Ulrich Bierbach Assistant Professor Diplom (Chemistry), 1989, University of Oldenburg, Germany Ph.D., 1992, University of Oldenburg, Germany (S. Pohl) Postdoctoral Fellow (German Research Council, DFG), 1992–1993, Leiden University, The Netherlands (J. Reedijk) DFG Research Fellow, 1994–1996, Virginia Commonwealth University (N. Farrell) Research Associate, 1996–1998, Virginia Commonwealth University (N. Farrell) Postdoctoral Research Associate, 1998–1999, University of Minnesota (L. Que, Jr.)

Mailing Address: Chemistry Department, Wake Forest University, Winston-Salem, NC 27109.
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Phone: (336) 758-3507
Homepage: http://www.wfu.edu/academics/bierbachgp
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Research Interests

General Research Interests

Research in my lab explores the modes of action of endogenous biometal sites (e. g., metalloproteins involved in carcinogenesis) and exogenous metal-based drugs. Specifically, transition metal (e. g., Fe, Pt, Rh, Ir) complexes will be developed for therapeutic applications (cancer, AIDS), and their interaction with potential biomolecular targets (DNA, DNA-processing enzymes) will be studied using techniques such as optical and magnetic resonance spectroscopies, electrochemical analysis and molecular biology methods.

Specific Projects

1. Design of Multifunctional Platinum-Based Antitumor Complexes: What are the Factors Causing Irreparable Damage of Small-Molecule Drugs to Double Stranded DNA?

This project involves: Computer-assisted design and synthesis of multifunctional platinum antitumor complexes; drug-DNA binding experiments (topological changes in double-stranded DNA are studied by means of multinuclear/multidimensional NMR spectroscopy, molecular modeling techniques and electrophoretic gel mobility shift assays using plasmid DNA); cytotoxicity studies in vitro and in vivo; DNA repair assays.

2. Development of Rhodium- and Iridium-based Crosslinking and DNA Cleaving Agents for Biochemical and Therapeutic Applications

This project involves: "Biological activation" of kinetically inert Rh(III) and Ir(III) complexes, e.g., for the photodynamic therapy (PDT) of cancer; exploring photochemical properties of redox-labile d⁶ complexes associated with d-d and LMCT states; reactivity in biological media/affinity to potential biological targets (small-molecule models, NMR spectroscopic investigation); DNA-DNA and DNA-protein crosslinking studies; reactivity of metal-nucleic acid conjugates (hydrolytic vs. oxidative nucleic acid degradation relevant to antisense technology); screening for radical pathways (EPR spectroscopy) initiated by photolysis products; cytotoxicity assays.

3. How does Metal-based Ribonucleotide Reductase (RNR) Inhibition Work? Design of a Radical Trap for Probing Subunit R2 Inactivation - RNR as a Target for Anticancer and Antiviral Agents
   
   This project involves: Synthesis of radical scavenging coordination compounds of first-row transition metals (Fe, Ni, Co, Cu) containing redox-labile donor sets; examination of redox and electronic properties (cyclic voltammetry, UV-vis spectroscopy); studies on the radical quenching properties in model systems and in the tyrosine free radical carrying subunit R2 of the native enzyme (bacterial, viral, mammalian) using EPR and rapid-mixing (stopped-flow) UV-vis techniques; antiviral and antitumor activity of the complexes (inhibition of DNA synthesis and antiproliferative effects due to loss of enzymatic activity).

Further Research Interests

(I) Cancer prevention by sulfur and selenium nucleophiles

The interaction of biological and synthetic organosulfur and organoselenium compounds with heme-iron containing enzymes involves various biological effects: (i) Inhibition of cytochrome P450 by such species is known to offer phase I chemoprotection against carcinogenic substrates, probably by inhibiting the monooxygenase activity of the enzyme. The isothiocyanate sulfuraphane, found in edible plants belonging to the family Cruciferae (broccoli, cauliflower, Brussels sprouts), has recently been shown to be an effective anticarcinogen. (ii) Nitric oxide synthase (NOS), which catalyzes the conversion of L-arginine to citrulline and nitric oxide (NO), is inhibited by a variety of S-donors (e. g., thiocitrulline, a thiourea derivative). It has been suggested that such inhibitors may have therapeutic utility in treating hypotension, which results from the overproduction of NO.

