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John T. Groves Hugh Stott Taylor Chair of Chemistry Research Program |
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- 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 and industrial processes, are catalyzed by metals. Current efforts focus on understanding the mechanisms of metalloproteins, the design of new, biomimetic catalysts and the molecular mechanisms of these processes, studies of host-pathogen interactions related to iron acquisition by small molecule siderophores 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 as models of the cytochrome 450 active site 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. In a recently-initiated project, we are employing arrays of metalloporphyrin catalysts to reliably and efficiently produce the anticipated human metabolites of drug molecules
- We have discovered that ruthenium porphyrin complexes are competent catalysts for the aerobic oxidation of simple organic compounds at ambient temperature and pressure. Very high catalytic efficiencies and turnover rates have been achieved with this system. We are investigating the mechanism of this remarkably mild process for which there is considerable commercial interest. Another recent outgrowth of these studies has been the recognition that trans-dioxomanganese(V) complexes {O=Mn(V)=O] are stable and isolable. Yet upon protonation these catalysts re able to insert oxygen into unreactive C-H bonds at stupendous rates.
- Our interest in oxidizing enzymes has led us to develop techniques for characterizing and using the oxygenase enzymes found within whole cells. This approach has enabled us to look directly at thte mechanism of action of alkane hydroxylases in new and uncharacterized organisms.
- In another outgrowth of the water-soluble metalloporphyrins project, we have shown that the peroxynitrite ion, which can be formed in vivo from the facile reaction of superoxide with NO, has the unique ability to cross phospholipid membranes and diffuse freely from compartment to compartment within a cell. Damage done to proteins, such as protein tyrosine nitration, by peroxynitrite may form part of molecular bases of the immune response and cytochrome c-mediated apoptosis. These pathways may also explain such conditions as diabetes and ischemia-reperfusion injury.
- Knowledge of the chemical mechanisms of cell damage due to oxidative processes could lead to effective pharmacological treatments. Our water-soluble metalloporphyrins, such as FP15, a PEGylated iron porphyrin, has shown profound biological activities in animals by capturing peroxynitrite within cells and preventing the tissue damage caused by this powerful oxidant.
- We have an active interest in elucidating the molecular mechanisms and pathways by which pathogenic organisms sequester the iron they need from the hot tissue. Our primary pathway is the biosynthesis of small molecule 'siderophores'. A very interesting class of iron-binding siderophores has amphiphilic properties, having a polar head group containing the iron binding site and one or two hydrophobic side chains reminiscent of a phospholipid. The first of these to be discovered were the exochelins and mycobactins of Mycobacter tuberculosis, rhizobactin 1021 from a terrestrial, nitrogen-fixing symbiont and acinetoferrin from the pathogens Acinetobacter haemoliticus and Acinetobacter baumanii. The amphiphilic marinobactins and acquachelins have been discovered more recently in marine bacteria, indicating that such structures are widely distributed in nature. Current interest in the iron-uptake strategies of pathogenic organisms stems from their increasing antibiotic resistance and the rising numbers of difficult-to-treat infections in humans. Our interest in iron and membrane dynamics has led us to investigate how the amphiphilic nature of these compounds may be advantageous to these organisms. The effort has involved chemical synthesis of siderophores and their analogs and the characterization of the behavior of these molecules in phospholipids membranes and whole cells.
203 Hoyt Laboratory
Department of Chemistry
Tel 609-258-3593 Fax 609-258-0348
e-mail : jtgroves@princeton.edu