2007
DOI: 10.1021/tx7002257
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Quinone Formation as a Chemoprevention Strategy for Hybrid Drugs: Balancing Cytotoxicity and Cytoprotection

Abstract: Cellular defense mechanisms that respond to damage from oxidative and electrophilic stress, such as from quinones, represent a target for chemopreventive agents. Drugs bioactivated to quinones have the potential to activate antioxidant/electrophile responsive element (ARE) transcription of genes for cytoprotective phase 2 enzymes such as NAD(P)H-dependent quinone oxidoreductase (NQO1) but can also cause cellular damage. Two isomeric families of compounds were prepared, including the NO-NSAIDs (NO-donating nons… Show more

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Cited by 59 publications
(95 citation statements)
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“…A first mechanism proposes that QM-derived NO-ASAs are able to react with bionucleophiles, including DNA, to generate cytotoxic and genotoxic compounds and, consequently, trigger DNA fragmentation [26]. A second mechanism argues the fact that these QMs can act upon antioxidant responsive elements (AREs) that, in turn, activate the transcription of genes for antioxidant cytoprotective enzymes, such as NAD(P)H-dependant quinone oxireductase 1 (NQO1) [27]. Thus, there is a balance between these two mechanisms of action that lead, respectively, to cytotoxic versus cytoprotective effects [27].…”
Section: Examples Of Qms That Are Anticancer Compoundsmentioning
confidence: 99%
See 1 more Smart Citation
“…A first mechanism proposes that QM-derived NO-ASAs are able to react with bionucleophiles, including DNA, to generate cytotoxic and genotoxic compounds and, consequently, trigger DNA fragmentation [26]. A second mechanism argues the fact that these QMs can act upon antioxidant responsive elements (AREs) that, in turn, activate the transcription of genes for antioxidant cytoprotective enzymes, such as NAD(P)H-dependant quinone oxireductase 1 (NQO1) [27]. Thus, there is a balance between these two mechanisms of action that lead, respectively, to cytotoxic versus cytoprotective effects [27].…”
Section: Examples Of Qms That Are Anticancer Compoundsmentioning
confidence: 99%
“…A second mechanism argues the fact that these QMs can act upon antioxidant responsive elements (AREs) that, in turn, activate the transcription of genes for antioxidant cytoprotective enzymes, such as NAD(P)H-dependant quinone oxireductase 1 (NQO1) [27]. Thus, there is a balance between these two mechanisms of action that lead, respectively, to cytotoxic versus cytoprotective effects [27]. These mechanisms are controlled, at least partly, by the protein, Keap1, wherein the alkylation of CYS residues by Michael reagents leads to the dissociation of its complex with Nrf2 and eventual ARE activation [28].…”
Section: Examples Of Qms That Are Anticancer Compoundsmentioning
confidence: 99%
“…with Jurkat cells, describing the para-isomer to be considerably more potent than meta-NO-ASA (Nath et al, 2005;Rosetti et al, 2006). Due to the structural position of the NO-group, only the para-isomer is capable to generate a quinone methide after esterase bioactivation (Dunlap et al, 2007). Overall, the findings suggest a pivotal role for aromatic resonance interaction.…”
Section: Introductionmentioning
confidence: 82%
“…Subsequently, a crucial role for aromatic resonance interaction can be suggested. In general it has been speculated that a major requirement for the cytotoxic effect is the presence of an aromatic ring substituted with both a masked phenolic group and a para-methylene group allowing the generation of a quinone methide [Dunlap et al 2009[Dunlap et al , 2007Hulsman et al 2007]. Owing to the structural position of the ÀONO 2 group, the meta-isomer is not capable of generating such a toxic methide.…”
Section: Discussionmentioning
confidence: 99%