Design, synthesis, and evaluation of small-molecule libraries

Accounts of Chemical Research

Volumn 29, Issue 3, 1996, Pages 132-143

  Ellman, Jonathan A ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 2842561522     PISSN: 00014842     EISSN: None     Source Type: Journal    
DOI: 10.1021/ar950190w     Document Type: Article

References (79)

1. Chen, J. K.; Schreiber, S. L. Angew. Chem., Int. Ed. Engl. 1995, 34, 953-969. Schreiber and co-workers have elegantly demonstrated the utility of compound-library-based approaches to identify molecular probes for the study of biological systems in their study of SH3 domains using biased peptide libraries.
2. Gracheck, S. J.; Miller, P. F.; Marks, J. S. Annu. Rep. Med. Chem. 1993, 28, 161-167.
3. For reviews on peptide libraries, see: (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233-1251. (b) Pinilla, C.; Appel, J.; Blondelle, S.; Dooley, C.; Dorner, B.; Eichler, J.; Ostresh, J.; Houghten, R. A. Biopolymers (Pept. Sci.) 1995, 37, 221-240. (c) Pavia, M. R.; Sawyer, T. K.; Moos, W. H. BioMed. Chem. Lett. 1993, 3, 387-396. (d) Jung, G., Becksickinger, A. G. Angew. Chem., Int. Ed. Engl. 1992, 31, 367-383. (e) Dower, W. J.; Fodor, S. P. A. Annu. Rep. Med. Chem. 1991, 26, 271-280. In addition, an excellent bibliography of articles in the field of library synthesis (both peptide libraries and organic compound libraries) is maintained on the Internet by the journal Molecular Diversity. The site is accessed at http: //vesta.pd.com/index.html and is edited by Dr. Michal Lebl.
4. For reviews on peptide libraries, see: (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233-1251. (b) Pinilla, C.; Appel, J.; Blondelle, S.; Dooley, C.; Dorner, B.; Eichler, J.; Ostresh, J.; Houghten, R. A. Biopolymers (Pept. Sci.) 1995, 37, 221-240. (c) Pavia, M. R.; Sawyer, T. K.; Moos, W. H. BioMed. Chem. Lett. 1993, 3, 387-396. (d) Jung, G., Becksickinger, A. G. Angew. Chem., Int. Ed. Engl. 1992, 31, 367-383. (e) Dower, W. J.; Fodor, S. P. A. Annu. Rep. Med. Chem. 1991, 26, 271-280. In addition, an excellent bibliography of articles in the field of library synthesis (both peptide libraries and organic compound libraries) is maintained on the Internet by the journal Molecular Diversity. The site is accessed at http: //vesta.pd.com/index.html and is edited by Dr. Michal Lebl.
5. For reviews on peptide libraries, see: (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233-1251. (b) Pinilla, C.; Appel, J.; Blondelle, S.; Dooley, C.; Dorner, B.; Eichler, J.; Ostresh, J.; Houghten, R. A. Biopolymers (Pept. Sci.) 1995, 37, 221-240. (c) Pavia, M. R.; Sawyer, T. K.; Moos, W. H. BioMed. Chem. Lett. 1993, 3, 387-396. (d) Jung, G., Becksickinger, A. G. Angew. Chem., Int. Ed. Engl. 1992, 31, 367-383. (e) Dower, W. J.; Fodor, S. P. A. Annu. Rep. Med. Chem. 1991, 26, 271-280. In addition, an excellent bibliography of articles in the field of library synthesis (both peptide libraries and organic compound libraries) is maintained on the Internet by the journal Molecular Diversity. The site is accessed at http: //vesta.pd.com/index.html and is edited by Dr. Michal Lebl.
6. For reviews on peptide libraries, see: (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233-1251. (b) Pinilla, C.; Appel, J.; Blondelle, S.; Dooley, C.; Dorner, B.; Eichler, J.; Ostresh, J.; Houghten, R. A. Biopolymers (Pept. Sci.) 1995, 37, 221-240. (c) Pavia, M. R.; Sawyer, T. K.; Moos, W. H. BioMed. Chem. Lett. 1993, 3, 387-396. (d) Jung, G., Becksickinger, A. G. Angew. Chem., Int. Ed. Engl. 1992, 31, 367-383. (e) Dower, W. J.; Fodor, S. P. A. Annu. Rep. Med. Chem. 1991, 26, 271-280. In addition, an excellent bibliography of articles in the field of library synthesis (both peptide libraries and organic compound libraries) is maintained on the Internet by the journal Molecular Diversity. The site is accessed at http: //vesta.pd.com/index.html and is edited by Dr. Michal Lebl.
