 242, 1768-1771 and references cited therein.
24. Kawano, K.; Kobayashi, Y.; Kyogoku, Y.; Morikawa, T.; Sakakibara, S. Conformational Studies of Oxytocin Analogues With Different Ring Sizes. Biochim. Biophys. Acta 1979, 578, 87-95 and references cited therein.
25. 1. J. Med. Chem. 1976, 19, 250-254 and references cited therein.
26. Barany, G.; Merrifield, R. B. A New Amino Protecting Group Removable by Reduction. Chemistry of the Dithiasuccinoyl (Dts) Function. J. Am. Chem. Soc. 1977, 99, 7363-7365.
27. Barany, G.; Merrifield, R. B. Solid-Phase Peptide Synthesis. In The Peptides; Gross, E., Meienhofer, J., Eds.; Academic: New York, 1979; Vol. 2, pp 1-284.
28. Albericio, F.; Hammer, R. P.; García-Echeverría, C.; Molins, M. A.; Chang, J. L.; Munson, M. C.; Pons, M.; Giralt, E.; Barany, G. Cyclization of disulfide-containing peptides in solid-phase synthesis. Int. J. Pept. Protein Res. 1991, 37, 402-413 and references cited therein.
29. Munson, M. C.; Barany, G. Synthesis of α-Conotoxin SI, a Bicyclic Tridecapeptide Amide with Two Disulfide Bridges: Illustration of Novel Protection Schemes and Oxidation Strategies. J. Am. Chem, Soc. 1993, 115, 10203-10210 and references cited therein.
30. Brois, S. J.; Pilot, J. F.; Barnum, H. W. A New Pathway to Unsymmetrical Disulfides. The Thiol-Induced Fragmentation of Sulfenyl Thiocarbonates. J. Am. Chem. Soc. 1970, 92, 7629-7631.
31. Schroll, A. L.; Barany, G. A New Protecting Group for the Sulfhydryl Function of Cysteine. J. Org. Chem. 1989, 54, 244-247.
32. α-9-Fluorenylmethyloxycarbonyl (Fmoc) Strategy of Peptide Synthesis. J. Org. Chem. 1992, 57, 3013-3018.
33. Munson, M. C.; Lebl, M.; Slaninová, J.; Barany, G. Solid-Phase Synthesis and Biological Activity of the Parallel Dimer of Deamino-Oxytocin. Pept. Res. 1993, 6, 155-159.
34. 19 disulfide bridge.) Helv. Chim. Acta 1973, 56, 1370-1381.
35. Hiskey, R. G.; Muthukumaraswamy, N.; Vunnam, R. R. Sulfur-Containing Polypeptides XVII. The S-Carbomethoxysulfenyl Derivative as a Protective Group for Cysteine. J. Org. Chem. 1975, 40, 950-953.
36. Kemp, D. S.; Carey, R. I. Synthesis of a 39-Peptide and a 25-Peptide by Thiol Capture Ligations: Observation of a 40-Fold Rate of Acceleration of the Intramolecular O,N-Acyl-Transfer Reaction between Peptide Fragments Bearing only Cysteine Protective Groups. J. Org. Chem. 1993, 58, 2216-2222 and previous contributions from this research team.
37. Veber, D. F.; Milkowski, J. D.; Varga, S. L.; Denkewalter, R. G.; Hirschmann, R. Acetamidomethyl. A Novel Thiol Protecting Group for Cysteine. J. Am. Chem. Soc. 1972, 94, 5456-5461.
38. Barany, G.; Schroll, A. L.; Mott, A. W.; Halsrud, D. A. A General Strategy for Elaboration of the Dithiacarbonyl Functionality, -(C=O)SS-: Application to the Synthesis of Bis(chlorocarbonyl)-disulfane and Related Derivatives of Thiocarbonic Acids. J. Org. Chem. 1983, 48, 4750-4761. This paper describes preparations of organosulfur reagents and substrates for model reactions and also provides literature references and spectra to those compounds which were previously known, i.e., Cl(C=O)SCl (5), MeO-(C=O)SCl (6), EtSS(C=O)Cl, EtSS(C=O)OMe, EtSSEt, EtSSSEt, and EtSSSSEt.
39. Böhme, H.; Steudel, H.-P. Über unsymmetrische Diacylsulfide und ihre Spaltung mit Chlor oder Brom. (Unsymmetrical Diacyl Sulfides and Their Fission by Chlorine or Bromine.) Liebigs Ann. Chem. 1969, 730, 121-132.
40. Böhme, H.; Brinkmann, M.; Steudel, H.-P. Gewinnung und Umsetzungen von Chlordisulfanylderivaten der Kohlensäure. (Preparation and reactions of chlorodisulfanyl derivatives of carbonic acid.) Liebigs Ann. Chem. 1981, 1244-1251.
41. Barany, G.; Mott, A. W. Chemistry of Bis(alkoxycarbonyl)-polysulfanes and Related Compounds. J. Org. Chem. 1984, 49, 1043-1051.
42. Schroll, A. L.; Barany, G. Novel Symmetrical and Mixed Carbamoyl and Amino Polysulfanes by Reactions of (Alkoxydichloromethyl)polysulfanyl Substrates with N-Methylaniline. J. Org. Chem. 1986, 51, 1866-1881.
