Synthesis of Small Molecule and Polymeric Systems for the Controlled Release of Sulfur Signaling Molecules

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Virginia Tech

Hydrogen sulfide (H₂S) was recognized as a critical signaling molecule in mammals nearly two decades ago. Since this discovery biologists and chemists have worked in concert to demonstrate the physiological roles of H₂S as well as the therapeutic benefit of exogenous H₂S delivery. As the understanding of H₂S physiology has increased, the role(s) of other sulfur-containing molecules as potential players in cellular signaling and redox homeostasis has begun to emerge. This creates new and exciting challenges for chemists to synthesize compounds that release a signaling compound in response to specific, biologically relevant stimuli. Preparation of these signaling compound donor molecules will facilitate further elucidation of the complex chemical interplay within mammalian cells.

To this end we report on two systems for the sustained release of H₂S, as well as other sulfur signaling molecules. The first system discussed is based on the N-thiocarboxyanhydride (NTA) motif. NTAs were demonstrated to release carbonyl sulfide (COS), a potential sulfur signaling molecule, in response to biologically available nucleophiles. The released COS is shown to be rapidly converted to H₂S in the presence of the ubiquitous enzyme carbonic anhydrase (CA). A synthetic route that affords NTAs with reactive functionalities was devised and the functional "parent" NTAs were successfully conjugated to a variety of substrates, ranging from small molecules to polymers. These functional NTAs provide a platform from which a library of NTA-based COS/H₂S may be readily prepared convergently in an effort to move towards H₂S-releasing drug and polymer conjugates. Additionally, preliminary in vitro cytotoxicity studies indicate that NTAs are noncytotoxic at concentrations above 100 µM.

The second system discussed in this dissertation leverages the 1,6-benzyl elimination reaction (or self-immolative reaction) to facilitate the release of a persulfide (R–SSH) from a small molecule prodrug platform as well as a separate system that releases COS/H₂S from a polymer. The self-immolative persulfide prodrug was designed to be responsive to reactive oxygen species (ROS) and demonstrates efficacy as an antioxidant in vitro. Furthermore, the polymeric COS/H₂S self-immolative system was designed to respond to reducing agents, including H₂S itself, and shows promise as a H₂S signal amplification platform.

hydrogen sulfide (H₂S), carbonyl sulfide (COS), persulfide, 1,6-benzyl elimination, ring-opening