Skip to main content
SpringerLink
Log in

Combinatorial chemistry: Mixture-based combinatorial libraries of acyclic and heterocyclic compounds from amino acids and short peptides

  • Chapter
Modern Methods of Drug Discovery

Part of the book series: EXS ((EXS,volume 93))

Abstract

Combinatorial chemistry is recognized worldwide as a powerful technology for drug discovery. This technology has gained wide acceptance by most pharmaceutical and biotechnology companies as well as academia [1-2]. The power of combinatorial chemistry lies in its ability to accelerate the drug discovery process through the rapid synthesis and subsequent screening of a larger number of compounds than previously possible. In a recent paper on combinatorial libraries, we reviewed the solid-phase chemistry used to prepare small molecule and heterocyclic mixture-based libraries [3]. Herein we provide a perspective on synthetic combinatorial approaches using mixture-based libraries, as well as an illustration of our work in the generation of libraries of acyclic and heterocyclic compounds from amino acids and/or short peptides.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anonymous (1998) Breakthrough of the year. Science 282: 2156–2161

    Google Scholar 

  2. Lebl M (1999) Parallel personal comments on “classical” papers in combinatorial chemistry. J Comb Chem 1: 3–24

    Article  PubMed  CAS  Google Scholar 

  3. Houghten RA, Pinilla C, Appel JR et al (1999) Mixture-based synthetic combinatorial libraries. J Med Chem 42: 3743–3778

    Article  PubMed  CAS  Google Scholar 

  4. Houghten RA (1985) General method for the rapid solid-phase synthesis of large numbers of peptides: Specificity of antigen-antibody interaction at the level of individual amino acids. Proc Natl Acad Sci USA 82: 5131–5135

    Article  PubMed  CAS  Google Scholar 

  5. Geysen HM, Meloen RH, Barteling SJ (1984) Use of a peptide synthesis to probe viral antigens for epitopes to a resolution of a single amino acid. Proc Natl Acad Sci USA 81: 3998–4002

    Article  PubMed  CAS  Google Scholar 

  6. Frank R, Doring R (1988) Simultaneous multiple peptide synthesis under continuous flow conditions on cellulose paper discs as segmental solid supports. Tetrahedron 44: 6031–6040

    Article  CAS  Google Scholar 

  7. Nefzi A, Ostresh JM, Houghten RA (1997) The current status of heterocyclic combinatorial libraries. Chem Rev 97: 449–472

    Article  PubMed  CAS  Google Scholar 

  8. Fruchtel JS, Jung G (1996) Organic chemistry on solid supports. Angew Chem Int Ed Engl 35: 17–42

    Article  Google Scholar 

  9. Fruchtel JS, Jung G (1996) Organic chemistry on solid supports — basic principles for combinatorial chemistry. In: Jung G (ed) Combinatorial peptide and nonpeptide libraries. Verlag Chemie, Weinheim, 19–78

    Chapter  Google Scholar 

  10. Zwick MB, Shen JQ, Scott J (1998) Phage-displayed peptide libraries. Curr Opin Biotechnol 9: 427–436

    Article  PubMed  CAS  Google Scholar 

  11. Koivunen E, Arap W, Valtanen H et al (1999) Tumor targeting with a selective gelatinase inhibitor. Nature Biotechnol 17: 768–774

    Article  CAS  Google Scholar 

  12. Geysen HM, Rodda SJ, Mason Ti (1986) A priori delineation of a peptide which mimics a discontinuous antigenic determinant. Mot Immunol 23: 709–715

    Article  CAS  Google Scholar 

  13. Houghten RA, Pinilla C, Blondelle SE et al (1991) Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery. Nature 354: 84–86

    Article  PubMed  CAS  Google Scholar 

  14. Lam KS, Salmon SE, Hersh EM et al (1991) A new type of synthetic peptide library for identifying ligand-binding activity. Nature 354: 82–84

    Article  PubMed  CAS  Google Scholar 

  15. Furka A, Sebestyen F, Asgedom M et al (1991) General method for rapid synthesis of multicomponent peptide mixtures. Int J Pept Protein Res 37: 487–493

    Article  PubMed  CAS  Google Scholar 

  16. Dooley CT, Chung NN, Wilkes BC et al (1994) An all D-amino acid opioid peptide with central analgesic activity from a combinatorial library. Science 266: 2019–2022

    Article  PubMed  CAS  Google Scholar 

  17. Lam KS, Lebl M, Krchnak V et al (1993) Discovery of D-amino-acid-containing ligands with selectide technology. Gene 137: 13–16

