Uncaging carbon disulfide. Delivery platforms for potential pharmacological applications: a mechanistic approach

We describe the kinetics of the formation and decay of a series of dithiocarbamates under physiological conditions. The goal is to provide a toolbox of compounds that release CS(2) by well-defined kinetics in such media. Carbon disulfide is a known environmental toxin, but there is fragmentary evidence suggesting that CS(2) may have bioregulatory and/or therapeutic roles in mammalian biology. Further investigation of such roles will require methodologies for controlled delivery of this bioactive small molecule to specific targets. Reported here are mechanistic and computational studies of CS(2) release from a series of dithiocarbamate anions (DTCs), where R(2)N represents several different secondary amido groups. The various DTCs under physiologically relevant conditions show a tremendous range of reactivities toward CS(2) dissociation with decay lifetimes ranging from ∼2 s for imidazolidyldithiocarbamate (ImDTC(–)) to ∼300 s for diisopropyldithiocarbamate (DIDTC(–)) to >24 h for pyrrolidinyldithiocarbamate (PDTC(–)) in pH 7.4 phosphate buffer solution at 37 °C. Thus, by making the correct choice of these tools, one can adjust the flux of CS(2) in a biological experiment, while the least reactive DTCs could serve as controls for evaluating the potential effects of the dithiocarbamate functionality itself. Kinetics studies and density functional calculations are used to probe the mechanism of DTC(–) decay. In each case, the rate of CS(2) dissociation is acid dependent; however, the DFT studies point to a mechanistic pathway for ImDTC(–) that is different than those for DIDTC(–). The role of general acid catalysis is also briefly probed.