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Strategies in the Racemization-Free Synthesis of Polytripeptide Models of Collagen

  • Rao S. Rapaka
  • D. E. Nitecki
  • Rajendra S. Bhatnagar
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 86A)

Abstract

Synthesis of racemization-free sequential polypeptides is a major challenge to the peptide chemist. The loss of optical integrity at a single residue can drastically alter the properties of the polymer. We have investigated racemization in the synthesis of polytripeptide models of collagen. The conformational features of collagen are determined by a large imino content and the presence of Gly in every third position. Thus polymers of tripeptides containing Pro and Gly with an asymmetric residue A permit evaluation of the contribution of A to collagen conformation. in the synthesis of such polymers, the position of Pro in the tripeptide is of importance because of its variable reactivity at the N or C terminal residue. N-terminal Pro is more reactive but also sterically hinders polycondensation. Terminal Pro also participates in undesirable side reactions such as formation of urea or diketopiperazine derivatives and cyclization. Cyclization can be avoided by using concentrated solutions of monomer. Racemization occurs during the synthesis of OCl5Ph or ONp esters but not in the synthesis of ONSu esters. This, however, does not guarantee formation of optically pure products. Best results are obtained with ONSu esters and limited use of base during polymerization. Polymerization appears to be stereoselective since the largest molecular weight polymers are purest, smallest molecular weight products highly racemized.

