METAL CATALYZED BIOCHEMICAL TRANSFORMATIONS

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The major thrust of our research program is at the interface of organic, inorganic, and biological chemistry. Many biochemical transformations as well as important synthetic an industrial processes are catalyzed by metals. Recent efforts have focused on the design of new, biomimetic catalysts and the molecular mechanisms of these processes, the design and assembly of large scale membrane-protein-small molecule constructs, strategies for the assembly of biogenic hard materials, and molecular probes of the role of peroxynitrite in biological systems. The heme prosthetic group is found in a variety of enzymes involved in oxygen metabolism. The cytochromes P450 of lung, liver and epithelial tissue are known to play a central role in carcinogen activation, drug and xenobiotic detoxification, steroid and prostaglandin metabolism, and, most recently, the production of the intracellular signal molecule NO. The goals of this program have been to elucidate the organic and inorganic chemistry of these processes. Our two-pronged approach has been (i) to employ substrates for cytochrome P450 designed to reveal the nature of unseen intermediates in the reaction mechanism and (ii) to develop model systems as chemical paradigms for these processes. One specific application of the work is the design of selective inhibitors which could have pharmacological uses. The characterization of synthetic oxo-metalloporphyrin complexes has begun to provide a rational basis for the development of new catalysts and selective molecular detectors. Thus, relatively small changes in the size and shape of a metalloporphyrin catalyst may cause large changes in the relative reactivity of various substrates. The same criteria have allowed the development of chiral porphyrins capable of catalytic asymmetric epoxidation and hydroxylation. In the most favorable case found to date, the epoxidation of styrene was found to occur with a 95% enantiomeric excess. The synthesis and evaluation of this and other families of chiral porphyrins are now in progress. In particular, we are devising techniques that will provide a understanding of why one asymmetric catalyst gives a high enantiomeric excess while a very similar structure does not.