Jeffrey M. Zaleski

Background:

• Jane Coffin Childs Postdoctoral Fellow, Stanford University, 1993-96
• Indiana University Teaching Excellence Recognition Award, 1998 and 2000

The design and function of novel pharmaceutical agents or reaction pathways involving transition metal complexes currently constitute one of the frontiers of inorganic chemistry. This broad area of research possesses several facets including the following: (1) the determination of structure/function relationships of enzyme active sites for the design of potent enzyme activators or inhibitors, (2) investigation of the interaction of therapeutic complexes with their specific targets, (3) the development of strategies to initiate novel reactivity, and (4) the evolution of experimental approaches to probe the details of important biological reactions. Progress in each of these areas is essential to an understanding of how more effective drugs can be prepared.

Research being conducted in my group is fundamental to these general themes. Our primary focus is the use of various steady state and time-resolved spectroscopic methods including optical absorption, Raman, and circular dichroism to investigate the structure and kinetics of biologically relevant intermediates involved in enzyme and drug-related reaction mechanisms. This information is important for determining the pathways by which multistep biochemical reactions occur.

In addition, we are interested in designing strategies to promote novel biochemical reactivity using excited-state photochemistry. The absorption of photons by molecules can be used to trigger release of ligands or redistribute charge within a complex. This leads to the formation of transient molecular and electronic structures that are highly reactive with biological substrates. Our goal is to study the structure and kinetics of these excited-state transients in order to prepare complexes with novel chemical reactivity.

One specific area of research is the design of photoactivatable DNA cleaving agents. DNA cleaving agents are particularly important because they play a prominent role in anticancer therapy and molecular biology. Many systems currently being studied rely on thermodynamically favorable chemical reactions involving reducing agents, hydrogen peroxide, or molecular oxygen. The efficiency, selectivity, and toxicity of these DNA cleavers are governed by several molecular properties that are difficult to control in concert. Photodynamic therapy has attempted to eliminate some of these parameters by driving antitumor reactions photochemically through generation of singlet oxygen. Although this approach has proven fruitful, the bimolecular nature of the reaction diminishes the effectiveness and specificity. Therefore, we are interested in the design of unimolecular DNA cleavers that can be triggered via low energy optical excitation. The strategy we are currently investigating involves the formation of excited state biradical species by either direct excitation or electron transfer. These reactive intermediates are potentially capable of performing hydrogen atom abstraction from DNA and hence double stranded cleavage.

Selected Publications:

"Direct spectroscopic detection of a Zwitterionic excited state," with D. Engelbretson, G. E. Leroi, and D. G. Nocera. Science, 265, 759 (1994).

"Spectroscopic definition of the geometric and electronic structure of the non-heme ferrous active site in bleomycin: correlation with oxygen reactivity," with K. E. Loeb, et al. J. Am. Chem. Soc., 117, 4545 (1995).

"Spectroscopic investigation of the metal ligation and reactivity of the ferrous active sites of bleomycin and bleomycin derivatives," with K. E. Loeb, C. D. Hess, S. M. Hecht, and E. I. Solomon. J. Am. Chem. Soc., 120, 1249 (1998).

"Spectroscopic investigation of reduced protocatechuate 3,4-dioxygenase: charge-induced alterations in the active site iron coordination environment," with M. I. Davis, et al. Inorg. Chem., 38, 3676 (1999).

"Transition metal Kinamycin model as DNA-photocleavers for hypoxic environments: bis(9-diazo-4,5-diazafluorene) copper(II) nitrate," with H. J. Eppley, S. M. Lato, and A. D. Ellington. Chem. Commun., 23, 2405 (1999).

"Photoactivated DNA-cleavage via charge transfer promoted N₂ release from tris[3-hydroxy-1,2,3-benzotriazine-4(3H)-one]iron(III)," with T. D. Maurer, S. M. Lato, and A. D. Ellington. Chem. Commun., 24, 69 (2000).

"Metalloenediynes: ligand field control of Bergman cyclizations," with P. J. Benites. J. Am. Chem. Soc., 122 (2000).

"Structure and thermal reactivity of a novel Pd(0) metalloenediyne," with N. S. Coalter et al. J. Am. Chem. Soc., 122, 3112 (2000).

"Mg2 -induced thermal enediyne cyclization at ambient temperature," with D. S. Rawat. J. Am. Chem. Soc., 123, 9675 (2001).

"UDFT and MCSCF descriptions of photochemical Bergman cyclization of enediynes," with A. E. Clark and E. R. Davidson. J. Am. Chem. Soc., 123, 2650 (2001).

"Cu(II) mediated intramolecular carbene cation radical formation: relevance to unimolecular metal-ligand radical intermediates," with B. J. Kraft, H. J. Eppley, and J. C. Huffman. J. Am Chem. Soc., 124, 272 (2002).