    Article  PubMed  CAS  Google Scholar 

  18. Blondelle SE, Takahashi E, Weber PA et al (1994) Identification of antimicrobial peptides using combinatorial libraries made up of unnatural amino acids. Antimicrob Agents Chemother 38: 2280–2286

    Article  PubMed  CAS  Google Scholar 

  19. Eichler J, Lucka AW, Houghten RA (1994) Cyclic peptide template combinatorial libraries: Synthesis and identification of chymotrypsin inhibitors. Pept Res 7: 300–307

    PubMed  CAS  Google Scholar 

  20. Blondelle SE, Perez-Pays E, Houghten RA (1996) Synthetic combinatorial libraries: Novel discovery strategy for identification of antimicrobial agents. Antimicrob Agents Chemother 40: 1067–1071

    PubMed  CAS  Google Scholar 

  21. Dooley CT, Chung, NN, Wilkes, BC et al (1994) An all D-amino acid opioid peptide with central analgesic activity from a combinatorial library. Science 266: 2019–2022

    Article  PubMed  CAS  Google Scholar 

  22. Dooley CT, Kaplan RA, Chung NN et al (1995) Six highly active mu-selective opioid peptides identified from two synthetic combinatorial libraries. Pept Res 8: 124–137

    PubMed  CAS  Google Scholar 

  23. Kramer TH, Toth G, Haaseth RC et al (1991) Influence of peptidase inhibitors on the apparent agonist potency of delta selective opioid peptides In vitro. Life Sci 48: 882–886

    Google Scholar 

  24. Dooley CT, Houghten RA (1995) Identification of mu-selective polyamine antagonists from a synthetic combinatorial library. Analgesia 1: 400–404

    CAS  Google Scholar 

  25. Blondelle SE, Houghten RA, Perez-Paya E (1996) Identification of inhibitors of melittin using non-support-bound combinatorial libraries. J Biol Chem 271: 4093–4099

    Article  PubMed  CAS  Google Scholar 

  26. Burton DR, Barbas CF, III, Persson MAA et al (1991) A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Proc Nati Acad Sci USA 88: 10134–10137

    Article  CAS  Google Scholar 

  27. Motti C, Nuzzo M, Meola A et al (1994) Recognition by human sera and immunogenicity of HBsAg mimotopes selected from an M13 phage display library. Gene 146: 191–198

    Article  PubMed  CAS  Google Scholar 

  28. Pinilla C, Appel J, Blondelle SE et al (1995) A review of the utility of peptide combinatorial libraries. Biopolymers (Peptide Science) 37: 221–240

    Article  CAS  Google Scholar 

  29. Tercet NK, Bojanic D, Brown D et al (1995) BioMed Chem Lett 5: 917–922

    Article  Google Scholar 

  30. Pinilla C, Appel JR, Blanc P et al (1992) Rapid identification of high affinity peptide ligands using positional scanning synthetic peptide combinatorial libraries. Biotechniques 13: 901–905

    PubMed  CAS  Google Scholar 

  31. Spatola AF, Crozet Y, DeWit D et al (1996) Rediscovering an endothelin antagonist (BQ-123): A self-deconvoluting cyclic pentapeptide library. J Med Chem 39: 3842–3846

    Article  PubMed  CAS  Google Scholar 

  32. Szymonifka MJ, Chapman KT (1995) Magnetically Manipulable Polymeric Supports for Solid Phase Organic Synthesis. Tetrahedron Lett 36: 1597–1600

    Article  CAS  Google Scholar 

  33. Gallop MA, Barrett RW, Dower WJ et al (1994) Applications of combinatorial technologies to drug discovery. 1. Background and peptide combinatorial libraries. J Med Chem 37: 1233–1251

    Article  PubMed  CAS  Google Scholar 

  34. White SP, Scott DL, Otwinowski Z et al (1990) Crystal structure of cobra-venom phospholipase A2 in a complex with a transition-state analogue. Science 250: 1560–1563

    Article  PubMed  CAS  Google Scholar 

  35. Ostresh JM, Winkle JH, Hamashin VT et al (1994) Peptide libraries: Determination of relative reaction rates of protected amino acids in competitive couplings. Biopolymers 34: 1681–1689

    Article  PubMed  CAS  Google Scholar 

  36. Ostresh JM, Schoner CC, Hamashin VT et al (1998) Solid phase synthesis of trisubstituted bicyclic guanidines via cyclicization of reduced N-acylated dipeptides. J Org Chem 63: 8622–8623

