A convenient approach for evaluating the toxicity profiles of in vitro neuroprotective alkylaminophenol derivatives.
The cytotoxicity profiles of a series of quinol-type derivatives were examined through simple Escherichia coli plate assays discriminating the two main cytotoxicity mechanisms associated with polyphenol oxidation to quinone. Toxicity mediated by reactive oxygen species (ROS-TOX) was detected in the OxyR(-) assay using cells sensitive to oxidative stress due to a deficiency in the OxyR function. Toxicity arising from the high susceptibility of quinone toward endogenous nucleophiles (Q-TOX) was detected using OxyR(+) cells, in the presence of a nitric oxide donor to promote the quinol oxidation to the corresponding quinone. The toxicity profile markedly depended on structural features. Strong ROS-TOX required a pyrogallol arrangement (exifone; 2,3,4-trihydroxybenzophenone, 1; baicalein) or a 2-aminoresorcinol sequence (3-amino-2,4-dihydroxybenzophenone, 4). The pyrogallol moiety determined a low Q-TOX, suggesting the conversion of quinones into oxidation products of low toxicity. Compounds lacking a 2-hydroxyl substituent (derivatives 2 and 5, related to 1 and 4, respectively) induced a weak ROS-TOX, but a significant Q-TOX. The electrochemical oxidation of the studied compounds corroborated the crucial role of the 2-hydroxyl group, which had two effects: to protect the quinonoid species from Michael addition, the reaction at the origin of Q-TOX, and, due to the contraction of hydrogen bonding, to stabilize every intermediary oxidation product, very likely involved in ROS-TOX.
Urios
Amparo
A
Centro de Investigación Príncipe Felipe, Valencia, Spain.
Largeron
Martine
M
Fleury
Maurice-Bernard
MB
Blanco
Manuel
M
D004268:DNA-Binding Proteins / Q000235:genetics; D004563:Electrochemistry; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics; D044950:Flavanones / Q000737:chemistry / Q000633:toxicity*; D006873:Hydroquinones / Q000737:chemistry / Q000633:toxicity*; D009154:Mutation; D018696:Neuroprotective Agents / Q000737:chemistry / Q000633:toxicity*; D018384:Oxidative Stress / Q000235:genetics; D010636:Phenols / Q000737:chemistry / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D018675:Toxicity Tests; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D044950:Flavanones; D006873:Hydroquinones; D018696:Neuroprotective Agents; D010636:Phenols; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D014157:Transcription Factors; C499299:oxyR protein, E coli