Graduate Study in - Chemistry - Johns Hopkins University

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David P. Goldberg Inorganic Chemistry Bioinorganic Chemistry Environmental Chemistry dpg@jhu.edu Our research addresses a number of interesting challenges in inorganic/bioinorganic chemistry. Currently, our group is divided into two main areas. Part of our research group is interested in the synthesis, physical properties and reactivity of new porphyrinoid compounds. We have recently discovered a method for synthesizing corrolazines, a new class of porphyrin-like compounds that are related to ring-contracted compounds called corroles. Corroles, known for over 30 years, have a remarkable advantage over porphyrins in stabilizing high-valent oxidation states (e.g. Mn V , Fe IV , Co IV , Ni III ), yet little is known about their ability to function as catalysts and/or mimics for biological systems because of the difficulties encountered in their preparation. We have synthesized Co, Ni, Cu, Mn, and Fe corrolazines, and are now mapping out a new area of metallocorrolazine reactivity and catalysis. Applications immediately envisioned for these complexes include their reactivity toward O 2 and H 2 O 2 for oxygen activation, the oxygenation/functionalization of substrates such as hydrocarbons, and their use in mediating the dehalogenation of environmentally significant organohalides. In another area, we are designing and synthesizing small-molecule analogues of the active sites of certain metalloproteins. Many biological processes rely on transition metals to effect catalytic reactions. For example, peptide deformylase (PDF) relies on an unusual (His) 2 (Cys)Fe II (OH 2 ) active site for deformylation during bacterial protein synthesis. We have synthesized new N 2 S thiolate ligands to mimic the His 2 Cys coordination sphere found in PDF, and have prepared a family of new transition metal complexes with these ligands. Some of these complexes represent stabilized forms of intermediates postulated to exist during catalysis, such as [(PATH)Zn(formate)], which was prepared from the useful synthon [(PATH)Zn(Me)]. Other complexes exhibit the functional capacity to effect the hydrolysis of certain substrates (e.g. esters), and these reactions are being examined through kinetic studies. We have recently prepared new, more elaborate ligands with imidazole donors and are exploring their transition metal chemistry, including dinuclear, hydroxo-bridged zinc complexes that are relevant to enzymes that cleave DNA and RNA. The study of these complexes will shed light on the fundamental role of metal ions in the related biological systems, and may lead to the development of industrially important catalysts and novel pharmaceutical agents. Ph.D. Massachusetts Institute of Technology NIH Postdoctoral Fellow, Northwestern University NSF CAREER Award Alfred P. Sloan Research Fellowship Recent publications include: Chang, S.; Karambelkar, V. V.; di Targiani, R. C.; Goldberg D. P. “Model Complexes of the Active Site of Peptide Deformylase: A New Family of Mononuclear N 2 S-M II Complexes,” Inorg. Chem., 2001, 40, 194-195. Ramdhanie, B.; Stern, C. L.; Goldberg. D. P. “Synthesis of the First Corrolazine: A New Member of the Porphyrinoid Family” J. Am. Chem. Soc., 2001, 123, 9447-9448. Chang, S.; Sommer, R.; Rheingold, A.; Goldberg, D. P. “A Model Complex of a Possible Intermediate in the Mechanism of Action of Peptide Deformylase: First Example of an N 2 SZn-formate Complex,” J. Chem. Soc., Chem. Commun., 2001, 2396-2397. Chang, S.; Karambelkar, V. V.; Sommer, R.; Rheingold, A.; Goldberg, D. P. “New Monomeric Cobalt(II) and Zinc(II) Complexes of a Mixed N,S(alkylthiolate) Ligand: Model Complexes of (His)(His)(Cys) Metalloprotein Active Sites,”Inorg. Chem. 2001, 41, 239- 248. Graduate Study in Chemistry at The Johns Hopkins University 11
Marc M. Greenberg Organic and Bioorganic Chemistry mgreenberg@jhu.edu Ph.D., Yale University American Cancer Society Postdoctoral Fellow, California Institute of Technology Alfred P. Sloan Research Fellowship As the carrier of genetic information, it is no surprise that DNA damage and repair is important in aging and a variety of genetically based diseases, such as cancer. However, modified nucleic acids are becoming increasingly important as diagnostic tools and therapeutic agents. The pivotal roles of DNA in chemistry and biology are interwoven. For instance, the reactivity of DNA with reactive oxygen species determines the types of structural modifications (lesions) formed. The interaction of lesions with repair and polymerase enzymes in turn determines their biological effects. Identifying the location and level of DNA lesions in the genome may assist the diagnosis and treatment approach of disease. Our research group uses organic chemistry to address questions concerning the reactivity, function, structure, and uses of nucleic acids. Examples of current projects in our group are: • determining how nucleic acids are oxidatively damaged by synthesizing molecules (e.g 1) that enable us to independently generate reactive intermediates at defined sites in DNA. • elucidating the effects of specific DNA lesions (e.g. 2, 3) on the function of nucleic acids, and their structural basis. • the development of methods and applications for modified oligonucleotide synthesis. To bring these projects to fruition we synthesize novel molecules and study their behavior using a variety of physicochemical, biochemical, and biological techniques. Recent accomplishments by our research group in these areas include: • the discovery of novel pathways for DNA damage that produce tandem lesions (Scheme 1). • the discovery of the first example of irreversible inhibition of DNA repair by a DNA lesion (Scheme 2). • the first synthesis of oligonucleotides containing formamidopyrimidine lesions (e.g. Fapy•dG) and determination of their effects on DNA repair and polymerase enzymes. • the development of highly efficient, convergent methods for oligonucleotide conjugate synthesis. In addition to continuing these research projects, the above discoveries have given rise to new projects in our group that include the development of novel radiosensitizing agents and mechanism based inhibitors of DNA repair enzymes. Selected publications include: Fapy•dA Induces Nucleotide Misincorporation Translesionally by a DNA Polymerase. Delaney, M. O.; Wiederholt, C. J.; Greenberg, M. M. Angew. Chem. Int. Ed. 2002, 41, 771. Oxygen Dependent DNA Damage Amplification Involving 5,6-Dihydrothymidin-5-yl in a Structurally Minimal System. Tallman, K. A.; Greenberg, M. M. J. Am. Chem. Soc. 2001, 123, 5181. (3) The 2-Deoxyribonolactone Lesion Produced in DNA by Neocarzinostatin and Other DNA Damaging Agents Forms Cross-Links with the Base-Excision Repair Enzyme Endonuclease III. Hashimoto, M.; Greenberg, M. M.; Kow, Y. W.; Hwang, J.-T.; Cunningham, R. P. J. Am. Chem. Soc. 2001, 123, 3161. Introducing Structural Diversity in Oligonucleotides Via Photolabile, Convertible C5-Substituted Nucleotides. Kahl, J. D.; Greenberg, M. M. J. Am. Chem. Soc. 1999, 121, 597. Scheme 1 Scheme 2 1 2 12 Graduate Study in Chemistry at The Johns Hopkins University
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