Synthesis of Chrysin, Quercetin and Naringin Nitroderivatives: Antiproliferative, Anti-inflammatory and Antioxidant Activity

Background: Flavonoids are an important group of natural products because they possess various biological activities such as antioxidant, anti-inflammatory, and anti-cancer. The modification of their structure could improve their biological activities. The nitro group is included in diverse pharmaceuticals with various biological activities, such as anti-cancer and anti-inflammatory agents. Objective: The study aimed to introduce a nitro group into the structure of flavonoids in order to observe how their anti-proliferative, antioxidant, and anti-inflammatory activities change. Methods: : In this investigation, we established diverse conditions of aromatic nitration of chrysin (1), quercetin (2), and naringin (3) flavonoids using bismuth (III) nitrate, acetic acid or silica gel, and NOx gases. The anti-proliferative activity in CaSki, MDA, and SK-LU-1 cancer cell lines and the anti-inflammatory activity and antioxidant activity of flavonoids and nitro derivatives were evaluated as well. Results: As a result, mild nitration conditions were established, and 8-nitrochrysin, 5’nitroquercetin, and 3’nitronaringin were obtained. The number and hydroxyl group position in the flavonoid are important to carry out the nitration reaction. Although chrysin showed higher anti-proliferative activity than quercetin and naringin, the introduction of the nitro group at C-8 did not improve its antiproliferative, antioxidant, and anti-inflammatory activities. On the other hand, the introduction of the nitro group at C-5̍ in quercetin structure was important to improve its antioxidant and antiproliferative activities on cancer cell lines. The introduction of the nitro group at C-3’ in naringin improved its anti-inflammatory activity, but not its antioxidant and anti-proliferative activities. Chrysin, 8-nitrochrysin, quercetin, and 5’-nitroquercetin did not show necrotic activity. Conclusion: The introduction of a nitro group into flavonoids structure improved their antiproliferative, antioxidant, and anti-inflammatory activities. These results promote future investigations of structural modification on 2-phenylbenzopyran skeleton to optimize their biological activity.