7. For reviews on peptide libraries, see: (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233-1251. (b) Pinilla, C.; Appel, J.; Blondelle, S.; Dooley, C.; Dorner, B.; Eichler, J.; Ostresh, J.; Houghten, R. A. Biopolymers (Pept. Sci.) 1995, 37, 221-240. (c) Pavia, M. R.; Sawyer, T. K.; Moos, W. H. BioMed. Chem. Lett. 1993, 3, 387-396. (d) Jung, G., Becksickinger, A. G. Angew. Chem., Int. Ed. Engl. 1992, 31, 367-383. (e) Dower, W. J.; Fodor, S. P. A. Annu. Rep. Med. Chem. 1991, 26, 271-280. In addition, an excellent bibliography of articles in the field of library synthesis (both peptide libraries and organic compound libraries) is maintained on the Internet by the journal Molecular Diversity. The site is accessed at http: //vesta.pd.com/index.html and is edited by Dr. Michal Lebl.
8. For reviews on oligonucleotide libraries, see: (a) Gold, L.; Polisky, B.; Uhlenbeck, O.; Yarus, M. Annu. Rev. Biochem. 1995, 64, 763-797. (b) Ecker, D. J.; Vickers, T. A.; Hanecak, R.; Driver, V.; Anderson, K. Nucleic Acids Res. 1993, 21, 1853-1856. (c) Bock, L. C.; Griffin, L C.; Latham, J. A.; Vermaas, E. H.; Toole, J. J. Nature 1992, 355, 564-566.
9. For reviews on oligonucleotide libraries, see: (a) Gold, L.; Polisky, B.; Uhlenbeck, O.; Yarus, M. Annu. Rev. Biochem. 1995, 64, 763-797. (b) Ecker, D. J.; Vickers, T. A.; Hanecak, R.; Driver, V.; Anderson, K. Nucleic Acids Res. 1993, 21, 1853-1856. (c) Bock, L. C.; Griffin, L C.; Latham, J. A.; Vermaas, E. H.; Toole, J. J. Nature 1992, 355, 564-566.
10. For reviews on oligonucleotide libraries, see: (a) Gold, L.; Polisky, B.; Uhlenbeck, O.; Yarus, M. Annu. Rev. Biochem. 1995, 64, 763-797. (b) Ecker, D. J.; Vickers, T. A.; Hanecak, R.; Driver, V.; Anderson, K. Nucleic Acids Res. 1993, 21, 1853-1856. (c) Bock, L. C.; Griffin, L C.; Latham, J. A.; Vermaas, E. H.; Toole, J. J. Nature 1992, 355, 564-566.
11. Smith, A. B.; Hirschmann, R.; Pasternak, A.; Akaishi, R.; Guzman, M. C.; Jones, D. R., Keenan, T. P.; Sprengeler, P. A.; Darke, P. L.; Emini, E. A.; Holloway, M. K.; Schleif, W. A. J. Med. Chem. 1994, 37, 215-218.
12. Kim, E. E.; Baker, C. T.; Dwyer, M. D.; Murcko, M. A.; Rao, B. G.; Tung, R. D.; Navia. M. A. J. Am. Chem. Soc. 1995, 117, 1181-1182.
