个人简介

A.B. (1971): Brown University Ph.D. (1976) : Massachusetts Institute of Technology Postdoctoral Fellowship (1977-1978) : University of California, San Diego Bioorganic Chemistry

研究领域

Bioorganic Chemistry

Heme Uptake by Pathogenic Bacteria. A number of pathogenic bacteria grow with hemin as their major or sole source of iron. Heme Uptake by Pathogenic Bacteria In collaboration with Dr. Caroline Genco (Boston University) we have probed heme uptake by the outer membrane hemoglobin/heme receptor HmuR in Porphyromonas gingivalis. Relative binding affinities of a series of porphyrins, with various central metal atoms, indicated that the active site has a histidine. P. gingivalis has two proteases which can cleave heme-containing proteins, gingipain K (Kgp), a lysine-specific cysteine protease, and gingipain R1 (HRgpA), one of two arginine-specific cysteine proteases. Kgp and HRgpA were demonstrated to bind various porphyrins and metalloporphyrins with affinities similar to hemin, indicating that binding of Kgp and HRgpA to these porphyrins doesnot require a metal present within the porphyrin ring. This work continued with measurement of the heme binding. Current work in our laboratory involves one of the ABC transporters in Streptococcus pyogenes. This work, in collaboration with Dr. Zehava Eichenbaum (Georgia State University), focuses on the heme binding protein (HBP). Spectroscopic characterization of the heme site and the studies of the thermodynamics of denaturation are underway. Metalloporphyrins as Anticancer Agents. The goal of cancer radiotherapy is to cause lethal damage to the malignant cells. DNA is the critical target, but radiation damages all cellular components. It would be desirable to have a sensitizing agent which targets DNA to enhance damage specifically at the DNA. One approach is to bind specific heavy atoms to the DNA. These can absorb the radiation and convert it to low energy electrons via a mechanism termed the Auger process. The expectation is that the electrons released will produce substantial local damage in the DNA, which will be difficult for the cellular enzymes to repair. Our work involves the synthesis of cationic porphyrins bearing heavy atoms. Biological studies have been done in collaboration with Dr. Brenda Laster (Ben Gurion University of the Negev, Israel). Initial work involved chemical, biochemical and in vivo studies on PtTMPyP4. Current work involves the synthesis and study of a series of indium, molybdenum, palladium, ruthenium and zirconium cationic porphyrins. Threading Intercalators. Intercalators are flat molecules that slide between the base pairs of duplex DNA. Studies during the 1980s showed that intercalators bearing two side chains could form intercalative complexes with DNA in which one side chain lies in the major groove and the other side chain lies in the minor groove. Because it was topologically necessary for the side chains to “thread” through the DNA complex to achieve this geometry, these molecules were termed “threading intercalators.” To date, we have synthesized more than 50 compounds based on the naphthalene diimide and anthraquinone ring systems. Our kinetic studies, in collaboration with Dr. W. David Wilson (Georgia State University) show that molecules as long as 18 and with diameters as large as 8.5 can thread through duplex DNA. Detailed studies of the association and dissociation rate constants reveal that the association rate is a function of the size of the side chain, but that the dissociation rate has little dependence on the size of the side chain. A recent study on a series of anthraquinones established the important of the length of the chain in controlling DNA binding. Further work in this area involves studies of the kinetics of intercalators with only one side chain, to determine if the observed size effect is unique to threading intercalators or general. Our series of compounds, with side chains graded both in size and hydrophobicity, provides an outstanding series with which to study the details of DNA binding.

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Y. Cao, A. F. Gill, and D. W. Dixon. Synthesis and characterization of a water-soluble porphyrin with a cyclic sulfone. Tetrahedron Lett. 50 (30):4358-4360, 2009. R. A. I. Abou-Elkhair, D. W. Dixon, and T. L. Netzel. Synthesis and electrochemical evaluation of conjugates between 2′-deoxyadenosine and modified anthraquinone: Probes for hole transfer studies in DNA. J.Org.Chem. 74 (13):4712-4719, 2009. Y. Cao, D. J. Rabinowitz, D. W. Dixon, and T. L. Netzel. Synthesis, electrochemistry and hydrolysis and anthraquinone derivatives. Synth.Commun., 39, 4230-4238, 2009. M. Ouattara, E. B. Cunha, X. Li, Y.-S. Huang, D. W. Dixon, and Z. Eichenbaum. Shr of Group A Streptococcus is a new type of composite NEAT protein involved in sequestering heme from methemoglobin. Mol.Microbiol. 78 (3):739-756, 2010. R. E. McKnight, E. Reisenauer, M. V. Pintado, S. R. Polasani, and D. W. Dixon. Substituent effect on the preferred DNA binding mode and affinity of a homologous series of naphthalene diimides. Bioorg.Med.Chem.Lett. 21 (14):4288-4291, 2011.