Keywords

Active Ester Molecular Weight Polymer High Molecular Weight Polymer Sequential Polypeptide Active Amino Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Bell, J., Boohan, R., Jones, H. and Moore, R. (1975a) Sequential polypeptides. Part IX. The synthesis of two sequential polypeptide elastin models. Int. J. Peptide Protein Res. 7 227.Google Scholar
  2. Bell, J., Jones, J. and Webb, C., (1975b) Sequential polypeptides Part X. The synthesis of some sequential polypeptide collagen models with functional side chains. Int. J. Peptide Protein Res. 7 235.Google Scholar
  3. Bhatnagar, R. and Rapaka, R. (1976) Synthetic polypeptide models of collagen synthesis and applications in The Biochemistry of Collagen, G. N. Ramachandran, Ed., Chicago, Plenum Press, p. 479.Google Scholar
  4. Bloom, S., Dasgupta, S., Patel, R. and Blout, E., (1966) The synthesis of glycyl-L-prolylglycyl and glycyl-L-prolyl-L-alanyl oligopeptides and sequential polypeptides. J. Amer. Chem. Soc. 88 2035.CrossRefGoogle Scholar
  5. Bodanszky, M., Sheehan, J., Ondetti, M. and Lande, S. (1963) Glycine analogs of bradykinin. J. Amer. Chem. Soc. 85 991.CrossRefGoogle Scholar
  6. Bodanszky, M. and Ondetti, M. (1966) in Peptide Synthesis, New York, Interscience Publishers, p. 26.Google Scholar
  7. Bonora, G. and Toniolo, C. (1974) Sequential oligopeptides: Synthesis and characterization of the oligopeptides and polypeptides with the repeating sequence L-norvalyl-glycyl-L-proline. Biopolymers 13 1055.PubMedCrossRefGoogle Scholar
  8. Brack, A. and Spach, G. (1970) Nouvelles conformations de co-polypeptides ordonnes a base de L-alanine et de glycine, Comptes Rendus Acad. Sci. Ser. C. 271 916.Google Scholar
  9. Brown,F., DiCorato, A., Lorenzi, G. and Blout, E.,(1972) Synthesis & structural studies of two collagen analogues: Poly (L-Prolyl-L-Seryl-Glycyl) and Poly (L-Prolyl-L-Alanyl-Glycyl ). J. Mol. Biol. 63. 85.PubMedCrossRefGoogle Scholar
  10. Chakravarty, P., Mathur, K. and Dhar, M. (1973) Synthesis of poly (Glu-Ala-Ala-Ala-Ser) and Poly (Ala-Ala-Glu-Ala-Ser) as model receptors for acetylcholine. Indian J. Biochem. Biophysics 10. 233.Google Scholar
  11. Cowell, R. and Jones, J. (1971), Sequential polypeptides, Part I. Use of mono-esters of catechol in the synthesis of sequential polypeptides. J. Chem. Soc (C) 1082.Google Scholar
  12. Dale, J. and Titlestad, K. (1969) Cyclic oligopeptides of sarcosine (N-methylglycine), J. Chem. Soc. Chem. Commun. 656.Google Scholar
  13. Deber, C., Torchia, D. and Blout, E. (1971) Cyclic peptides I. Cyclic (tri-L-prolyl) and derivatives: Synthesis and molecular conformation from nuclear magnetic resonance, J. Amer. Chem.Soc 93 4893.CrossRefGoogle Scholar
  14. DeTar, D. and Estrin, N., (1966) An optically pure sequence peptide Poly.Gly.Gly.Phe. Tetrahedron Lett. 48 5985.CrossRefGoogle Scholar
  15. DeTar, D., Silverstein, R. and Rogers, F. Jr. (1966) Reactions of carbodiimides. III. The reactions of carbodiimides with peptide acids, J. Amer. Chem. Soc. 88 1024.CrossRefGoogle Scholar
  16. DeTar, D., Albers, R. and Gilmore, F. (1972) Synthesis of sequence peptide polymers related to collagen, J. Org.Chem. 37 4377.PubMedCrossRefGoogle Scholar
  17. Doyle, B., Traub, W., Lorenzi, G., Brown, F. III, Blout, E. (1970) Synthesis and structural investigation of poly (L-alanyl-L-alanyl-glycine) J. Mol. Biol. 51 47.PubMedCrossRefGoogle Scholar
  18. Fairweather, R. and Jones, J., (1972) Sequential polypeptides. Part IV. The synthesis of poly-(L-alanyl-glycyl-L-proline) and its stereoisomers. J. Chem.Soc.Rerkin Trans. I 1908.Google Scholar
  19. Fairweather, R. and Jones, H., (1973) The antigenicity of sequential polypeptides I. The synthesis of some sequential collagen models. Immunology 25 241.PubMedGoogle Scholar
  20. Goodman, M. and Steuben, K., (1959) Peptide synthesis via amino acid active esters, J. Amer. Chem. Soc. 81 3980.CrossRefGoogle Scholar
  21. Halpern, B. and Nitecki, D. (1967) The deblocking of t-butyloxy-carbonyl peptides with formic acid. Tetrahedron Lett. 31 3031.PubMedCrossRefGoogle Scholar
