Grant: Discovery Grants Program - Individual

Due to the far reaching consequences of the recent research results, the proposed research program we will continue to explore over the next five year deals with exploitation of an area virtually exclusively developed in our labs. In what appears to be a simple extension of metal ion catalyzed acyl and phosphoryl transfer processes, we have studied metal catalyzed alcoholysis reactions of carboxylate and phosphate esters in the light alcohols, notably methanol and ethanol. Metal ions such as Zn^2+, Cu^2+ and lanthanides such as La3+ as well as complexes of these greatly accelerate the methanolysis of esters, activated amides, phosphate diesters and phosphate triesters at room temperature and essentially neutral pH in alcohol. This has led to the development of effective, patented methods for decontamination of organophosphorus based pesticides and chemical weapons. In addition, recent results have shown that various dinuclear Zn(II) complexes provide accelerations of 10^12-10^14-fold for the cleavage of two series of phosphate diesters that are commonly used as simple models for RNA and DNA. In the proposed work we intend to investigate the mechanism of these very fast reactions using solvent deuterium kinetic isotope studies for the cleavage of the RNA and DNA models promoted by a set of mono and di-Zn(II) containing complexes in deuterio-methanol and ethanol. We will mount a major effort to understand a very recent finding in our labs where one of our dinuclear Zn(II) complexes, in ethanol containing small amounts of water, can accelerate the hydrolysis of a phosphate diester by ~10^17-fold. We will investigate the catalysis of cleavage of a series of beta-lactams afforded by these di- and mononuclear Zn(II) complexes as models for the Zn(II) class B1 metallo-beta-lactamases, which are currently of interest as pathogenic bacteria that produce these enzymes have a great resistance to therapeutic treatment with beta-lactam antibiotics. This research program will provide training for several students and post-doctoral persons, and at the same time will lay the foundation for the development of several new catalytic systems that may find practical use for transformation of important biological and industrial materials.