Abstract:
Chromium(VI) complexes are potent mutagens and carcinogens when inhaled, while the potential of these complexes to generate similar effects when taken orally is an area of active debate. The focus on this work is to investigate how chromium binds to DNA on a molecular level. The exact mechanism(s) of action of this activity is unknown, but potential mechanisms can be grouped into two categories. The first is mechanisms associated with redox chemistry during reduction of Cr(VI). Numerous studies have been focused on studying this potential mechanism. The second mechanism is based on the generated Cr(III) binding to DNA to form binary and ternary complexes. Virtually no data on the molecular level structure of these Cr(III)- DNA complexes exists. Such studies are complicated by the spectroscopic and magnetic properties of Cr(III). Second, previous studies have used plasmid DNA, DNA polymers, calf thymus DNA, or DNA isolated from cultured cells, which because of their size and complexity, present numerous potential Cr-binding sites with a range of binding constants. What is required to determine the preferential sites for Cr-binding and to characterize the structure of these sites is the use of DNA oligomers significantly smaller in size whose base sequences can be carefully designed and which can be synthesized in appreciable quantities. Results of spectroscopic and magnetic studies (1H and 31P nuclear magnetic resonance spectroscopy including multidimensional techniques, pulsed electron paramagnetic resonance spectroscopy, and infrared spectroscopy) to characterize the binding of Cr(III) to such DNA oligomers indicate that Cr(III) as [Cr(H2O)5]3+ can bind specifically to the guanine N7 position of B-form double stranded DNA without direct interaction with the phosphate backbone and resulting in minimal distortions in iii the structure of the DNA. A potential Cr(III)-based inter-strand crosslink of DNA has been characterized. Preliminary steps to synthesize and characterize ternary Cr(III)-small molecule- DNA compounds have been investigated.
