Date of Award

11-2010

Degree Type

Thesis

Degree Name

MS Chemistry

Department

Chemistry and Biochemistry

Advisor

W. Rorer Murphy

Committee Member

John Sowa

Committee Member

Stephen Kelty

Keywords

DNA Binding, Ruthenium nitro nitrosyl, Tumor, Anti-tumor drugs

Abstract

The complex [Ru(bpy)z(NO)(N02)](PF6)2 was investigated as a potential anti­ tumor drug option. The nitrosyl group was displaced by reaction with azide ion in acetone to yield the solvento complex in situ. The products isolated from addition of a solution or slurry of guanine, adenine, cytosine or thiamine to the resulting [Ru(bpy)(N02)(acetone)t were investigated by electronic absorption spectroscopy, infra­ 1 red spectroscopy, H NMR spectroscopy and cyclic voltammetry. The results of the studies showed that guanine, adenine and thiamine form adducts with Ru(bpy)z(N02)(acetone)t. However, each base forms a unique complex as shown by electronic spectroscopy. Guanine is the strongest field ligand, indicating likely coordination to N-7. The spectrum of the adenine adduct was consistent with the ligand exerting a slightly weaker field than guanine. This may be indicative of binding to the primary amine site. The thiamine adduct was weaker field yet, but still clearly different from the solvento complex. Thiamine presents several potential binding sites, thus, many may be involved. Cytosine showed no evidence of binding. In the case of adenine and thiamine, the hydrochloride salts were used, and gave the unexpected, but welcome, result of converting some of the nitro complexes to the corresponding nitrosyl, [Ru(bpy)2(NO)(base)]\ according to well-known chemistry. The pK. for the nitro to nitrosyl conversion is typically around 6.4, which indicates that under physiological conditions, a significant fraction of the complex will be in the nitrosyl form. As it is known that biologically active reducing agents such as NAD+ can reduce coordinated nitrosyls to the nitroxyl radical (and even further, to NH3, given sufficient reducing equivalents), the chemistry described above presents a viable method for introducing the nitroxyl radical into DNA. Since tumors tend to be hypoxic, formation of site specifically localized nitroxyl radical can have profound implications. As further proof of concept, Z8A 8 mer (CG)4 DNA strand was reacted with excess ruthenium nitro nitrosyl compound, and separated via size exclusion chromatography. Two distinct bands were observed when the sample was running through the burette, demonstrating that the ruthenium complex did in fact bond to the (CG)4 DNA sequence.

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