Monday, June 18, 2007
Golden Eagle Eyrie (Boise Centre on the Grove)

Synthesis of prodrug analogs of D609 with extended antioxident and anticancer activity

Jessica Ketrenos and G. Patrick Meier. Washington State University, Pullman, WA

D609 is a potential candidate for further development as a unique drug with anticancer and anti-radiation poisoning activity. With its ability to act as a selective antitumor agent, a potent antioxidant, and a cytoprotectant, it could provide dual therapy and benefit further research in the fight against cancer. Two of the major problems with D609 are that it has relatively low activity and secondly that it contains a dithiocarbonate (xanthate) group that is chemically unstable. This class of compounds readily undergoes oxidation to form a disulfide bond, resulting in the loss of biological activities. We hypothesize that protecting the xanthate as a carbonate prodrug which is directed to specific cell lines would allow the slow, local release of xanthate D609. This would result in a higher local concentration and protect it from abiotic oxidation. In order to study this hypothesis, we have initiated the synthesis of a series of carbonate protected analogs of D609. The first of these prodrugs is a simple carbonate protected D609, while the second analog is a choline analog. These prodrugs are designed to decrease abiotic oxidation and to site-selectively deliver D609. The synthesis and biological activity of these compounds will be discussed.