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Associate Member, Materials
Science Institute
Associate Member, Institute
of Molecular Biology
B.S., University of Massachusetts, North Dartmouth, 1976. Ph.D., Harvard University, 1981 (R. B. Woodward). Postdoctoral: Massachusetts Institute of Technology, 1981-83 (Christopher Walsh). Honors and Awards: NIH Postdoctoral Fellow, 1981-83; Alfred P. Sloan Fellow, 1987-89; Visiting Professor, Phillips Universitat, Marburg, Germany, 1991; Visiting Professor, Harvard University, 1992, 1993. At Oregon since 1983.
Research Interests
Single-Molecule Molecular Motors
In Nature there are many spectacular examples of nanoscale molecular devices. Molecular switches are common. Molecular motors are also widespread. We are working on creating synthetic non-biological molecular motors. Part of the inspiration for this project comes from biology. Part comes from recent developments in nanochemistry and nanotechnology. We are focusing on rotary motors. Our approach will use energy-driven diastereoselective reactions in chiral molecules to drive repeated 360-degree bond rotation in a preferred direction.
Oxidatively-Activated Self-Regulating Antioxidants
Many common antioxidants also have pro-oxidant activity. For example, when vitamin E is at highconcentration vitamin E radical can act as a pro-oxidant initiator of lipid peroxidation. We are designing and testing new synthetic antioxidants which have the antioxidant and pro-oxidant activity blocked by an oxidatively-removable protecting group. When autoxidation chain reactions are occurring, the protecting group should be oxidized then removed to release a standard antioxidant, such as vitamin E, which can suppress autoxidation chain reactions. The overall result should be low concentrations of active antioxidant/pro-oxidant molecules yet have the ability to respond to, and suppress, autoxidation reactions by sensing them then releasing antioxidant molecules.
In addition to antioxidant activity, the molecules we are designing and testing should be useful for several fundamental and applied areas of study. The oxidatively-released blocking group could be used to mask a fluorescent probe, producing a fluorescent signal when oxidative activity is detected. Tumors and infections are often sites of elevated oxidative activity forming so-called reactive oxygen species (ROS). The oxidatively-released blocking group could be used to mask potent anticancer agents or antibiotics, for oxidatively-mediated site-specific release at the tumor or site of infection.
Enzyme-Mimetic Molecularly-Imprinted Polymers as Oxidation Catalysts
Oxidase enzymes oxidize substrates using molecular oxygen. Synthetic non-biological oxidases could be useful catalysts in organic chemistry. Molecularly imprinted polymers imprinted with redox-active cofactors and a binding site for substrates could become important new oxidation catalysts. Polymer-bound catalysts provide easy workup of reactions by simple filtration. Catalyst selectivity can be custom-tailored in the imprinting process. The catalysts should be environmentally-friendly with molecular oxygen as the oxidant. The only by product is H2O2 which is easy to disproportionate to molecular oxygen and water.
Oxidase reaction: RR'CHOH + O2 => RR'C=O + H2O2
Catalase or catalase-mimetic reaction: H2O2 => 1/2 O2 + H2O
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Overall Reaction: RR'CHOH + O2 => RR'C=O + 1/2 O2 + H2O
Design, Synthesis and Testing of Malate Synthase Inhibitors as New Types of Antibiotic
The glyoxylate shunt pathway is used by microorganisms to metabolize acetate or long chain fatty acids as a source of carbon. It diverts intermediates away from the tricarboxylic acid (TCA) cycle when the organisms are exposed to low oxygen conditions.
The glyoxylate shunt pathway has recently been recognized as new target for the design of antibiotics. Yeast and bacteria contain the pathways but humans do not. Thus, inhibitors of enzymes in the glyoxylate shunt pathway might be effective new types of antibacterial and antifungal agents. This is an especially timely topic because many deaths in AIDS patients are caused by yeast infections with Candida albicans and by bacterial infections with Mycobacterium tuberculosis. A recent summary of this topic can be found on the website of the journal Nature: http://www.nature.com/nsu/010705/010705-10.html.
Two of the five enzymes in the glyoxylate shunt pathway are unique to that pathway and are not found in humans. Those enzymes are isocitrate lyase and malate synthase. The Remington group at Oregon has previously solved the structure of malate synthase. Recently they have solved the structure with substrates or substrate analogs bound. This result is significant because that structure can be used to guide the design of potent inhbitors of malate synthase. Such inhibitors can be expected to be selective agents against fungi and bacteria, targeting their glyoxylate shunt pathway, without (ideally) significantly affecting any human enzymes and pathways.
The collaboration between the Branchaud and Remington groups involves the design, synthesis and evaluation of malate synthase inhibitors. This project will involve molecular modeling, organic synthesis, testing of enzyme-inhibitory properties, protein crystallography of enzyme-inhibitor complexes, and testing of antibiotic activity. It is unlikely that any single person could do all of those things, but organic chemists and biochemists can play major roles in different aspects of the project. Recently a couple of good lead compounds have been discovered.
Selected Publications:
"ATP Analogs with Non-transferable Groups in the g Position As Inhibitors of Glycerol Kinase", Bystrom, C. E.; Pettigrew, D. W.; Remington, S. J.; Branchaud, B. P. Bioorganic & Medicinal Chemistry Letters 1997, 7, 2613-2616.
"b-Haloethanol Substrates As Probes For Radical Mechanisms For Galactose Oxidase", Wachter, R. M.; Montague-Smith, M.; Branchaud, B. P. The Journal of the American Chemical Society 1997, 119, 7743-7749.
"A Synthesis of (-)-Tashiromine and Formal Synthesis of (+)-Tashiromine Utilizing a Highly Enantioselective Pyrrole/Cobaloxime ¹-Cation Cyclization", Gage, J. L..; Branchaud, B. P. Tetrahedron Letters 1997, 38, 7007-7010.
"Cross Coupling of Alkyl Cobaloximes With Maleic Anhydrides. Basic Studies and Applications to the Synthesis of Chaetomellic Acid A And C-Glycoside Maleic Anhydrides", Slade, R. M.; Branchaud, B. P. The Journal of Organic Chemistry 1998, 63, 3544-3549.
"An Approach to (+)-Pancratistatin from D-Glucose: A Conformational Lock Solves A Stereochemical Problem", Grubb, L. M.; Dowdy, A. L.; Blanchette, H. S.; Friestad, G. K.;; Branchaud, B.P. Tetrahedron Letters 1999, 40, 2691-2694.
To Contact Dr. Branchaud:
Phone: 541-346-4627
bbranch@oregon.uoregon.edu
WEBMASTER
lynde@oregon.uoregon.edu
