The power of combinatorial strategies for the generation of large populations of molecules has long been recognized in biology. It has been estimated that 5xlO-7 new antibody forming B cells are produced in the body every day, each producing a unique antibody molecule. This enormous variety provides a large range of binding regions that can be selected for their given complementarity for a target antigen in the immune system. In recent years there have been increasing attempts to reproduce the power of diversity in the generation of medium and large libraries of small molecules. These combinatorial methods have been directed to the formation either of oligomeric or of small molecule libraries designed to bind to a target (usually biological) receptor. The primary focus of this proposal is the development of libraries of synthetic receptors as the foundation of a novel approach to metal ion and molecule sensor design. An effective receptor requires the presence of multiple binding groups in a well- defined spacial arrangement and directed towards a central binding cleft or cavity. This can only be achieved by a convergent approach which allows different binding regions to be pre-formed before assembling them together to generate the final recognition site. This proposal represents a major new program aimed at the development of a combinatorial approach to the design of libraries of artificial molecular receptors. The central concept is that a templating metal scaffold can function both as a one step source of structural diversity and as an internal spectroscopic probe of substrate binding. Thus, both key problems in combinatorial chemistry are solved; a facile and compatible route to functional libraries and an internal screening device for identifying strong and effective binding ligands. The strength of the combinatorial approach is that it allows the generation of a large library of synthetic molecule or metal ion receptors that can then be screened for the desired selectivity. To achieve these goals we will prepare a series of terpyridine ligands functionalized with different binding regions which will then self-assemble around a transition metal center. The internal spectroscopic probe will then be used to screen the receptor library for strong and selective binding to a range of biologically interesting substrates. We anticipate that the receptor library strategy can be extended to the formation metal templated ionophores that change their colorimetric or fluorescence properties on binding to target metal ions. We will also prepare a series of functionalized bipyridine derivatives metal that will form a metal templated recognition site with three potential substrate binding regions.
| Sharma, T A; Carr, A J; Davis, R S et al. (1998) Aromatic analogs of arcaine inhibit MK-801 binding to the NMDA receptor. Bioorg Med Chem Lett 8:3459-64 |
