Trihydroxyflavones with antioxidant and anti-inflammatory efficacy.
The classical anti-inflammatory therapies are frequently ineffective and present numerous and severe side effects, especially in long term use, which requires the development of anti-inflammatory drugs with different scaffolds and mechanisms of action. Owing to the high antioxidant potential and anti-inflammatory activities already inferred for hydroxyflavones, we found it would be relevant to evaluate the anti-inflammatory potential of a series of trihydroxyflavones by testing their ability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) in cells and cell-free systems and to inhibit the proinflammatory pathways mediated by the enzymes cyclooxygenase (COX) and 5-lipoxygenase (5-LOX), in which reactive species have a proven involvement. The tested trihydroxyflavones proved to be effective inhibitors of neutrophils' oxidative burst and were shown to scavenge different ROS and RNS in cell-free systems. The most active compound in the majority of the assays was 3,3',4'-trihydroxyflavone, which was somehow expected due to the presence of the ortho-dihydroxy in the B-ring, an important structural feature in terms of free radical scavenging activity. Additionally, the studied compounds were able to inhibit the production of leukotriene B(4)  by 5-LOX in activated neutrophils. 3,5,7-Trihydroxyflavone was able to inhibit both COX-1 and COX-2, which makes it a dual inhibitor of COX and 5-LOX pathways and, therefore, a promising candidate for a new therapeutic option in the treatment of inflammatory processes.
REQUIMTE, Departamento de Ciências Químicas, Universidade do Porto, Porto, Portugal.
Ana
A
Gomes
Diana
D
Couto
Andreia
A
Alves
Irene
I
Dias
Marisa
M
Freitas
Graça
G
Porto
José Alberto
JA
Duarte
Eduarda
E
Fernandes
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002474:Cell-Free System / Q000187:drug effects / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D005419:Flavonoids; D044948:Flavonols; D016859:Lipoxygenase Inhibitors; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C529890:3',4'-dihydroxyflavonol