Dynamic Combinatorial Chemistry Employing Boronic Acids/ Boronate Esters Leads to Potent Oxygenase Inhibitors

摘要

The application of dynamic reactions is a promising approach for the discovery of small-molecule ligands for proteins. To date, however, this method is limited by the few appropriate reactions and the techniques used for the analysis of protein-ligand complexes."Dynamic" functional group intercon-vertions that have been employed include the conversion of thiols to disulfides, the aldol reaction, and the addition of nucleophiles to ketones and aldehydes. The reaction of boronic acids with diols to form boronate esters is attractive for dynamic-library formation, because it is reversible in aqueous solution in a pH-dependent manner. The dynamic boronic acid/boronate ester system has been used to form supramolecular switches, some of which have been used for sugar detection.However, this system has not been used for the identification of protein ligands. Proof of principle work with proteases, which react reversibly with boronic acids, suggests that boronic acid/boronate ester systems might be useful for the identification of enzyme inhibitors.