Human Topoisomerase IB (TOP1) and Topoisomerase II? (TOP2?) are essential nuclear enzymes that control DNA topology during DNA replication, gene transcription and cell division. These enzymes carry out their catalytic function by making transient single-strand (type I) or double-strand (type II) breaks in the DNA. In vivo, these complexes are short-lived but can be exploited by anti-cancer drugs to mechanistically kill cancer cells. Two general classes of compounds can kill cancer cells through a topo-targeted mechanism. Interfacial Poisons (IFPs) act at the enzyme-DNA interface to inhibit the religation reaction, resulting in the accumulation of DNA double-stand breaks (DSBs) in the genomic setting. Catalytic Inhibitor Compounds (CICs) act by interfering with other steps of the catalytic cycles such as DNA/protein binding or the cleavage reaction. In this work we identify new Au3+ macrocyclic gold complexes that act as CICs of both TOP1 and TOP2?. The complexes exhibit square planar geometry with an aromatic system that allows for DNA intercalation with binding affinities in the low micromolar range. A cytotoxicity screen across 60 human cancer cell lines performed by the National Cancer Institute (NCI, USA) reveals significant anti-tumor potential. Our lead compound (butyl gold(III) macrocycle, cmpd 3.) is currently undergoing further studies in animal models at the NCI. In vitro assays with purified DNA and enzyme reveal the Au3+ ion to be the quintessential switch that allows for DNA intercalation and subsequent inhibition of TOP1 and TOP2?.
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Muller, Mark T.
Bachelor of Science (B.S.)
Burnett School of Biomedical Sciences
Molecular Biology and Microbiology
Dissertations, Academic -- Medicine;Medicine -- Dissertations, Academic
Length of Campus-only Access
Honors in the Major Thesis
Fagenson, Alexander, "Gold (iii) macrocycles are dna intercalators that inhibit topoisomerase i and ii" (2012). HIM 1990-2015. 1262.