- Investigations into the carbonic anhydrase inhibition of COS-releasing donor core motifs
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Carbonyl sulfide (COS) releasing scaffolds are gaining popularity as hydrogen sulfide (H2S) donors through exploitation of the carbonic anhydrase (CA)-mediated hydrolysis of COS to H2S. 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/H2S donors. Because the intermediate release of COS en route to H2S 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 CO2 and CS2 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/H2S donor motifs.
- Steiger, Andrea K.,Zhao, Yu,Choi, Won Jin,Crammond, Alder,Tillotson, McKinna R.,Pluth, Michael D.
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p. 124 - 130
(2017/12/04)
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- Thiocarbonylthio compounds (S=C(Z)S-R) in free radical polymerization with reversible addition-fragmentation chain transfer (RAFT polymerization). Effect of the activating Group Z
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Free-radical polymerization in the presence of suitable addition-fragmentation chain transfer agents [S=C(Z)S-R] (RAFT agents) possess the characteristics of a living polymerization (i.e., polymer products can be reactivated for chain extension and/or block synthesis, molecular weights are predetermined by RAFT agent concentration and conversion, narrow polydispersities are possible). Styrene polymerizations (110°C, thermal initiation) were performed for two series of RAFT agents [S=C(Z)S-CH2Ph and S=C(Z)S-C(Me)2CN]. The chain transfer coefficients decrease in the series where Z is Ph > SCH2Ph ~ SMe ~ Me ~ N-pyrrolo ? OC6F5 > N-lactam > OC6H5 > O(alkyl) ? N(alkyl)2 (only the first five in this series provide narrow polydispersity polystyrene ( trithiocarbonates ~ dithioalkanoates > dithiocarbonates (xanthates) > dithiocarbamates. However, electron-withdrawing substituents on Z can enhance the activity of RAFT agents to modify the above order. Thus, substituents that render the oxygen or nitrogen lone pair less available for delocalization with the C=S can substantially enhance the effectiveness of xanthates or dithiocarbamates, respectively. The trend in relative effectiveness of the RAFT agents is rationalized in terms of interaction of Z with the C=S double bond to activate or deactivate that group toward free radical addition. Molecular orbital calculations and the estimated LUMO energies of the RAFT agents can be used in a qualitative manner to predict the effect of the Z substituent on the activity of RAFT agents.
- Chiefari, John,Mayadunne, Roshan T.A.,Moad, Catherine L.,Moad, Graeme,Rizzardo, Ezio,Postma, Almar,Skidmore, Melissa A.,Thang, San H.
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p. 2273 - 2283
(2007/10/03)
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