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.
Highlights
Chalcones are intermediary compounds of biosynthetic pathways of a very large and diverse group of plant constituents known collectively as flavonoids (Harborne and Williams 2000)
Chalcones are effective in vivo as cellproliferation inhibitors, anti-tumor promoting, antiinflammatory and chemopreventive agents (Go et al 2005; Nowakowska 2007; Amslinger 2010; Rahman 2011; Sahu et al 2012; Maydt et al 2013; Sing et al 2014; Rozmer and Perjési 2016; Gomes et al 2017; Zhuang et al 2017)
Several biological effects (e.g., NQO1-inducer (Dinkova-Kostova et al 2001), anti-inflammatory (Jin et al 2008; Amslinger 2010; Maydt et al 2013;), GST P1-1 inhibitory (Wang et al 2009) of chalcones have been associated with their Michael-type reactivity towards GSH
Summary
Chalcones are intermediary compounds of biosynthetic pathways of a very large and diverse group of plant constituents known collectively as flavonoids (Harborne and Williams 2000). Nucleophilic addition of cellular thiols onto the polarized carbon-carbon double bond (Michael-reaction) is frequently associated with the biologic effects of chalcones and other α,β-unsaturated carbonyl compounds (Go et al 2005; Nowakowska 2007; Amslinger 2010; Maydt et al 2013; Gomes et al 2017; Perjési et al 2019). Several biological effects (e.g., NQO1-inducer (Dinkova-Kostova et al 2001), anti-inflammatory (Jin et al 2008; Amslinger 2010; Maydt et al 2013;), GST P1-1 inhibitory (Wang et al 2009) of chalcones have been associated with their Michael-type reactivity towards GSH.
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