# (E)-2-Benzylidenecyclanones: Part XXI—Reaction of Cyclic Chalcone Analogs with Cellular Thiols: Comparison of Reactivity of (E)-2-Arylidene-1-Indanone with -1-Tetralone and -1-Benzosuberone Analogs in Thia-Michael Reactions

## TL;DR

This paper compares how different ring sizes in certain chemical compounds affect their reactivity with cellular thiols and their cytotoxicity in cancer cells.

## Contribution

The study introduces a comparison of thiol reactivity and cytotoxicity among cyclic chalcone analogs with varying ring sizes.

## Key findings

- Compounds with six- and seven-membered rings showed higher cytotoxicity than five-membered ring analogs.
- Thiol reactivity and cytotoxicity depend on ring size and aromatic substituents.
- Molecular modeling explained differences in reactivity between indanone and carbocyclic analogs.

## Abstract

In vitro cytotoxicity of three (E)-3-(4′-X-benzylidene)-1-indanones (2a-c) displayed lower cytotoxicity towards murine P388 and L1210 leukemic cells as well as human Molt 4/C8 and CEM T-lymphocytes than the respective six- (3a-c) and seven-membered (4a-c) analogs. To study whether thiol reactivity—as a possible basis of their mechanism of action—correlates with the observed cytotoxicities, kinetics of the non-enzyme catalyzed reactions with reduced glutathione (GSH) and N-acetylcysteine (NAC) of 2a-c were investigated. Furthermore, it was also the aim of the work to compare the thiol reactivity of the open-chain chalcones (1) and their carbocyclic analogs (2-4) with different ring sizes (n = 5–7). 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 high initial rate and low conversion of the 2a indanone in comparison with those of the carbocyclic analog tetralone (3a) and benzosuberone (4a). Thiol reactivity and cancer cell cytotoxicity showed a dependence on both the ring size and the nature of aromatic substituents.