Research in this field will focus on structural and mechanistic aspects of the deactivation of the heme-iron cofactors by the above S- and Se-donors using small synthetic models and relevant biological materials.

(II) Metal-based antimetastatic drugs

The major cause of death in patients with solid tumors is not the growth of the primary tumor, but rather the dissemination of secondary lesions outside the boundary of the primary tumor (metastasis). Metastasis is favored by cancer cells that show elevated levels of proteolytic enzymes (membrane degrading metalloproteinases, cysteine proteinases) and cell-adhesion molecules (e. g., glycoproteins).

Future projects will explore the rational design of metal-containing drugs that target the above-mentioned biomolecules critical to tumor metastasis. This project was inspired by the unprecedented antimetastatic activity of a metal complex, trans-[Ru^IIICl₄(dmso)(imidazole)]^-, which probably interacts with a proteolytic system of the cancer cell.

Recent Publications

U. Bierbach, Y. Qu, T. W. Hambley, J. Peroutka, H. L. Nguyen, M. Doedee and N. Farrell: Synthesis, structure, biological activity, and DNA binding of platinum(II) complexes of the type trans-[PtCl₂(NH₃)L] (L = planar nitrogen base). Effect of L and cis/trans isomerism on sequence specificity and unwinding properties observed in globally platinated DNA. Inorg. Chem. 38:3535 (1999).

N. Farrell, Y. Qu, U. Bierbach, M. Valsecchi and E. Menta: Structure-activity relationships within dinuclear and trinuclear platinum phase I clinical anticancer agents. In 30 Years of Cisplatin – Chemistry and Biochemistry of a Leading Anticancer Drug. B. Lippert, ed.; Verlag HCA, Basel, Switzerland, 1999.

U. Bierbach and N. Farrell: Structural and reactivity studies on the ternary system guanine/methionine/trans-[PtCl₂(NH₃)L)] (L = NH₃, quinoline): Implications for the mechanism of action of nonclassical trans-platinum antitumor complexes. JBIC, 3:570 (1998).

A. Zákovscá, O. Nováková, Z. Balcarová, U. Bierbach, N. Farrell, and V. Brabec: DNA interactions of antitumor trans-[PtCl₂(NH₃)quinoline]. Eur. J. Biochem., 254:547 (1998).

U. Bierbach, T. W. Hambley and N. Farrell: Modification of Platinum(II) Antitumor Complexes with Sulfur Ligands. 1. Synthesis, Structure and Spectroscopic Properties of Cationic Complexes of the Types [PtCl(diamine)(L)]NO₃ and [{PtCl(diamine)}₂(L-L)](NO₃)₂ (L = Monofunctional Thiourea Derivative; L-L = Bifunctional Thiourea Derivative). Inorg. Chem. 37:708 (1998).

U. Bierbach, J. D. Roberts and N. Farrell: Modification of Platinum(II) Antitumor Complexes with Sulfur Ligands. 2. Reactivity and Nucleotide Binding Properties of Cationic Complexes of the Types [PtCl(diamine)(L)]NO₃ and [{PtCl(diamine)}₂(L-L)](NO₃)₂ (L = Monofunctional Thiourea Derivative; L-L = Bifunctional Thiourea Derivative) in Relation to Their Cytotoxicity. Inorg. Chem. 37:717 (1998).

U. Bierbach and N. Farrell: Modulation of Nucleotide Binding of Trans-Platinum Complexes by Planar Ligands. A Combined Proton NMR and Molecular Mechanics Study. Inorg. Chem. 36:3657 (1997).

U. Bierbach, T. W. Hambley, J. D. Roberts, and N. Farrell: Oxidative Addition of the Dithiobis(formamidinium) Cation to Platinum(II) Chloro Am(m)ine Compounds: Studies on Structure, Spectroscopic Properties, Reactivity and Cytotoxicity of a New Class of Platinum(IV) Complexes Exhibiting S-Thiourea Coordination. Inorg. Chem. 35:4865 (1996).

U. Bierbach and J. Reedijk: An Unusual Route to Potential Platinum Antitumor Compounds: Synthesis, Reactivity, and Spectroscopic Properties of the Pt^IV Complex fac-[PtCl₃(NH₃)₂L]Cl. Angew. Chem. Int. Ed. Engl. 33:1632 (1994).