DOI

10.17077/etd.2kl2-023b

Document Type

Dissertation

Date of Degree

Fall 2018

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmaceutical Sciences and Experimental Therapeutics

First Advisor

Kerns, Robert J.

First Committee Member

Doorn, Jonathan

Second Committee Member

Hiasa, Hiroshi

Third Committee Member

Roman, David

Fourth Committee Member

Wu, Meng

Fifth Committee Member

Jin, Zhendong

Abstract

DNA topoisomerases are responsible for managing the topology of DNA and play critical roles in many biological processes involving DNA. DNA topoisomerases are known therapeutic targets of several successful anticancer chemotherapeutics. Most clinically used topoisomerase-targeting anticancer drugs convert the enzyme into a cellular poison by trapping a covalent topoisomerase-DNA catalytic intermediate as a topoisomerase-drug-DNA ternary complex. Formation of ternary complex leads to cytotoxic events, such as inhibition of DNA replication, DNA strand breaks, and ultimately cell death. This mode of action is associated with the development of secondary leukemias and cardiotoxicity.

Two lead molecules were discovered that catalytically inhibit human topoisomerase I and II. The lead molecules guiding this work do not act as topoisomerase poisons, which may eliminate some of the severe side effects associated with current topoisomerase-targeting agents. These lead molecules were found to exhibit anti-proliferative activity against several cancer cell lines in cell culture and against colon cancer in an animal model. Thus, these novel small molecules or their structural derivatives with improved human topoisomerase I inhibitory activity and biophysical properties, may be developed as novel anticancer therapeutics.

An important objective of this work was to explore structural requirements required for inhibition of human topoisomerases I and II. To achieve this objective, functional group modifications to the N-1, C-3, C-6, C-7, and C-8 positions of the quinolone core were explored to gain an understanding of structural requirements for inhibition of human topoisomerases while striving to improve potency and biophysical properties.

In addition to exploration of structural requirements for human topoisomerase inhibition, the in vitro anti-proliferative activity of novel fluoroquinolone analogs identified was determined. As fluoroquinolones are known to partially intercalate DNA, the role of N-1 aryl fluoroquinolone-DNA binding in anti-proliferative activity and human topoisomerase I inhibition was also evaluated.

Pages

xxii, 216 pages

Bibliography

Includes bibliographical references (pages 144-155).

Copyright

Copyright © 2018 Justine Lane Delgado

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