Different reactivity to glutathione but similar tumor cell toxicity of chalcones and their quinolinone analogues

Autor: Manoel Odorico de Moraes, Laszlo Prokai, Jean M. F. Custodio, Hamilton B. Napolitano, Pál Perjési, Caridad N. Perez, Andrea F. Moura, Giulio D. C. d’Oliveira
Rok vydání: 2019
Předmět:
Zdroj: Medicinal Chemistry Research. 28:1448-1460
ISSN: 1554-8120
1054-2523
Popis: Non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) onto two open-chain sulfonamide chalcones and two quinolinone-chalcone hybrids were studied to investigate the relationship between tumor cell cytotoxic activities and GSH-reactivities of the compounds. The consumption of the chalcones or the quinolinone-chalcone hybrids due to conjugation with GSH was evaluated by analytical high-performance liquid chromatography, and the formed diastereomeric adducts were identified by liquid chromatography–mass spectrometry. When the reaction was conducted with the open-chain chalcones, the equilibria were shifted towards formation of the respective GSH-conjugates. On the other hand, the cyclic chalcone derivatives with the quinolinone moiety were found to equilibrate to mixtures containing predominantly the reactants despite the strong electron withdrawing group present in the B-ring of the compounds. The observed opposite behavior can be rationalized by reduced thiol-reactivity of the quinolinone-chalcone hybrids and fast decomposition of their GSH-conjugates. A combined X-ray diffraction and theoretical approach were used to explain the observed difference in the reactivities towards GSH. However, structural differences did not influence tumor cell (SF-295, PC-3 and HCT-116) cytotoxicity of the evaluated compounds. Accordingly, the altered GSH-reactivity seems to be not a determining factor in the tested tumor cell cytotoxic activity of the investigated compounds.
Databáze: OpenAIRE
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