Tricyclodecan-9-yl-xanthogenate (D609) was originally developed as an antitumor and antiviral agent. Recently, we have discovered that D609 is a novel and potent antioxidant and cytoprotectant that has the ability to protect mice from ionizing radiation (IR)-induced lethality. Similar to the other known nucleophilic sulfur antioxidants, D609 has a -SH group presented as a xanthate (-C [=S] S-/-C [=S] SH) moiety that scavenges free radicals in a manner similar to that of the sulfhydryl (-SH) moiety of glutathione (GSH) and WR1065 (the active compound of amifostine). However, unlike all other known nucleophilic sulfur antioxidants, D609 is unique because it is also a selective tumor cytotoxic agent, possibly by inhibition of sphingomyelin synthase (SMS). Inhibition of SMS by D609 increases the intracellular level of ceramide and decreases that of diacylglycerol (DAG) thus favoring the induction of cell cycle arrest, senescence, and apoptosis in tumor cells in a cell type dependent manner. The xanthate group of D609 appears to be part of the SMS inhibitory pharmacophore, since blocking this group by S-alkylation abolishes that activity. However, this moiety is oxidatively unstable and is thought to undergo facile oxidation in biological systems, contributing to the poor antitumor activity of D609 observed in vivo. We hypothesize that S-modification of D609 through a metabolically labile linkage (alkoxyphosphoryl or alkoxylacyl) will protect the pharmacophore (-C [=S] SH) and lead to prodrugs with increased oxidative stability, improved pharmacokinetics and enhanced therapeutic efficacy. To test this hypothesis, we will pursue the following specific aims: 1). To rationally design, synthesize and select lead D609 prodrugs with optimal oxidative stability, appropriate hydrolytic properties and superior pharmacokinetics for in vivo therapeutic evaluation; 2). To assess the therapeutic efficacy of select D609 prodrugs for radiation protection and for tumor therapy with or without IR in a mouse model. We believe that D609 prodrugs have the potential to be developed as a unique double agent for cancer therapy. When used as an adjuvant with IR and/or chemotherapy, D609 prodrugs may provide dual therapeutic benefits against cancer, e.g. protection of normal tissues and enhanced tumor cell killing.