  22. Hardy, P., Rydon, H. and Thompson, R. (1972) Polypeptides part XVII. The synthesis of some sequential polypeptides of γ-benzyl D-glutamate and L-leucine. J. Chem. Soc.Perkins Trans. 15.Google Scholar
  23. Holme, D. and Goldberg, D., (1975) Coupled optical rate determinations of amino acid oxidase activity, Biochim. Biophys. Acta 377 61.PubMedGoogle Scholar
  24. Johnson, B. (1974) Synthesis, structure and biological properties of sequential polypeptides J. Pharm. Sci 63 313.PubMedCrossRefGoogle Scholar
  25. Katakai, R., Oya, M. and Iwakura, Y. (1975) Synthesis and conformational study of sequential polypeptides, (L-Ala-L-Val-Gly)n and (L-Val-L-Ala-Gly)n Biopolymers 14 1315.PubMedCrossRefGoogle Scholar
  26. Kopple, K., (1972) Synthesis of cyclic peptides J. Pharm. Sci. 61 1345.CrossRefGoogle Scholar
  27. Kovacs, J., Giannotti, R. and Kapoor, A. (1966) Peptides with known repeating sequence of amino acids. Synthesis of poly-L-glutamyl-L-alanyl-L-phenylalanine pentachlorophenyl active ester. J. Amer. Chem. Soc. 88 2282.CrossRefGoogle Scholar
  28. Kovacs, J., Schmit, G. and Ghatak, U. (1968) Polypeptides with known repeating sequences of amino acids. Comparison of several methods used for the synthesis of poly-y-D and L-glutamylglycine and investigation of its serological reaction with antianthrax immune serum. Biopolymers 6 817.PubMedCrossRefGoogle Scholar
  29. Kovacs, J., Meyers, G., Johnson, R., Giannotti, R., Cortegiano, H. and Roberts, J. (1972) in Progress in Peptide Research Vol. 2, p. 185–193, Saul Lande, Ed., Gordon and Breach, New York. “On the problem of racemization during the synthesis of sequential polypeptides”.Google Scholar
  30. Ramachandran, J., Berger, A. and Katchalski, E. (1971) Synthesis and physicochemical properties in aqueous solution of the sequential polypeptide poly (Tyr-Ala-Glu)n. Biopolymers 10 1829.PubMedCrossRefGoogle Scholar
  31. Rapaka, R. and Bhatnagar, R. (1975a) Synthesis of polypeptide models of collagen. Int. J. Peptide Protein Res. 7 119.CrossRefGoogle Scholar
  32. Rapaka, R. and Bhatnagar, R. (1975 b) Polypeptide models of collagen. Synthesis of (Pro-Pro-β-Ala)n. Int. J Peptide Protein Res 7 475.CrossRefGoogle Scholar
  33. Rapaka, R., Bhatnagar, R. and Nitecki, D. (1976a) Racemization in the synthesis of polytripeptide models of collagen. Biopolymers 15 317.PubMedCrossRefGoogle Scholar
  34. Rapaka, R., Bhatnagar, R. and Nitecki, D. (1976b) Racemization in the synthesis of sequential polypeptides using N-hydroxysuccinimide esters. Biopolymers 15 1585.PubMedCrossRefGoogle Scholar
  35. Rapaka, R. and Bhatnagar, R. (1976c) Polypeptide models of collagen: synthesis of (Pro-Pro-Ala)n and (Pro-Pro-Val)n. Int. J. Peptide Protein Res. 8 371.CrossRefGoogle Scholar
  36. Rothe (1965) Synthesis of cyclotri-L-prolyl, a cyclotripeptide having a nine membered ring, Angew. Chem. Int. Ed. 4 356.Google Scholar
  37. Stewart, F. (1965) The synthesis and polymerization of peptide p-nitrophenyl esters, Aust. J. Chem. 18 887.CrossRefGoogle Scholar
  38. Tomida, I., Kayahara, H. and Iriye, R., (1973a) Racemization in the coupling reaction, Pro-Val + Pro with the activated ester methods, Agr. Biol. Chem 37 2549.CrossRefGoogle Scholar
  39. Tomida, I., Kayahara, H. and Iriye, R. (1973b) Racemization in the coupling reaction with the several methods beside the activated ester. Methods Agr. Biol. Chem. 37 2557.CrossRefGoogle Scholar
  40. Urry, D., Mitchell, L., Ohnishi, T. and Long, M., Proton and carbomagnetic resonance studies of the synthetic poly-pentapeptide of elastin. J. Mol. Biol. 96 101.Google Scholar
  41. Zeiger, A., Lange, A. and Maurer, P. (1973) Synthesis of two sequential polypeptides by dispersion in benzene and their circular dichroism spectra in aqueous solution: poly (L-Glu-L-Lys-L-Ala-Gly) and Poly (L-Ala-D-Glu-L-Lys-D-Ala-Gly). Biopolymers 12 2135.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • Rao S. Rapaka
    • 1
  • D. E. Nitecki
    • 1
  • Rajendra S. Bhatnagar
    • 1
  1. 1.University of California, San FranciscoSan FranciscoUSA

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