Investigations into the carbonic anhydrase inhibition of COS-releasing donor core motifs.

Carbonyl sulfide (COS) releasing scaffolds are gaining popularity as hydrogen sulfide (HS) donors through exploitation of the carbonic anhydrase (CA)-mediated hydrolysis of COS to HS. The majority of compounds in this emerging class of donors undergo triggerable decomposition (often referred to as self-immolation) to release COS, and a handful of different COS-releasing structures have been reported. One benefit of this donation strategy is that numerous caged COS-containing core motifs are possible and are poised for development into self-immolative COS/HS donors. Because the intermediate release of COS en route to HS donation requires CA, it is important that the COS donor motifs do not inhibit CA directly. In this work, we investigate the cytotoxicity and CA inhibition properties of different caged COS donor cores, as well as caged CO and CS motifs and non-self-immolative control compounds. None of the compounds investigated exhibited significant cytotoxicity or enhanced cell proliferation at concentrations up to 100 μM in A549 cells, but we identified four core structures that function as CA inhibitors, thus providing a roadmap for the future development of self-immolative COS/HS donor motifs.