Carol Parish, assistant professor of chemistry, has learned that the National Science Foundation will provide $72,000 to fund her work on anti-cancer drugs at the Colleges. The project titled “Cycloaromatization of Arenediynes” will explore the electronic molecular effects associated with anti-cancer warhead drugs called enediynes. Enediynes are a class of molecules referred to as prodrugs. Prodrugs are drugs whose molecular behavior can be controlled such that they are activated only in the presence of a cancer cell, thus avoiding the harmful side effects associated with many chemotherapeutic treatments.
Naturally occurring anticancer agents, such as Dynemicin A, contain reactive, electron rich enediyne moieties shown in red. Under the proper conditions, the enediyne group undergoes a Bergman cyclization that results in a p-benzyne diradical that can abstract hydrogen atoms from DNA resulting in cancer cell death. In order to design anticancer agents or other endiynes of biological interest it is important to understand the factors that affect the rate of Bergman cyclization. This study will use quantum mechanical and reaction field theory methods to understand how the rate of Bergman cyclization in 10-membered enediynes is influenced by various electronic factors. Using appropriate model systems we will investigate the effects of pH, molecular charge distribution, tautomerism and solvation. High level ab initio calculations will be performed on each of the enediynes prepared in our collaborator’s laboratory (KC Russell, Northern Kentucky University) in order to evaluate their structure, stability, cyclization barriers, thermochemistry and singlet-triplet energy differences. An understanding of how these factors effect the rate of cyclization will allow the development of more effective anticancer prodrug warheads – enediynes that cyclize and cause cell death only under certain, controlled conditions.
The electronic nature of these drugs will be investigated using computational chemistry methods run on Beowulf supercomputer clusters at HWS as well as on the Molecular Education and Research Consortium in Undergraduate computational chemistry (MERCURY) supercomputers located at Hamilton College. The NSF funding will be used to support summer research fellowships for HWS chemistry and biochemistry undergraduates who are interested in participating in this research. The funding will also allow for students and faculty to attend national conferences to present the results of their calculations as well as to publish the results of their work in peer review journals.
Students interested in this research should contact Professor Parish.