& Polymers Molecularly Imprinted Polymers: Compromise between Flexibility and Rigidity for Improving Capture of Template Analogues Antonelle Pardo ,* [a, b, c] Laetitia Mespouille, [b] Philippe Dubois, [b] Bertrand Blankert, [c] and Pierre Duez [a] Abstract: New synthetic strategies for molecularly imprinted polymers (MIPs) were developed to mimic the flexibility and mobility exhibited by receptor/enzyme binding pockets. The MIPs were prepared by bulk polymerization with quercetin as template molecule, acrylamide as functional monomer, ethylene glycol dimethacrylate as cross-linker, and THF as porogen. The innovative grafting of specific oligoethylene glycol units onto the imprinted cavities allowed MIPs to be obtained that exhibit extended selectivity towards template analogues. This synthetic strategy gives promising perspec- tives for the design of molecular recognition of molecules based on a congruent pharmacophore, which should be of interest for drug development. Introduction The molecular imprinting technique (MIT), invented by Wulff and Sarhan in 1972 [1] and much expanded by Mosbach et al. in the 1980s, [2] continues to be a very attractive technique for molecular recognition. In the field of polymer science, MIT is based on the molecular-recognition properties of synthetic cross-linked materials owing to the introduction of template molecules during formation of the polymeric 3D structure. [3] Hence, the resulting material has cavities complementary to the template in terms of size, shape, and corresponding func- tionality. The preparation of molecularly imprinted polymers (MIPs) involves the formation of a pre-polymerization complex between template molecules and functional monomers that can interact through covalent or noncovalent interactions. The subsequent copolymerization of the monomers with an excess of cross-linker leads to the formation of a polymer network around the template molecules. Removal of the latter leaves binding sites able to selectively recognize the template and more or less analogous molecules. MIPs have been applied as molecular-recognition elements in areas such as sensors, [4] enzyme catalysis, [4b,c, 5] drug deliv- ery, [6] chiral resolution, [7] and particularly in chromatography as solid-phase extraction sorbents (MIP-SPE). [8] Due to their out- standing advantages, including high selectivity, [9] chemical and physical robustness, [10] and ease and low cost of preparation, MIPs have become the most powerful alternative to conven- tional nonspecific SPE sorbents (normal- and reversed-phase, ionic, and other special sorbents) to efficiently separate target analytes from matrix compounds. Natural products, the richest source of drugs and lead struc- tures, received huge attention in recent years for MIP-SPE ap- plications. The wide potential of MIP-SPE in studies on natural products, not only for the selective extraction of a target com- pound but also for the concomitant discovery of new drug candidates, has been demonstrated. [8e, 11] The potential of MIPs as drug-discovery tools is evident, since the action of the ma- jority of drugs relies on enzyme–drug or receptor–drug molec- ular-recognition phenomena, which are often the basis for studies on structure–activity relationships. [12] However, some features must still be improved for MIPs to revolutionize the drug-discovery process. Instead of absolute specificity for their template, the MIPs used in drug discovery must preferably show a somewhat wider selectivity to recognize molecules with similar size, shape, and functionality to the template, in order to find likely congruent pharmacophores. The different published methods to create MIPs with extended selection characteristics are essentially based on refining the choice of template. [11b, 13] However, the high rigidity of the system is a lim- iting parameter in the specific field of drug discovery, since cavities do not exhibit enough mobility and flexibility to extend recognition towards analogues of the template. Decreasing the rigidity by modifying the formulation of the [a] A. Pardo , Prof. Dr. P. Duez Laboratory of Therapeutic Chemistry and Pharmacognosy Research Institute for Health Sciences and Technology University of Mons - UMONS Place du Parc 20, 7000 Mons (Belgium) Fax: (+ 32) 065373426 E-mail : Antonelle.Pardo@umons.ac.be [b] A. Pardo , Dr. L. Mespouille, Prof. Dr. P. Dubois Center of Innovation and Research in Materials and Polymers (CIRMAP) Laboratory of Polymeric and Composite Materials University of Mons - UMONS Place du Parc 20, 7000 Mons (Belgium) [c] A. Pardo , Prof. Dr. B. Blankert Laboratory of Pharmaceutical Analysis University of Mons - UMONS Place du Parc 20, 7000 Mons (Belgium) Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/chem.201303216. Chem. Eur. J. 2014, 20, 3500 – 3509  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3500 Full Paper DOI: 10.1002/chem.201303216