43. Schroll, A. L.; Eastep, S. J.; Barany, G. Synthesis and Characterization of Methoxy(thiocarbonyl)sulfenyl Chloride. J. Org. Chem. 1990, 55, 1475-1479.
44. Albericio, F.; Kneib-Cordonier, N.; Biancalana, S.; Gera, L.; Masada, R. I.; Hudson, D.; Barany, G. Preparation and Application of the 5-(4-(9-Fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxyphenoxy)valeric Acid (PAL) Handle for the Solid-Phase Synthesis of C-Terminal Peptide Amides under Mild Conditions. J. Org. Chem. 1990, 55, 3730-3743.
45. Barany, G.; Solé, N. A.; Van Abel, R. J.; Albericio, F.; Selsted, M. E. Recent Advances in Solid Phase Peptide Synthesis. In Innovation and Perspectives in Solid Phase Synthesis. Polypeptides and Oligonucleotides 1992; Epton, R., Ed.; Intercept Ltd.: Andover, England, 1992; pp 29-38.
46. Barany, G.; Albericio, F.; Solé, N. A.; Griffin, G. W.; Kates, S. A.; Hudson, D. Novel polyethylene glycol-polystyrene (PEG-PS) graft supports for solid-phase peptide synthesis. In Peptides 1992, Proceedings of the Twenty-Second European Peptide Symposium; Schneider, C. H., Eberle, A. N., Eds.; Escom Science Publishers: Leiden, The Netherlands, 1993; pp 267-268.
47. Zalipsky, S.; Chang, J. L.; Albericio, F.; Barany, G. Preparation and applications of polyethylene glycol - polystyrene graft resin supports for solid-phase peptide synthesis. React. Polym. 1994, 22, 243-258.
48. Pseudodilution is defined by: Mazur, S.; Jayalekshmy, P. Chemistry of Polymer-bound o-Benzyne. Frequency of Encounter between Substituents on Cross-Linked Polystyrenes. J. Am. Chem. Soc. 1979, 101, 677-683. Also, see refs 20, 28, and 29 for precedents from our laboratory and ref 4 for a comprehensive literature review and perspective on the applications of this principle to the formation of sulfur - sulfur bonds in solid-phase synthesis.
49. 10 were made by reactions of piperidine with the corresponding chloroformate and dithiocarbonyl chloride, using methods described in ref 38.
50. Harpp has shown that simple methoxycarbonyl alkyl disulfanes, RSS(C=O)OMe, react in the presence of base to form trisulfanes, RSSSR (refs 50 and 51).
51. Harpp, D. N.; Granata, A. Organic Sulfur Chemistry. XXI. Trisulfide Formation by Alkoxide Decomposition of Sulfenyl-thiocarbonates. Tetrahedron Lett. 1976, 35, 3001-3004.
52. Harpp, D. N.; Granata, A. Cyclic Trisulfides by Alkoxide Decomposition of Bis(sulfenyl) Thiocarbonates. J. Org. Chem. 1979, 44, 4144-4148.
53. 1H NMR and comparison to standards. Other aspects of this experiment were as in ref 49.
54. 2 mixtures for Fmoc removal, but these deprotection cocktails are less preferred because (i) rates are slower and (ii) with time, a precipitate of piperidinium hydrochloride forms, which can lead to problems with automated synthesizers; see ref 55.
55. Review: Fields, G. B. Methods for Removing the Fmoc Group. In Methods in Molecular Biology: Peptide Synthesis Protocols; Pennington, M. W., Dunn, B. M., Eds.; Humana: Totowa, NJ, 1994; Vol. 35, pp 17-27.
56. In ref 20 which applied Boc chemistry, the resin-bound intermediate for cyclization had an N-terminal cysteine (originally protected by S-trityl) and an internal Cys(Scm) obtained by conversion of internal Cys(Acm) with MeO(C=O)SCl (6). For the experiment of Scheme 5, which relies on Fmoc chemistry, we observed ∼20% chain loss after treatment with Cl(C=O)SCl (5), and in addition, the final yield for cleavage of the PAL anchoring linkage was the unusually low 70%. These factors are in part contributing to the relatively lower overall isolated yields (based on the initial loading of resin) of cyclized peptides from these experiments.
57. +] (procedure matches the successful text experimental for oxytocin trisulfide, substituting Fmoc building block 4f for Boc building block 4e).
58. Kates, S. A.; Solé, N. A.; Beyermann, M.; Barany, G.; Albericio, F. Optimized Preparation of Deca(L-Alanyl)-L-Valinamide by 9-Fluorenylmethyloxycarbonyl (Fmoc) Solid-Phase Synthesis on Polyethylene Glycol-Polystyrene (PEG-PS) Graft Supports, with 1,8-Diazobicyclo[5.4.0]-undec-7-ene (DBU) Deprotection. Pept. Res. 1996, 9, 106-113 and references cited therein.
59. Ueki, M.; Amemiya, M. Removal of 9-Fluorenylmethyloxycarbonyl (Fmoc) Group with Tetrabutylammonium Flouride. Tetrahedron Lett. 1987, 28, 6617-6620.