13. For reviews on small-molecule libraries, see: (a) Ellman, J. A.; Thompson, L. A. Chem. Rev. 1996, 96, 555-600. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1401. (c) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135-8173. (d) Blondelle, S. E.; Perezpaya, E.; Dooley, C. T.; Pinella, C.; Houghten, R A. Trends Anal. Chem. 1995, 14, 83-92. (e) Lebl, M.; Krchnak, V.; Sepetov, N. F.; Seligmann, B.; Strop, P.; Felder, S.; Lam, K. S. Biopolymers (Pept. Sci.) 1995, 37, 177-198. (f) Desai, M. C.; Zuckermann, R. N.; Moos, W. H. Drug. Dev. Res. 1994, 33, 174-188. (g) Janda, K D Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 10779-10785. (h) Moos, W H.; Green, G. D.; Pavia, M. R. Annu. Rep. Med. Chem. 1993, 28, 315-324
14. For reviews on small-molecule libraries, see: (a) Ellman, J. A.; Thompson, L. A. Chem. Rev. 1996, 96, 555-600. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1401. (c) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135-8173. (d) Blondelle, S. E.; Perezpaya, E.; Dooley, C. T.; Pinella, C.; Houghten, R A. Trends Anal. Chem. 1995, 14, 83-92. (e) Lebl, M.; Krchnak, V.; Sepetov, N. F.; Seligmann, B.; Strop, P.; Felder, S.; Lam, K. S. Biopolymers (Pept. Sci.) 1995, 37, 177-198. (f) Desai, M. C.; Zuckermann, R. N.; Moos, W. H. Drug. Dev. Res. 1994, 33, 174-188. (g) Janda, K D Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 10779-10785. (h) Moos, W H.; Green, G. D.; Pavia, M. R. Annu. Rep. Med. Chem. 1993, 28, 315-324
15. For reviews on small-molecule libraries, see: (a) Ellman, J. A.; Thompson, L. A. Chem. Rev. 1996, 96, 555-600. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1401. (c) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135-8173. (d) Blondelle, S. E.; Perezpaya, E.; Dooley, C. T.; Pinella, C.; Houghten, R A. Trends Anal. Chem. 1995, 14, 83-92. (e) Lebl, M.; Krchnak, V.; Sepetov, N. F.; Seligmann, B.; Strop, P.; Felder, S.; Lam, K. S. Biopolymers (Pept. Sci.) 1995, 37, 177-198. (f) Desai, M. C.; Zuckermann, R. N.; Moos, W. H. Drug. Dev. Res. 1994, 33, 174-188. (g) Janda, K D Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 10779-10785. (h) Moos, W H.; Green, G. D.; Pavia, M. R. Annu. Rep. Med. Chem. 1993, 28, 315-324
16. For reviews on small-molecule libraries, see: (a) Ellman, J. A.; Thompson, L. A. Chem. Rev. 1996, 96, 555-600. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1401. (c) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135-8173. (d) Blondelle, S. E.; Perezpaya, E.; Dooley, C. T.; Pinella, C.; Houghten, R A. Trends Anal. Chem. 1995, 14, 83-92. (e) Lebl, M.; Krchnak, V.; Sepetov, N. F.; Seligmann, B.; Strop, P.; Felder, S.; Lam, K. S. Biopolymers (Pept. Sci.) 1995, 37, 177-198. (f) Desai, M. C.; Zuckermann, R. N.; Moos, W. H. Drug. Dev. Res. 1994, 33, 174-188. (g) Janda, K D Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 10779-10785. (h) Moos, W H.; Green, G. D.; Pavia, M. R. Annu. Rep. Med. Chem. 1993, 28, 315-324
17. For reviews on small-molecule libraries, see: (a) Ellman, J. A.; Thompson, L. A. Chem. Rev. 1996, 96, 555-600. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1401. (c) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135-8173. (d) Blondelle, S. E.; Perezpaya, E.; Dooley, C. T.; Pinella, C.; Houghten, R A. Trends Anal. Chem. 1995, 14, 83-92. (e) Lebl, M.; Krchnak, V.; Sepetov, N. F.; Seligmann, B.; Strop, P.; Felder, S.; Lam, K. S. Biopolymers (Pept. Sci.) 1995, 37, 177-198. (f) Desai, M. C.; Zuckermann, R. N.; Moos, W. H. Drug. Dev. Res. 1994, 33, 174-188. (g) Janda, K D Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 10779-10785. (h) Moos, W H.; Green, G. D.; Pavia, M. R. Annu. Rep. Med. Chem. 1993, 28, 315-324
