Abstract
The Ugi four-component reaction employing naturally occurred ferulic acid (FA) is proposed as a convenient method to synthesize feruloyl tertiary amides. Applying this strategy, a peptoid-like derivative of ferulic acid (FEF77) containing 2 additional hydroxy-substituted aryl groups, has been synthesized. The influence of the configuration of the double bond of ferulic acid and feruloyl amide on the antioxidant activity has been investigated thanks to light-mediated isomerization studies. At the cellular level, both FA, trans and cis isomers of FEF77 were able to protect human endothelial cord vein (HECV) cells from the oxidative damage induced by exposure to hydrogen peroxide, as measured by cell viability and ROS production assays. Moreover, in steatotic FaO rat hepatoma cells, an in vitro model resembling non-alcoholic fatty liver disease (NAFLD), the molecules exhibited a lipid-lowering effect, which, along with the antioxidant properties, points to consider feruloyl amides for further investigations in a therapeutic perspective.
Highlights
Ferulic acid (FA) belongs to the phenolic acid group commonly present in plant tissues.It is widely found in fruits, vegetables, whole grains, cereal seeds, coffee, beer [1,2], as well as in numerous non-edible bio-resources such as bagasse, wheat bran, and beetroot pulp, etherified to lignin or esterified to hemicelluloses
FA induces the translocation of NF-E2-related factor (Nrf2) into the nucleus, where it hetero-dimerizes with musculoaponeurotic fibrosarcoma protein (Maf) and binds to antioxidant response element (ARE), promoting the transcription of oxidative stress-responsive genes [5]
FA has been proven to modulate proteins belonging to matrix metalloproteinase (MMP) family, which are involved in several disorders [4], and to inhibit mammalian target of rapamycin, the master key regulator of autophagy process, controlling several survival or death signaling pathways that may commit the fate of cancer cells [7]
Summary
Ferulic acid (FA) belongs to the phenolic acid group commonly present in plant tissues. It is widely found in fruits, vegetables, whole grains, cereal seeds, coffee, beer [1,2], as well as in numerous non-edible bio-resources such as bagasse, wheat bran, and beetroot pulp, etherified to lignin or esterified to hemicelluloses. FA displays low toxicity, quite efficient intestinal absorption and high stability [3]. These properties, together with the powerful antioxidant activity, render FA a suitable candidate to be considered for the treatment of several oxidative stress-based pathologies such as cancer, cardiomyopathy, skin disorders, brain disorders, viral infections, diabetes, etc. Two major mechanisms are involved in the antioxidant activity: H-atom abstraction (HAT) and single-electron transfer (SET)
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