60. As controls, peptide-resins after on-resin cyclization to create either deaminooxytocin or oxytocin (disulfides) were treated with piperidine - DMF (1:4, 2 × 10 min) prior to acidolytic release of peptide from the support. The HPLC profiles were identical with those obtained in the standard experiments (i.e., without piperidine exposure), from which we conclude that the cyclic disulfide bridges resist the base. Incidentally, we were unable to assess the stability of the deaminooxytocin trisulfide to piperidine - DMF because on-resin cyclization experiments to generate this species gave either no reaction or mixtures of di-, tri-, and tetrasulfides (discussed in text).
61. We suspect, but did not prove, that these fractions comprised principally the antiparallel dimer(s) of oxytocin. FABMS showed that one of the dimer fractions had four sulfurs and a separately resolved, later eluting dimer fraction had five sulfurs. Isomeric dimers (four sulfurs) of oxytocin were resolved and characterized by: Yamashiro, D.; Hope, D. B.; du Vigneaud, V. Isomeric Dimers of Oxytocin. J. Am. Chem. Soc. 1968, 90, 3857-3860.
62. Holton, P. A Modification of the Method of Dale and Laidlaw for Standardization of Posterior Pituitary Extract. Br. J. Pharmacol. 1948, 3, 328-334.
63. Munsick, R. A. Effect of Magnesium Ion on the Response of the Rat Uterus to Neurohypophysical Hormones and Analogues. Endocrinology 1960, 66, 451-457.
64. Pliška, V. Determination of Rate Constants of Drug Elimination from the Receptor Compartment by an Infusion Method: Neurohypophysical Hormones and Their Structural Analogues. Eur. J. Pharmacol. 1969, 5, 253-262. Our procedure is modified slightly, insofar as we anesthetize rats with urethane rather than with alcohol as described in the cited paper.
65. Krejčí, I.; Kupková, B.; Vávra, I. The Effect of Some 2-O-Alkyltyrosine Analogues of Oxytocin and Lysine Vasopressin on the Blood Pressure of the Rat, Rabbit, and Cat. Br. J. Pharmacol. Chemother. 1967, 30, 497-505.
66. Jošt, K.; Lebl, M.; Brtník, F. Tables of Analogs In Handbook of Neurohypophyseal Hormone Analogs; Jošt, K., Lebl, M., Brtník, F., Eds.; CRC: Boca Raton, FL, 1987; Vol. II, Part II, Chapter 6, pp 127-267.
67. Fahrenholz, F.; Hackenberg, M.; Müller, M. Identification of myometrial oxytocin-receptor protein. Eur. J. Biochem. 1988, 174, 81-85.
68. Fahrenholz, F.; Boer, R.; Crause, P.; Fritzsch, G.; Grzonka, Z. Interactions of Vasopressin Agonists and Antagonists with Membrane Receptors. Eur. J. Pharmacol. 1984, 100, 47-58.
69. Wanner, O.; Pliška, V. Oxytocin Effect on the Depolarized Rat Uterus: A Mathematical Approach Using System Identification. In Physical and Chemical Basis of Biological Information Transfer; Vassileva-Popova, J. G., Ed.; Plenum: New York, 1973; pp 21-34.
70. Gazis, D. J.; Roy, J.; Schwartz, I. L. Prolonged Responses by the Rat Uterus In Vivo to Deamino-Oxytocin Disproportionate to its Estimated Plasma Half-Life. Endocrinology 1980, 106, 805-810.
71. Barth, T.; Krejčí, I.; Vaněčková, J.; Jošt, K.; Rychlík, I. Prolonged Action of Deamino-Carba Analogues of Oxytocin on the Rat Uterus in Vivo. Eur. J. Pharmacol. 1974, 25, 67-70.
72. Haskell-Luevano, C.; Miwa, H.; Dickinson, C.; Hadley, M. E.; Hruby, V. J.; Yamada, T.; Gantz, I. Characterizations of the Unusual Dissociation Properties of Melanotropin Peptides from the Melanocortin Receptor, hMC1R. J. Med. Chem. 1996, 39, 432-435.
73. In contrast to the relative lack of knowledge about the oxytocin receptor and its interactions with appropriate peptide ligands, there exists a wealth of information of the binding of vasopressin to its various receptor subtypes (all G-protein-binding receptors, as is the oxytocin receptor). For the vasopressin receptors, relevant issues include lateral mobility, internalization, endocytosis, receptor desensitization, and recycling, as discussed further in refs 74-76.
74. Fishman, J. B.; Dickey, B. F.; Bucher, N. L. R.; Fine, R. E. Internalization, Recycling, and Redistribution of Vasopressin Receptors in Rat Hepatocytes. J. Biol. Chem. 1985, 260, 12641-12646.
75. 2 Receptors. J. Biol. Chem. 1992, 267, 1109-1115.
76. Jans, D. A.; Pavo, I. A Mechanistic Role for Polypeptide Hormone Receptor Lateral Moblity in Signal Transduction. Amino Acids 1995, 9, 93-109.