SYNTHESIS OF CARDIOVASCULAR POLYETHER ANTIBIOTICS

Naturally occurring polyether ionophores (e.g. lasalocid, monensin) have important inotropic properties. It is believed that these properties are a function to the ability of such molecules to bind and transport cations across biological membranes. The objective of this proposal is to develop powerful methods by which new, artificial ionophores which have highly selective cation-binding and transporting properties may be designed and prepared. Previous work has shown that the highest selectivity for binding closely related cations is found with ionophores which have limited conformational flexibility. In this application, I propose designs and syntheses of a series of new, podand ionophores which are conformationally homogeneous nd thus are more rigid than most previously studied ionophores. We will determine the three-dimensional structures and binding properties of these new ionophores in order to establish the relationship between their chemical structures and ionophoric properties. We will use the data obtained to validate a computational method using free energy perturbation for predicting the ionophoric properties of new ionophores. A key goal of this proposal is to develop a reliable computational tool which allows hypothetical designs for new ionophores to be tested by a calculation for their ion- binding or transporting properties. Such a tool would allow the design of optimally selective new ionophores prior to time-consuming synthesis.