MSU Chemistry and Biochemistry Research

Description coming soon.

There are two basic areas of research I am involved in:

         1. I'm working to evaluate and modify the laboratory curriculum for the general chemistry courses. The evaluation process started with an open-ended survey and will eventually move into conducting one-on-one or group interviews with students and faculty involved with the curriculum. Modifications involve creating and implementing new experiments, transcribing existing experiments into electronic form, integrating inquiry based procedures, and updating the supplementary exercises from each experiment.

         2. The second interest I have is in how students at all levels approach data acquisition in their chemistry laboratory classes. More specifically, how do students approach an experiment, what are their views toward that experiment, and how do their views affect their approach and data analysis. These issues can be directly related to student's perceptions of academic dishonesty in the classroom laboratory. Currently, I am working with students at the high school level.

Study of secretase linked with Alzheimer's disease, kinetic studies of triosephosphateisomerase, isolation and characteriztion of DNA and RNA related to enzymes.

Interactions of protons and zinc²⁺ ions with 9-anthrylmethyl- bis (2-picolyl)amine display unique fluorescence behavior. With protons the fluoresence in off at low pH, on at mediium pH, and off again at high pH (ie the molecule functions as an off-on-on switch for protons. In contrast, the molecule responds to zinc²⁺ ions as an off-on switch with flouresence increasing with the zinc²⁺ ion concentration. This research may lead to more efficeinet sensors for Zn²⁺ ions. The structure of the ZnCl₂ Complex of -anthrylmethyl-bis(2-picolyl)amine is shown below.

Construction and use of modified electrodes as species specific sensors, synthesis and study of novel photoactive transition metal complexes.

A promising new anticancer drug is Thymitaq (See structure below, left). Although this drug displays significant antitumor activity, it unfortunately exhibits several undesirable side effects. A well known strategy in drug research is to prepare compounds with similar structures to a effective compound with hopes that the new compound will meet or surpass the antitumor efficiency of the original drug while minimizing or eliminating the detremental effects. Such an analog was designed, synthesized, and characterized (See structure below, right). This new compound is to be submitted for drug screening.

Computational studies of the conformational energies of various heterocyles.

Targeting Antibiotic Resistance: Mechanism-Based Drug Design of Metallo-Lactamases Inhibitors

       Carbapenems such as imipenem have proven to be useful for the treatment of a variety of Gram-negative and Gram-positive infections. Carbapenems and other b-lactam antibiotics covalently modify penicillin-binding proteins (PBPs) involved in the peptidoglycan biosynthetic pathway of cell wall assembly in bacteria. Resistance to carbapenems can arise due to acquisition of low-affinity PBPs (e.g.,PBP2a of Staphylococcus aureus (S. aureus)), altered membrane permeability and/or expression of class A, B and D b-lactamases. Metallo-b-lactamases (MBLs) can hydrolyze a wide variety of substrates, including carbapenems (see below) as well as penicillin and cephalosporin members of the b-lactam class, rendering them ineffective as antibiotics. My research will focus initially on inhibitors of MBLs which may be useful in combination with carbapenem antibiotics against resistant bacterial strains. Many of the MBL inhibitors described in the literature interact with the binuclear Zn core of the enzyme active site thereby preventing nucleophilic attack of the carbapenem by the bridging water/hydroxide between the two Zn atoms. I will be collaborating with research groups from MSU and other Universities as well as from pharmaceutical laboratories to identify novel MBL inhibitors to aid our understanding of the hydrolytic mechanism.

UPDATE Toney Laboratory, Summer 2003

The laboratory has been buzzing with activity this summer with three independent study students from MSU, two students from the Undergraduate Program in Technology and Medicine at the Stevens Institute, two high school students from the Weston Scholars Program, and one high school student from the American Chemical Society’s SEED Program. In addition, Dr. Goutam Chakraborty, the new research associate kept things going smoothly. Current research projects include studying mechanisms of antibiotic resistance, the effect of dietary oils on pancreatic cells and, more recently, the main viral proteinase encoded by the SARS human coranvirus. These research projects have depended upon key collaborations with MSU faculty members. These currently include

• Prof. Andreas Koeller (ComputerScience; computer modeling of SARS viral proteinase1)
• Prof. Reginald Halaby (Biology; apoptosis in pancreatic cells)
• Prof. Shahla Wunderlich (Human Ecology; insulin secretion in pancreatic cells)
• Prof. Charles Du (Biology; microarray analysis of bacterial clinical pathogens)

In addition, collaborative research has been established with Prof. Edward Hyde at Rockefeller University to search for inhibitors of a bacterial antibiotic resistance factor using a chemical collection of >20,000 compounds. To that end, a collection of approx. 2,000 compounds have been obtained free of charge from the National Cancer Institute to test in our enzyme assays, available free of charge to academic investigators.

Recent Publications

1. Toney, J.H. Iseganan (Protegrin IB-367). Curr Opin Investig Drugs 2003 3, 225-228.
2. Toney, J.H. (2003). Cefetamet pivoxil. The Investigational Drugs Database.
3. Toney, J.H. (2003). PncCRM9 Antibacterial Vaccine. The Investigational Drugs Database.
4. Toney, J.H. Metallo-beta-lactamase inhibitors: could they give old antibacterials new life? Curr Opin Investig Drugs 2003, 4, 115-116.
5. Toney, J.H., Ogawa, A., Blair, M., and Park, Y.-W. A "mix and read" assay for insulin using fluorometric microvolume assay technology. Assay and Drug Development Technologies 2003, 1(4), 521-525.
6. Toney, J.H., and Koeller, A. Sabadinine: a potential non-peptide anti- SARS agent identified using structure-aided design. Journal of Medicinal Chemistry 2003, accepted.

Histidine is a common ligand for metal atoms in proteins. The imidazole portion of the histidine side chain often forms hydrogen bonds to hydrogen bond accepting groups in the protein. These hydrogen bond interactions are being studied in model compounds with formula [M(Im)₆](RCOO) ₂ (where Im = imidazole, and RCOO = a carboxylate ion). The M-Im-OOCR unit with a hydrogen bond between the imidazole N-H and and the carboxylate is a good mimic for a similar M-histidine-carboxylate hydrogen bonding interaction found in proteins. Because the model compound is easier to modify than the protein, a series of model complexes in which M and R are varied should lead to a better understanding of the structural and electronic properties of the hydrogen bonding interaction.