(<i>E</i>)-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
Gábor Bognár,
Fatemeh Kenari,
Zoltán Pintér,
Igor D. Borges,
Ademir J. Camargo,
Heibbe C. B. Oliveira,
Flávio Olimpio Sanches-Neto,
Valter H. Carvalho-Silva,
Hamilton B. Napolitano,
Pál Perjési
Affiliations
Gábor Bognár
Institute of Pharmaceutical Chemistry, University of Pécs, H-7624 Pécs, Hungary
Fatemeh Kenari
Institute of Pharmaceutical Chemistry, University of Pécs, H-7624 Pécs, Hungary
Zoltán Pintér
Institute of Pharmaceutical Chemistry, University of Pécs, H-7624 Pécs, Hungary
Igor D. Borges
Grupo de Química Teórica e Estrutural de Anápolis, Universidade Estadual de Goiás, Anápolis 75132-903, GO, Brazil
Ademir J. Camargo
Grupo de Química Teórica e Estrutural de Anápolis, Universidade Estadual de Goiás, Anápolis 75132-903, GO, Brazil
Heibbe C. B. Oliveira
Laboratório de Estrutura Eletrônica e Dinâmica Molecular, Universidade Federal de Goiás, Goiânia 74690-900, GO, Brazil
Flávio Olimpio Sanches-Neto
Laboratório de Estrutura Eletrônica e Dinâmica Molecular, Universidade Federal de Goiás, Goiânia 74690-900, GO, Brazil
Valter H. Carvalho-Silva
Laboratory for Modeling of Physical and Chemical Transformations, Research and Graduate Center, Goiás State University, Anápolis 75132-903, GO, Brazil
Hamilton B. Napolitano
Grupo de Química Teórica e Estrutural de Anápolis, Universidade Estadual de Goiás, Anápolis 75132-903, GO, Brazil
Pál Perjési
Institute of Pharmaceutical Chemistry, University of Pécs, H-7624 Pécs, Hungary
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.
