The long term goal of this research is to develop functional groups (""""""""molecular metaphors"""""""") which can be used to replace existing functional groups in, primarily, small molecules which interact with biological targets. These metaphors can be used in the design of new molecules to act as enzyme inhibitors, receptor antagonists, etc., and may also prove useful in the elucidation of some functions of biological targets. Along with the design element, specific methods for the synthesis of the metaphors in the biological context in which they are to be applied must be developed. The ultimate embodiment of this work would be a """"""""kit"""""""" of structures (and simple procedures to prepare them) which could be plugged, cassette-like, into a molecule of interest to modify its properties in a predictable way. This will enable chemists to more efficiently make new pharmaceuticals. This grant focuses on two functional groups widely distributed in biological molecules, enols and carboxylate groups, generally, but alpha-keto acids and their enols, specifically. It is intended to develop the vinyl fluoride functionality as an equivalent for enols, and to use this equivalence to develop inhibitors and stereochemical probes for enol-utilizing enzymes. The hypothesis that the stereochemistry of enzyme-bound enol intermediates can be elucidated by study of the properties of vinyl fluoride analogues will be tested. It is also intended to elucidate the basis for inhibition of pyruvate dehydrogenase complex by the natural product moniliformin. The inhibition of other pyruvate/thiaminpyrophosphate enzymes by moniliformin and analogues will be evaluated. The ability of squaric and deltic acid structures to substitute for carboxyl groups in enol-utilizing enzymes and in receptors will be studied. Methods for preparation of squaric and deltic acid derivatives will also be developed in this part of the project.
