New bis-urea cross-linking monomers as effective oxyanion receptors

A library of new polymerizable functional cross-linking monomers designed for complexation with the oxyanionic moiety of the chemotherapeutic drug methotrexate (MTX). The H NMR binding study of a variety of synthetic receptors and the compilation of the obtained results lead to the identification of monomers combining interactive functionality and a cross-linking format, specific binding receptors for dicarboxylate-containing drugs. Robust molecular recognition elements with antibody-like ability to bind and discriminate between molecules or other structures can today be synthesized using molecular imprinting techniques. Over the years, molecular imprinting of polymer matrixes has become a widely used approach to generate macromolecular receptors for target molecules. The non-covalent approach involves complexation in a solution of target molecules (templates) with functional monomers through supramolecular interaction, followed by a polymerization reaction with an excess of cross-linkers. Removal of the templates leaves behind specific recognition sites that are complementary to the template in terms of its shape, size and functionality in the polymer network. The use of molecularly imprinted polymers (MIPs) carries many applications in several areas. An important analytical application is the use of MIPs as chromatographic devices for separating chemically similar molecules. They are also exploited in the field of organic synthesis for their catalytic and enantio-selective potential and as substitute for biological target receptors in dynamic combinatorial chemistry. Drug discovery by dynamic combinatorial chemistry, classically involves the assembly of building blocks in the presence of a target receptor or enzyme that creates a driving force favoring the formation of the best-binding constituent. The presence of a targeted enzyme in the synthetic reaction mixture results in greater amounts of efficient inhibitors (target-accelerated synthesis) or shifts the synthetic equilibrium (dynamic combinatorial libraries, DCC) by binding tightly the strongest target binders. However, the biological receptors used in this approach are usually only stable over a small temperature range and in a specific media. Organic solvents, temperature, pH, exposition to light-waves and oxidative environments are among the conditions that must be carefully taken into consideration when using a biological receptor. These soft conditions restrict the field of usable functional reactants and obtainable products. The use of MIPs as a substitute for biological target receptors could allow a broader range of conditions for the DCC technique. MIPs are stable even at extreme temperatures and at pH where natural enzymes would degrade. Their use in combinatorial chemistry would surpass the limits encountered so far. To tailor MIPs with homogeneous cavities crafted for maximizing recognition towards a specific type of chemical structure, we initiated a procedure of systematic templatemoiety/receptor complexation analysis. Our approach involves a synthesis/binding study of a variety of receptors towards a specific ligand moiety. The obtained results allow us to select of hit-receptors possessing the best associations from the initial set of receptors. Compilation of data for various ligand moiety leads to the creation of broad libraries of polymerizable moiety-specific binding receptors available for the imprinting of drugs or other important compounds. Herein, we present a specific example of target-molecule which will lead to information about dicarboxylate containing molecules. We report the synthesis of a library of new polymerizable functional monomers designed for imprinting the chemotherapeutic drug methotrexate (MTX) shown in Figure 1.