Richard A. Manderville, Associate Professor
Honours., 1986, Queen's University,
Ph.D., 1992, Physical Organic Chemistry, Queen's University (Erwin Buncel)
Research Associate 1992-1995, BioOrganic Chemistry,
Professor of Chemistry, 1995-2001,
Professor of Chemistry, 2001-2004,
Department of Chemistry,
Tel: (519)-824-4120, Ext. 53963
Our research program focuses broadly on DNA interactions of xenobiotics that possess diverse biological activities. One area of study stems from our discovery that phenolic xenobiotics attach covalently to DNA and form carbon-(C) and oxygen-(O)-bonded C8-deoxyguanosine (dG) adducts through the intermediacy of the phenoxyl radical. Phenoxyl radicals are one-electron oxidation products of phenols that have been identified in numerous biological systems and are implicated in cancer and aging. Since the physical characteristics of phenolic C8-dG adducts within duplex DNA is not known, and given that this knowledge can lead to an understanding of their biological consequences, we wish to establish their chemical syntheses and incorporate them into DNA for structural characterization. This effort is predicted to determine their impact on duplex DNA structure, and provide diverse DNAs with new base-pairing, metal-binding, fluorescence and redox properties. The adducted DNAs will serve as DNA structural probes, substrates for biological studies on adduct mutagenicity, adduct repair or lack thereof, and as cancer chemopreventives. The long-term goal of this research program is, therefore, to provide the tools and methodologies needed to better understand the consequences of C8-dG attachment by phenolic substrates that include: human-made toxins, natural xenobiotics, anticancer agents, and proteins that contain tyrosine residues. With this can come a better understanding of their relationship to aging, mutagenicity and cancer.
Ambident Reactivity of Phenoxyl Radicals at C8 of dG.
A second, and more specific, project in our laboratory centers on gaining an understanding of the cancer-causing properties of ochratoxin A (OTA). OTA is a natural fungal toxin that is implicated in human kidney cancer. Our studies suggest that OTA is a genotoxin that reacts directly with DNA to form covalent DNA adducts that may initiate tumorigenesis. Currently, we wish to establish in vivo evidence for OTA-mediated DNA adducts using mass spectrometry and to incorporate OTA-adducts into duplex DNA for further study.
Ochratoxin A (OTA)
Students who are interested in graduate studies and wish to gain useful synthetic skills and acquire experience with a variety of spectroscopic tools are encouraged to inquire about projects in this area of BioOrganic chemistry.--READ MORE--