18. For reviews on small-molecule libraries, see: (a) Ellman, J. A.; Thompson, L. A. Chem. Rev. 1996, 96, 555-600. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1401. (c) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135-8173. (d) Blondelle, S. E.; Perezpaya, E.; Dooley, C. T.; Pinella, C.; Houghten, R A. Trends Anal. Chem. 1995, 14, 83-92. (e) Lebl, M.; Krchnak, V.; Sepetov, N. F.; Seligmann, B.; Strop, P.; Felder, S.; Lam, K. S. Biopolymers (Pept. Sci.) 1995, 37, 177-198. (f) Desai, M. C.; Zuckermann, R. N.; Moos, W. H. Drug. Dev. Res. 1994, 33, 174-188. (g) Janda, K D Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 10779-10785. (h) Moos, W H.; Green, G. D.; Pavia, M. R. Annu. Rep. Med. Chem. 1993, 28, 315-324
19. For reviews on small-molecule libraries, see: (a) Ellman, J. A.; Thompson, L. A. Chem. Rev. 1996, 96, 555-600. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1401. (c) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135-8173. (d) Blondelle, S. E.; Perezpaya, E.; Dooley, C. T.; Pinella, C.; Houghten, R A. Trends Anal. Chem. 1995, 14, 83-92. (e) Lebl, M.; Krchnak, V.; Sepetov, N. F.; Seligmann, B.; Strop, P.; Felder, S.; Lam, K. S. Biopolymers (Pept. Sci.) 1995, 37, 177-198. (f) Desai, M. C.; Zuckermann, R. N.; Moos, W. H. Drug. Dev. Res. 1994, 33, 174-188. (g) Janda, K D Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 10779-10785. (h) Moos, W H.; Green, G. D.; Pavia, M. R. Annu. Rep. Med. Chem. 1993, 28, 315-324
20. For reviews on small-molecule libraries, see: (a) Ellman, J. A.; Thompson, L. A. Chem. Rev. 1996, 96, 555-600. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1401. (c) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135-8173. (d) Blondelle, S. E.; Perezpaya, E.; Dooley, C. T.; Pinella, C.; Houghten, R A. Trends Anal. Chem. 1995, 14, 83-92. (e) Lebl, M.; Krchnak, V.; Sepetov, N. F.; Seligmann, B.; Strop, P.; Felder, S.; Lam, K. S. Biopolymers (Pept. Sci.) 1995, 37, 177-198. (f) Desai, M. C.; Zuckermann, R. N.; Moos, W. H. Drug. Dev. Res. 1994, 33, 174-188. (g) Janda, K D Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 10779-10785. (h) Moos, W H.; Green, G. D.; Pavia, M. R. Annu. Rep. Med. Chem. 1993, 28, 315-324
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63. Cyclization to provide 2 was initially attempted by macrolactamization between the i + 1 and i + 2 residues rather than by thioalkylation; however, cyclization with a range of activating agents and solid supports provided significant amounts of cyclic dimer. These results are in accord with the well-precedented difficulties in macrolactamization to provide 9- and 10-membered-ring structures, (a) Story, S. C.; Aldrich, J. V. Int. J. Pept. Protein Res. 1994, 43, 292-296. (b) Kemp, D. S.; Stites, W. E. Tetrahedron Lett. 1988, 29, 5057-5060.
64. Cyclization to provide 2 was initially attempted by macrolactamization between the i + 1 and i + 2 residues rather than by thioalkylation; however, cyclization with a range of activating agents and solid supports provided significant amounts of cyclic dimer. These results are in accord with the well-precedented difficulties in macrolactamization to provide 9- and 10-membered-ring structures, (a) Story, S. C.; Aldrich, J. V. Int. J. Pept. Protein Res. 1994, 43, 292-296. (b) Kemp, D. S.; Stites, W. E. Tetrahedron Lett. 1988, 29, 5057-5060.
65. Virgilio, A. A.; Ellman, J. A. In Combinatorial Chemistry and Molecular Diversity in Drug Discovery; Gordon, E. M., Kerwin, J. F., Jr., Eds.; Wiley: New York, in press.
66. Fifty percent of each compound in the library was employed to prepare a second library of sulfoxide containing turn mimetics by oxidation of the thioether with hydrogen peroxide in aqueous DMF. Unpublished results.
67. Dan Fitpatrick, Genentech, unpublished results, 1995.
68. Kick, E. K.; Ellman, J. A. J. Med. Chem. 1995, 38, 1427-1430.
69. 2-symmetric isosteres.
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