Schultz, T.W.; Yarbrough, J.W.; Woldemeskel, M. Toxicity to Tetrahymena and abiotic thiol reactivity of aromatic isothiocyanates. Cell Biol. Toxicol. 2005, 21, 3, 181–189.

Abstract

Toxicity (1/IGC(50)) in the Tetrahymena population growth assay and reactivity (1/EC(50)) with the thiol moiety of the cysteine residue of glutathione (GSH) were determined for a series of aromatic isothiocyanates (NCSs). Comparison of both toxicity and reactivity between the analogues revealed that derivatives with the NCS-moiety attached directly to an aromatic ring (e.g., phenyl derivatives) are less toxic and less reactive than those with the NCS attached to an aliphatic carbon (e.g., benzyl derivatives). These differences in potency are hypothesized to relate to difference in the ease of the Michael reaction, the proposed molecular mechanism. 1,4-Phenylene diisothiocyanate is more toxic and more reactive than its mono-NCS homologue. While there is good predictivity for the phenyl and naphthyl derivatives with the model log(1/IGC(50)) = 0.545(log K(ow)) + 16.21A(max) - 5.91, based on the 1-octanol/water partition coefficient (K(ow)) and maximum acceptor superdelocalizability (A(max)), toxicity of the other derivatives, which are outside the structural domain of the model training set, are poorly fitted. Owing to hydrolysis, the benzoyl, and cinnamyl analogues are less toxic than predicted by their thiol reactivity; however, the toxicity of the remaining compounds is modeled by the relationship log(1/IGC(50)) = 1.77 [log (1/EC(50))] + 0.60; n = 12, s = 0.34, r(2) = 0.718, q(2) = 0.629, F = 26.