This proposal aims at the development of H-phosphinic acids (RP(O)(OH)H) as synthetic intermediates for the preparation of biologically-active phosphorus-containing compounds. Recent advances in phosphorus-carbon bond formation are the stepping stone for novel applications. Focus is placed on two different health related areas which were chosen to show the synthetic flexibility of H-phosphinic acids: 1) the preparation and evaluation of gamma-aminobutyric acid (GABA) analogs relevant to the treatment of disorders of the central nervous system, where the phosphinic acid functionality is exploited as a carboxylate replacement; and 2) the development of a novel approach for the preparation of bisphosphonates under mild conditions relevant to the treatment of bone-related and other diseases, where the phosphinic acid functionality is a precursor to phosphonic acids. Compounds displaying promising in vitro biological activity will also be evaluated in vivo through consultants. While phosphinic acids are becoming popular pharmacophores in many other medicinal applications, their use in the above two areas has been largely unrealized. Thus, beyond the scope of this proposal, some of the chemistry detailed therein should make a significant contribution to the realm of phosphorus-based medicinal chemistry in general.
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