Sulfur dioxide (SO2) is a gaseous molecule produced endogenously from metabolism of sulfur-containing amino acids such as cysteine and homocysteine. Recent research has demonstrated that SO2 may possess various bioactivities, especially in the cardiovascular system. The therapeutic potential of this well-known air pollutant gas has raised increasing research interests in recent years. Currently, SO2 gas and mixed sulfite salt (HSO3-/SO32- 1:3 mixture) have been most widely used as SO2 source in research. However, it is difficult to control the dosage and establish concentration-activity relationship using either source due to SO2’s gaseous nature and uncontrollable release rate of mixed sulfite salt. The unavailability of proper SO2 donors has limited the understanding of SO2’s biological roles as well as exploring its potential therapeutic use. To overcome this problem, organic SO2 donors have been developed in recent years. Our group first demonstrated the applicability of using Diels-Alder reaction to release SO2 under physiological conditions with a bimolecule system. Then we further explored this strategy by incorporating the diene and dienophile into one single molecule. Tunable release rate was achieved in this system by modifying the substitution groups and the length of the tether. We also developed another system by trapping SO2 in molecules that imitate the intermediate of modified-Julia olefination reaction. With esterase triggering, the prodrugs would release SO2 under physiological conditions. The release rate can be tuned with half-life ranging from several minutes to several hours by varying the esterase-sensitive moieties. One of the prodrugs was tested for stability in existence of physiological relevant nucleophiles (e.g., cysteine) and showed no decomposition. Cell imaging studies further confirmed the applicability of this system in biological environment. In sum, three classes of SO2 prodrugs were developed with triggered release mechanism and tunable release rate.

Development of sulfur dioxide prodrugs with triggered release and tunable release rate

255th National Meeting (2018)

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