Synthesis of Sulfur-35-Labeled Trisulfides and GYY-4137 as Donors of Radioactive Hydrogen Sulfide

Abstract

Hydrogen sulfide has emerged as a key gasotransmitter in humans and in plants, and the addition of exogenous hydrogen sulfide has many beneficial effects in vivo and in vitro. A challenge in investigating the effect of exogenous hydrogen sulfide is tracking the location of exogenous hydrogen sulfide on an organism and cellular level. In this article, we report the synthesis of three key chemicals (cysteine trisulfide, glutathione trisulfide, and GYY-4137) that release radiolabeled 35 S as hydrogen sulfide. The synthesis started with the reduction of Na 2 35 SO 4 mixed with Na 2 SO 4 to generate hydrogen sulfide gas that was trapped with aq NaOH to yield radiolabeled Na 2 S. The Na 2 S was converted in one step to GYY-4137 at 65% yield. It was also converted to bis(tributyltin) sulfide that readily reacted with Nbromophthalimide to yield a monosulfur transfer reagent. Trisulfides were synthesized by reaction with the monosulfur transfer reagent and the corresponding thiols. The levels of radioactivity of the final products could be varied on a per gram basis to alter the radioactivity for applications that require different loadings of hydrogen sulfide donors.