Date of Award

Spring 1-1-2012

Document Type


Degree Name

Doctor of Philosophy (PhD)


Chemistry & Biochemistry

First Advisor

Tad H. Koch

Second Advisor

Dylan J. Taatjes

Third Advisor

Dave Walba

Fourth Advisor

Terry Potter

Fifth Advisor

Christopher Bowman


Doxorubicin (Dox) is an antitumor drug that has been used as a chemotherapeutic agent in the clinic for over 30 years. Dox treatments have been hindered by significant dose limiting cardiotoxic effects resulting in irreversible cardiomyopathy. A Dox variant, Doxazolidine (Doxaz) is a Dox-formaldehyde conjugate discovered in the Koch lab. Doxaz operates via a distinct mechanism, and exhibits an improved therapeutic profile compared to Dox. Doxaz suffers from poor aqueous stability; however, stabilization of Doxaz has been achieved through the use of enzymatically activated carbamate prodrugs. This thesis presents the synthesis and preliminary evaluation of Doxaz prodrugs intended for commercialization. The prodrugs contain the active platform therapeutic (Doxaz), an enzyme cleavage site, a self-eliminating spacer to increase cleavage efficiency, and in some cases, a maleimide moiety for passive targeting through albumin biniding. The enzymes targeted are proteases such as plasmin and cathepsin B. Also presented are prodrugs aimed at tumor associated hypoxia and enzymes such as NQO1 and NQO2. The synthesis of these prodrugs places an emphasis on scalable manufacturing processes. These prodrugs are currently, or will be undergoing complete biological characterization and animal studies in varying species.

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Chemistry Commons