Dissertation/Thesis Abstract

Computational Studies of Anti-Tumor Drug Tirapazamine and Reactions and Rearrangements of Nitrenes and Carbenes
by Liu, Jin, Ph.D., The Ohio State University, 2005, 226; 10834914
Abstract (Summary)

The two possible mechanisms of action of the anti-cancer drug tirapazamine have been investigated using density functional theory (DFT). Tirapazamine is inactive in oxygen-rich, healthy cells but is active in oxygen-poor, cancerous cells and induces DNA strand scission. We calculate that the mechanism proceeds via a series of electron-transfer/proton-transfer/fragmentation steps to eventually produce hydroxyl radical in a series of energetically favorable reactions. A direct mechanism involving hydrogen-atom abstraction from the sugar residues by a tirapazamine-centered radical anion or its conjugate acid is not energetically feasible. The calculations predict that tirapazamine, acting as a surrogate for molecular oxygen, can then react exothermically with the sugar-centered radical to oxygenate the radical center and thereby induce the DNA strand break. Related reactions of some tirapazamine analogs were studied.

Calculations were performed to understand the chemical and reactivity differences between acetylnitrene and methoxycarbonylnitrene as well as sulfonylnitrenes. Acetyl azide is calculated to decompose by concerted migration of the methyl group along with nitrogen extrusion. Methoxycarbonyl azide does have a preference for stepwise Curtius rearrangement via the free nitrene. Methanesulfonyl azide prefers to decompose to form singlet methanesulfonylnitrene rather than to extrude nitrogen in concert with sulfurylimine formation. The bimolecular reactions of acetylnitrene, methoxycarbonylnitrene and methanesulfonylnitrene with propane, ethylene and methanol were calculated and found to have enthalpic barriers that are near zero.

Similar calculations were performed on diazoketones, diazoesters and diazoalkanes. We find that conformations in which the migrating group and the diazo moiety have an anti disposition extrude nitrogen and undergo concerted Wolff Rearrangement to form ketene. When these groups have a syn disposition, carbenes are formed, and these intermediates subsequently rearrange. Diazoacetone favors a concerted thermal decomposition and methyl diazoacetate prefer stepwise carbene formation. These preferences are explained with the use of isodesmic equations, and upon consideration of the geometries of the transition states and the free carbenes.

The reactions with oxygen of triplet carbenes and triplet nitrenes were calculated. The fact that triplet carbenes react faster with oxygen than do triplet nitrenes has been explained on the basis of the strength of the bonds being formed.

Indexing (document details)
Advisor: Platz, Matthew
School: The Ohio State University
Department: Chemistry
School Location: United States -- Ohio
Source: DAI-B 79/09(E), Dissertation Abstracts International
Subjects: Chemistry
Keywords: Anti-tumor drug, Carbene, Mechanism, Nitrene, Radcial, Tirapazamine
Publication Number: 10834914
ISBN: 978-0-355-94694-9
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