Date of Award

January 2015

Degree Type


Degree Name

Doctor of Philosophy (PhD)


Medicinal Chemistry and Molecular Pharmacology

First Advisor

Mark Cushman

Committee Member 1

Casey Krusemark

Committee Member 2

Markus Lill

Committee Member 3

Gregory Knipp


The research in this thesis is focused on the design, synthesis, and biological evaluation of indenoisoquinolines that inhibit the human topoisomerase IB enzyme (Top1). At present, there are only two FDA-approved cancer chemotherapeutic drugs that target this enzyme. These agents bind to a covalent Top1-DNA cleavage complex intermediate that is formed when Top1 relaxes supercoiled DNA. The effect of this stabilization is that a DNA replication fork can “collide” with the cleavage complex, which produces cytotoxic DNA damage products. Although the present arsenal of Top1 inhibitors is effective in the treatment of solid tumors, their common camptothecin-based structure is plagued by physicochemical and pharmacological issues. For these reasons, alternative structures with Top1 inhibitory activity are currently needed. The objectives of this research were to: (1) establish new and improved synthetic routes to three clinically studied Top1 inhibitors that are based on an indenoisoquinoline scaffold; (2) investigate the structure-activity relationships (S.A.R.) of indenoisoquinolines substituted with carbohydrate-derived and carbohydrate-mimetic moieties; (3) seek out bioisosteric replacements for the nitro group in the highly active 3-nitroindenoisoquinoline Top1 inhibitor series; and (4) design and test dimeric indenoisoquinolines that could