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

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 Bring 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. Keywords Chalcones • Quinolinone • Glutathione • Michael reaction • Tumor cell cytotoxicity.

Reaction of Chalcones with Cellular Thiols. The Effect of the 4-Substitution of Chalcones and Protonation State of the Thiols on the Addition Process. Diastereoselective Thiol Addition

“…Since the 4-methoxy substitution can more effectively increase the electron density on the carbon–carbon double bond, and the formed chalcone is resonance stabilized, the elimination process is more effective in the case of 2 than 1 . Similar conclusions were made by d’Oliveira et al while investigating a few chalcones and their rigid quinolone analogues [ 35 ].…”

Synthesis, Structural and Biological Properties of the Ring-A Sulfonamido Substituted Chalcones: A Review

“…A number of synthetic routes have been reported for synthesis of the o / m / p -(sulfonamido)chalcones and their general synthesis involves the Claisen-Schmidt aldol condensation of o / m / p -sulfonamidoacetophenone precursors with benzaldehyde derivatives in the presence of an acid [ 20 ] or base [ 2 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 21 , 22 , 23 , 24 , 25 ] followed by spontaneous in situ dehydration of the incipient β-hydroxyketone intermediates. The sulfonamidoacetophenones 2 are, in turn, prepared from the corresponsing o / m / p -aminoacetophenones 1 with alkyl/arylsulfonyl chloride derivatives in the presence of an amine as a base in the absence or presence of a solvent ( Scheme 1 ).…”

“…These analytical techniques revealed that the conjugated carbon scaffolds of o / m / p -aminochalcones and their sulfonamide derivatives are essentially planar. However, twisting of the sulfonamide moiety from coplanarity of the conjugated carbon framework is commonly observed in the crystal structures of the ortho - [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ], meta - [ 22 , 23 ] and para -sulfonamido appended chalcones [ 24 , 33 ]. The twisting of the sulfonamide moiety from coplanarity of the conjugated carbon framework has also been observed in the crystal structures of the analogous N -(2-acetyl-4-(styryl)phenyl)sulfonamides [ 34 ] and the corresponding 5-styryl-2-sulfonamidochalcone hybrids [ 26 ].…”

“…XRD analyses of the 2-aminochalcones and their ortho -sulfonamidochalcone derivatives confirm the presence of a six-membered N–H···O intramolecularly hydrogen bonded ring in co-planarity with the conjugated scaffold [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. The highest frequency of intramolecular hydrogen bonds for the 2-aminochalcone derivatives found in the literature have planar six-membered pseudo ring stabilized by conjugation with a π-system, which mimic an aromatic ring [ 35 ].…”

“…It was concluded that chlorine atom in the para -position of the 3-phenyl ring plays a key role in its biological potential. The ortho -sulfonamidochalcones and their quinolinone-chalcone hybrids were also evaluated for cytotoxicity against PC-3 (prostate), HCT-116 (colon) and SF-295 (glioblastoma) human tumor cell lines [ 13 ]. Non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) onto two of these sulfonamidochalcones and their corresponding quinolinone-chalcone hybrids were also studied to investigate the relationship between tumor cell cytotoxic activities and GSH-reactivities of the compounds.…”