Spatially arrayed mixture (SpAM) technology: Synthesis of two-dimensionally indexed orthogonal combinatorial libraries

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 7, 1997, Pages 837-842

  Berk, Scott C ^a   Chapman, Kevin T ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE; DRUG DESIGN; DRUG SCREENING; DRUG SYNTHESIS; METHODOLOGY; STRUCTURE ACTIVITY RELATION; THEORY;

EID: 0030897331     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00113-3     Document Type: Article

References (18)

1. For several excellent reviews, see: (a) Gallop, M. A.: Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233.
2. (b) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E.M. Ibid. 1385.
3. Thompson, L. A.; Ellman, J. Chem. Rev. 1996, 96, 555.
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5. (b) Nicolaou, K. C.; Xiao, X-Y.; Parandoosh, Z.; Senyei, A.; Nova, M. P. Angew. Chem., Int. Ed. Engl. 1995, 34, 2289.
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10. Déprez, B.; Williard, X.; Bourel, L.; Coste, H.; Hyafil, F.; Tarter, A. J. Am. Chem. Soc., 1995, 117, 5405.
11. Two-dimensional indexing has been used to create the first set of mixtures for six-dimensional, iterative resynthesis-based peptide libraries. See: (a) Geysen, H. M.; Mason, T. J. Bioorg. Med. Chem. Lett. 1993, 3, 397.
12. (b) Houghton, R. A.; Dooley, C. T. Bioorg. Med. Chem. Lett. 1993, 3, 405.
13. Alternatively, the AB and CD plates could be produced by two different synthetic pathways, such as those shown below, where the order of the installation of each portion of the molecule is exploited to avoid using mixtures of reagents or partial reaction protocols. While this requires considerably more development time to work out the synthetic routes, there are no restrictions on the relative reactivity of the subunits. With the appropriate synthetic sequence, this strategy could also be applied to the synthesis of AC, AD, BC or BD plates. formula presented
14. Zuckermann, R. N.; Martin, E. J.; Spellmeyer, D. C.; Stauber, G. B.; Shoemaker, K. R.; Kerr, J. M.; Figliozzi, G. M.; Goff, D. A.; Siani, M. A.; Simon, R. J.; Banville, S. C.; Brown, E. G.; Wang, L.; Richter, L. S.; Moos, W. H. J. Med. Chem. 1994, 37, 2678.
15. (a) Simon, R. J.; Kania, R. S.; Zuckermann, R. N.; Huebner, V. D.; Jewell, D. A.; Banville, S.; Ng, S.; Wang, L.; Rosenberg, S.: Marlowe, C. K.; Spellmeyer, D. C.; Tan, R.; Frankel, A. D.; Santi, D. V.; Cohen, F. E.; Bartlett, P. A. Proc. Natl. Acad. Sci. USA 1992, 89, 9367.
16. (b) Zuckermann, R. N.; Kerr, J. M.; Kent, S. B.; Moos, W. H. J. Am. Chem. Soc. 1992 1/4, 10646.
17. See, for example: Ostresh, J. M.; Winkle, J. H.; Hamashin, V. T.; Houghten, R. A. Biopolymers 1994, 34, 1681.
18. As an alternative to isokinetic mixtures, Ellman has successfully employed a limiting amount (0.5 equiv) of an equimolar mixture of reagents: Backes, B. J.; Virgilio, A. A.; Ellman, J. A. J. Am. Chem. Soc. 1996, 118, 3055. A series of inidividual reactions with limiting amounts of each building block may also be employed.