    Article  CAS  Google Scholar 

  37. Nefzi A, Ostresh JM, Houghten RA (1999) Parallel solid phase synthesis of tetrasubstituted diethylenetriamines via selective amide alkylation and exhaustive reduction of N-acylated dipeptides. Tetrahedron 55: 335–344

    Article  CAS  Google Scholar 

  38. Nefzi A, Ostresh JM, Meyer J-P et al (1997) Solid phase synthesis of heterocyclic compounds from linear peptides: cyclic ureas and thioureas. Tetrahedron Lett 38: 931–934

    Article  CAS  Google Scholar 

  39. Nefzi A, Ostresh JM, Giulianotti M et al (1999) Solid-phase synthesis of trisubstituted 2-imidazolidones and 2-imidazolidinethiones. J Comb Chem 1: 195–198

    Article  CAS  Google Scholar 

  40. Udaka K, Wiesmuller K-H, Kienle S et al (1995) Decrypting the structure of major histocompatibility complex class I-restricted cytotoxic T lymphocyte epitopes with complex peptide libraries. J Exp Med 181: 2097–2108

    Article  PubMed  CAS  Google Scholar 

  41. Grass-Masse H, Ameisen JC, Boutillon C et al (1992) Synthetic vaccines and HIV-1 hypervariability: a mixotope approach. Pept Res 5: 211–216

    Google Scholar 

  42. Janda KD (1994) Tagged versus untagged libraries: Methods for the generation and screening of combinatorial chemical libraries. Proc Nati Acad Sci USA 91: 10779–10785

    Article  CAS  Google Scholar 

  43. Konings DAM, Wyatt JR, Ecker DJ et al (1996) Deconvolution of combinatorial libraries for drug discovery: Theoretical comparison of pooling strategies. J Med Chem 39: 2710–2719

    Article  PubMed  CAS  Google Scholar 

  44. Wilson-Lingardo L, Davis PW, Ecker DJ et al (1996) Deconvolution of combinatorial libraries for drug discovery; experimental comparison of pooling strategies. J Med Chem 39: 2720–2726

    Article  PubMed  CAS  Google Scholar 

  45. Blomberg K, Granberg C, Hemmila I et al (1986) EuropiumOlabelled target cells in an assay of natural killer cell activity. II. A novel non-radioactive method based on time-resolved fluorescence. Significance and specificity of the method. J lmmunol Meth 92: 117–123

    Article  CAS  Google Scholar 

  46. Dörner B, Ostresh TM, Blondelle SE et al (1997) Peptidomimetic synthetic combinatorial libraries. In: A Abell (ed): Advances in Amino Acid Mimetics and Peptidomimetics Vol 1. JAI Press, Greenwich, CT, 109–125

    Chapter  Google Scholar 

  47. Ostresh TM, Dorner B, Houghten RA (1998) Peralkylation: “Libraries from libraries”: Chemical transformation of synthetic combinatorial libraries. In: Cabilly S (ed): Combinatorial peptide library protocols. Humana Press, Totowa, New Jersey, 41–49

    Google Scholar 

  48. Ostresh JM, Dorner B, Blondelle SE, Houghten RA (1997) Soluble combinatorial libraries of peptides, peptidomimetics, and organics: fundamental tools for basic research and drug discovery. In: Wilson TR, Czarnik AW (eds): Combinatorial Chemistry. John Wiley & Son, Inc., New York, 225–240

    Google Scholar 

  49. Dörner B, Husar GM, Ostresh TM et al (1996) The synthesis of peptidomimetic combinatorial libraries through successive amide alkylation. Bioorg Med Chem 4: 709–715

    Article  PubMed  Google Scholar 

  50. Ostresh JM, Husar GM, Blondelle SE et al (1994) “Libraries from libraries”: Chemical transformation of combinatorial libraries to extend the range and repertoire of chemical diversity. Proc Natl Acad Sci USA 91: 11138–11142

    Article  PubMed  Google Scholar 

  51. Ostresh JM, Blondelle SE, Dörner B et al (1996) Generation and use of nonsupport-bound peptide and peptidomimetic combinatorial libraries. Methods Enzymol 267: 220–234

    Article  PubMed  CAS  Google Scholar 

  52. Cuervo JH, Weitl F, Ostresh TM, Hamashin VT, Hannah AL, Houghten RA (1995) Polyalkylamine chemical combinatorial libraries. In: Maia HLS (ed): Peptides 94: Proceedings of the 23rd European Peptide Symposium. ESCOM, Leiden, 465–466

