This ongoing project involves the use of pyrrole NH hydrogen bonding interactions to bind, transport, and sense anions of biological relevance. It builds on an approach to anion recognition that was first put forward by the P.I. and his coworkers almost a decade ago and which has evolved to the point where it is now being adopted by an increasing number of academic laboratories world-wide. Meanwhile, pyrrole-based anion recognition events have been invoked recently to explain the mode of action of prodigiosin, a naturally occurring tripyrrolic entity with promising immunosuppressive and anticancer activity. Similar NH-anion interactions are implicated in pathways promoted by L-pyrrolysine, a new genetically encoded amino acid discovered earlier this year. Thus, the incentive to make and study pyrrole-based anion receptors is greater than ever. This is true both with regard to probing the basic determinants of anion binding and in terms of generating systems capable of targeting problems of medical and public health importance. These latter are represented by such diverse challenges as anionic metabolite sensing, chemical warfare agent detection, control of phosphate and oxalate concentrations in patients suffering from kidney failure, and multiple opportunities in drug development. Work to date has established that i) pyrrole-based receptors can bind and sense such physiologically important anions as phosphate, chloride, and oxalate, as well as fluoride, in polar media, ii) the strength and selectivity of the binding process can be fine-tuned through structural modifications, and iii) polymers containing pyrrolic receptors can be made. It has also led to the finding that several polypyrrole systems developed in the P.l.'s laboratory display cytotoxicities that meet or exceed those of prodigiosin. The proposed research will thus focus on using new and extant pyrrole-based receptors to i) probe more fully the kinetics and thermodynamics of anion recognition, ii) generate phosphate and oxalate binding materials for treating end-stage renal disease, iii) create supported sensors for detecting the hydrolysis products of organophosphate nerve gases, and iv) develop lead compounds that can be taken forward as potential new anti-cancer drugs and immunosuppressive agents.
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