With this renewal award the Organic and Macromolecular Chemistry Program continues its support for the work of Dr. Edward. B. Skibo of the Department of Chemistry at Arizona State University in Tempe, Arizona. The research builds on earlier work studying reactive intermediates such as quinone methides, cyclopropyl quinone methides, activated aziridines, and iminium ions. Methods were developed to synthesize mitosenes labeled with 13C at the 1- and 10- positions using single-carbon 13C starting materials. These labeled mitosenes and similarly labeled aziridines incorporated into other know aklylating agents will be used to study the chemo and regioselectivity of reductive alkylation of DNA. 13 C NMR will be used to determine the initial product distributions and as a probe to follow product isolation.
The majority of antitumor agents function by the chemical modification of DNA, for example by the addition of alkyl groups which interfere with replication of the rapidly growing cells. Very little is known about what factors control the sites of alkylation, in part because of the difficulties of isolating the identifying the many possible products formed. The use of 13C enriched alkylating agents, coupled with 13C Nuclear Magnetic Resonance spectroscopy, should make it possible to determine alkylation sites and product distributions in crude reaction mixtures - giving fundamental insights which might assist the development of more effective chemotherapy treatments. This research is highly interdisciplinary, cutting across physical organic chemistry, medicinal chemistry, and biochemistry.