Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1448-1460 |
| Number of pages | 13 |
| Journal | Medicinal Chemistry Research |
| Volume | 28 |
| Issue number | 9 |
| DOIs | |
| State | Published - 1 Sep 2019 |
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Keywords
- Chalcones
- Glutathione
- Michael reaction
- Quinolinone
- Tumor cell cytotoxicity
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Different reactivity to glutathione but similar tumor cell toxicity of chalcones and their quinolinone analogues. / d’Oliveira, Giulio D.C.; Custodio, Jean M.F.; Moura, Andrea F.; Napolitano, Hamilton B.; Pérez, Caridad N.; Moraes, Manoel O.; Prokai, Laszlo; Perjési, Pál.
In: Medicinal Chemistry Research, Vol. 28, No. 9, 01.09.2019, p. 1448-1460.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Different reactivity to glutathione but similar tumor cell toxicity of chalcones and their quinolinone analogues
AU - d’Oliveira, Giulio D.C.
AU - Custodio, Jean M.F.
AU - Moura, Andrea F.
AU - Napolitano, Hamilton B.
AU - Pérez, Caridad N.
AU - Moraes, Manoel O.
AU - Prokai, Laszlo
AU - Perjési, Pál
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
KW - Chalcones
KW - Glutathione
KW - Michael reaction
KW - Quinolinone
KW - Tumor cell cytotoxicity
UR - http://www.scopus.com/inward/record.url?scp=85069462543&partnerID=8YFLogxK
U2 - 10.1007/s00044-019-02384-8
DO - 10.1007/s00044-019-02384-8
M3 - Article
VL - 28
SP - 1448
EP - 1460
JO - Medicinal Chemistry Research
JF - Medicinal Chemistry Research
SN - 1054-2523
IS - 9
ER -