Dynamic Combinatorial Chemistry with Novel Dithiol Building Blocks: Towards New Structurally Diverse and Adaptive Screening Collections

Abstract

We describe the synthesis of a range of novel dithiol-functionalized building blocks and demonstrate how they can be used to generate new structurally diverse dynamic combinatorial libraries. A proof-of-principle experiment using the catecholamine dopamine revealed that molecular recognition changed the library composition under biocompatible conditions and identified new promising candidate receptors of this biologically important neurotransmitter.

Key words

dynamic combinatorial chemistry - thiols - receptors - macrocycles - drugs

• References and Notes

• 1 Galloway WR. J. D, Isidro-Llobet A, Spring DR. Nat. Commun. 2010; 1: 801
• 2 Morton D, Leach S, Cordier C, Warriner S, Nelson A. Angew. Chem. Int. Ed. 2009; 48: 104
• 3 Schreiber SL. Nature (London) 2009; 457: 153
• 4 Galloway WR. J. D, Spring DR. Nature (London) 2011; 470: 43
• 5 O’Connor CJ, Beckmann HS. G, Spring DR. Chem. Soc. Rev. 2012; 41: 4444
• 6 Sauer WH, Schwarz MK. J. Chem. Inf. Comput. Sci. 2003; 43: 987
• 7 Galloway WR. J. D, Spring DR. Exp. Opin. Drug Discov. 2009; 4: 467
• 8 Ramström O, Lehn JM. Nat. Rev. Drug Discovery 2002; 1: 26
• 9 Corbett PT, Leclaire J, Vial L, West KR, Wietor JL, Sanders JK. M, Otto S. Chem. Rev. 2006; 106: 3652
• 10 Cougnon FB. L, Sanders JK. M. Acc. Chem. Res. 2012; 45: 2211
• 11 Beeren SR, Sanders JK. M. History and Principles of Dynamic Combinatorial Chemistry . In Dynamic Combinatorial Chemistry . Reek JN. H, Otto S. John Wiley and Sons; Weinheim: 2010: 1-21

For examples, see:
• 12a Lam RT, Belenguer A, Roberts SL, Naumann C, Jarrosson T, Otto S, Sanders JK. M. Science 2005; 308: 667
• 12b Cougnon FB. L, Jenkins NA, Pantoş GD, Sanders JK. M. Angew. Chem. Int. Ed. 2012; 51: 1433
• 12c Vial L, Ludlow RF, Leclaire J, Pérez-Fernandez R, Otto S. J. Am. Chem. Soc. 2006; 128: 10253

For example, see:
• 13a Wyatt EE, Fergus S, Galloway WR. J. D, Bender A, Fox DJ, Plowright AT, Jessiman AS, Welch MW, Spring DR. Chem. Commun. 2006; 3296
• 13b O’Connell KM. G, Beckmann HS. G, Laraia L, Horsler HT, Bender A, Venkitaraman AR, Spring DR. Org. Biomol. Chem. 2012; 10: 7545 ; see also ref. 1

For examples in the generation of structurally diverse small molcule collections from other research groups, see:
• 13c Valot G, Garcia J, Duplan V, Serba C, Barluenga S, Winssinger N. Angew. Chem. Int. Ed. 2012; 51: 5391
• 13d Kopp F, Stratton CF, Akella LB, Tan DS. Nat. Chem. Biol. 2012; 8: 358
• 14 DCC relies upon differences in noncovalent interactions (and thus thermodynamic stabilities) between library compounds and a target molecule and this in turn is dependent upon structural differences between the library compounds. See ref. 9.
• 15 Au-Yeung HY, Pantoş GD, Sanders JK. M. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 10466
• 16 Bodlenner A, Alix A, Weibel JM, Pale P, Ennifar E, Paillart JC, Walter P, Marquet R, Dumas P. Org. Lett. 2007; 9: 4415
• 17 For a related report on the use of disulfide-based DCC to identify receptors of ephedrine, see: Ludlow RF, Otto S. J. Am. Chem. Soc. 2008; 130: 12218
• 18a Hamieh S, Ludlow RF, Perraud O, West KR, Mattia E, Otto S. Org. Lett. 2012; 14: 5404

For examples of other synthetic receptors developed using DCC, see:
• 18b Rodriguez-Docamp Z, Eugenieva-Ilieva E, Reyheller C, Belenguer AM, Kubik S, Otto S. Chem. Commun. 2011; 47: 9798
• 18c Waters ML, James LI. US 20120190586 A1, 2012 ; see also ref. 17.