    Google Scholar 

  53. Griffith MC, Dooley CT, Houghten RA, Kiely JS (1996) Solid-phase synthesis, characterization, and screening of a 43,000-compound tetrahydroisoquinoline combinatorial library. In: Chaiken IM, Janda KD (eds): Molecular Diversity and Combinatorial Chemistry: Libraries and Drug Discovery. American Chemical Society, Washington, DC, 50–57

    Google Scholar 

  54. Pei Y, Houghten RA, Kiely JS (1997) Synthesis of 4-amino-3,4-dihydro-2(IH)-quinolines via B-lactam intermediates on the solid-phase. Tetrahedron Lett 38: 3349–3352

    Article  CAS  Google Scholar 

  55. Nefzi A, Ostresh TM, Houghten RA (1997) Solid phase synthesis of 1,3,4,7-tetrasubstituted perhydro-1,4-diazepine-2,5-diones. Tetrahedron Lett 38: 4943–4946

    Article  CAS  Google Scholar 

  56. Nefzi A, Giulianotti M, Houghten RA (1998) Solid phase synthesis of 2,4,5-trisubstituted thiomorpholin-3-ones. Tetrahedron Letters 39: 3671–3674

    Article  CAS  Google Scholar 

  57. Nefzi A, Ong, NA, Giulianotti, MA et al (1999) Solid phase synthesis of 1,4-benzothiazepin-5-one derivatives. Tetrahedron Lett 40: 4939–4942

    Article  CAS  Google Scholar 

  58. Meyer J-P, Ostresh TM, Houghten RA (1999) Combinatorial libraries of hydantoin and thiohydantoin derivatives, methods of making the libraries and compounds therein. U.S. Patent No. 5,859,190

    Google Scholar 

  59. Nefzi A, Ostresh JM, Giulianotti M et al (1998) Efficient solid phase synthesis of 3,5-disubstituted hydantoins. Tetrahedron Lett 39: 8199–8202

    Article  CAS  Google Scholar 

  60. Ostresh JM, Houghten RA (1999) Combinatorial libraries of imidazol-pyrido-indole and imidazol-pyrido-benzothiophene derivatives, methods of making the libraries and compounds therein. U.S. Patent No. 5,856,107

    Google Scholar 

  61. Nefzi A, Giulianotti M, Houghten RA (1999) Solid phase synthesis of 1,6-disubstituted 2,3-diketopiperazines and 1,2-disubstituted piperazines from N-acylated amino acids. Tetrahedron Lett 40: 8539–8542

    Article  CAS  Google Scholar 

  62. Nefzi A, Ostresh TM, Houghten RA (2001) Solid-phase synthesis of mixture-based acyclic and heterocyclic small molecule combinatorial libraries from resin-bound polyamides. Biopolymers (Peptide Science) 60: 212–219

    Article  CAS  Google Scholar 

  63. Blondelle, SE, Crooks, E, Ostresh, JM et al (1999) Mixture-based heterocyclic combinatorial positional scanning libraries: discovery of bicyclic guanidines having potent antifungal activity against Candida albicans and Cryptococcus neoformans. Antimicrob Agents & Chemother 43: 106–114

    CAS  Google Scholar 

  64. Nefzi A, Giulianotti MA, Houghten RA (2001) Solid-phase synthesis of bis-heterocyclic compounds from resin-bound orthogonally protected lysine. J Comb Chem 3: 68–70

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA, 92121, USA

    Adel Nefzi, John M. Ostresh & Richard A. Houghten

Authors
  1. Adel Nefzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John M. Ostresh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard A. Houghten
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Structural Bioinformatics and Drug Design, EnTec GmbH, Adolf-Reichwein-StraĂźe 20, Jena, D-07745, Germany

    Alexander Hillisch

  2. Institut fĂĽr Molekulare Biotechnologie e.V., Abt. Strukturbiologie-Kristallographie, BeutenbergstraĂźe 11, Jena, D-07745, Germany

    Rolf Hilgenfeld

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Basel AG

About this chapter

Cite this chapter

Nefzi, A., Ostresh, J.M., Houghten, R.A. (2003). Combinatorial chemistry: Mixture-based combinatorial libraries of acyclic and heterocyclic compounds from amino acids and short peptides. In: Hillisch, A., Hilgenfeld, R. (eds) Modern Methods of Drug Discovery. EXS, vol 93. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-7997-2_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-7997-2_6

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9397-8

  • Online ISBN: 978-3-0348-7997-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation