(E)-2-Benzylidenecyclanones: Part XX—Reaction of Cyclic Chalcone Analogs with Cellular Thiols: Unexpected Increased Reactivity of 4-Chromanone- Compared to 1-Tetralone Analogs in Thia-Michael Reactions

In vitro relative cytotoxicity (IC₅₀ (<b>IIb</b>)/IC₅₀ (<b>IIIb</b>) of (<i>E</i>)-3-(4'-methylbenzylidene)-4-chromanone (<b>IIIb</b>) towards human Molt 4/C8 and CEM T-lymphocytes showed a >50-fold increase in comparison to those of the respective tetralone derivative (<b>IIb</b>). On the other hand, such an increase was not observed in the analogous 4-OCH₃ (<b>IIc</b> and <b>IIIc</b>) derivatives. In order to study whether thiol reactivity-as a possible basis of the mechanism of action-correlates with the observed cytotoxicities, the kinetics of the non-enzyme catalyzed reactions with reduced glutathione (GSH) and N-acetylcysteine (NAC) of <b>IIIb</b> and <b>IIIc</b> were investigated. The reactivity of the compounds and the stereochemical outcome of the reactions were evaluated using high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Molecular modeling calculations were performed to rationalize the unexpectedly higher thiol reactivity of the chromanones (<b>III</b>) compared to the carbocyclic analog tetralones (<b>II</b>). The results indicate the possible role of spontaneous thiol reactivity of compounds <b>III</b> in their recorded biological effects.