(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 (IIb)/IC50 (IIIb) of (E)-3-(4′-methylbenzylidene)-4-chromanone (IIIb) towards human Molt 4/C8 and CEM T-lymphocytes showed a >50-fold increase in comparison to those of the respective tetralone derivative (IIb). On the other hand, such an increase was not observed in the analogous 4-OCH3 (IIc and IIIc) 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 IIIb and IIIc 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 (III) compared to the carbocyclic analog tetralones (II). The results indicate the possible role of spontaneous thiol reactivity of compounds III in their recorded biological effects.