SYNTHESIS OF POLYETHER ANTIBIOTICS/MONENSIN ANALOGS

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It is the goal of this program to develop efficient, practical (within the context of the complexity of the molecules involved) syntheses of the polyether ionophores. These antibiotics function as agents for ion/amine transport and through their ability to facilitate the transport of biologically relevant ions (Na+, K+, CA2+, etc.) or amines have the capacity to alter significantly cell metabolism. Commercially valuable as coccidiostats and anabolic agents, the polyether antibiotics are also proven cardiotonic agents. Therapeutic utilization of the ionophores as human cardiotonic agents is, however, severely limited by their toxicity and residual character that prevents effective dose regimes. Access to related chemical structures that still retain the ability to chelate metal ions/amines reversibly, but can overcome some of the toxicity and metabolic stability problems associated with the natural products may lead to useful therapeutic agents. It is the purpose of this effort to develop technology that can be generally applied to the synthesis of the characteristic polyether structure and design analogs of these ionophores that through biological testing will help define the requisite structural parameters for activity. Initial targets for the synthetic methodology part of the work are monensin and nigericin and then analogs related to these antibiotics will be prepared by that technology.