Trolox derivatives: Synthesis, structure–activity relationship and promote wound healing by regulating oxidative stress and inflammation

• Published in: Bioorganic chemistry 2024-12, Vol.154, p.108045, Article 108045
• Main Authors: Zhao, Jie, Gao, Shan, Zhou, Long, Rong, Kuanrong, Zuo, Fangfang, Tang, Wenjian, Zhu, Lili
• Format: Article
• Language: English
• Subjects: Anti-inflammatory; Antioxidant; ROS; Trolox; UVB; Wound healing
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.108045

[Display omitted] •Trolox ester 3d showed the balance of antioxidant and anti-inflammatory activity.•3d promoted wound healing in HaCaT cells damaged by UVB irradiation.•3d exerted benign activity through the Nrf2/HO-1 and NF-κB pathway.•In vivo experiment verified the excellent restorative effect of 3d cream. To find new antioxidants, 13 Trolox amides (2a–2m) and 7 Trolox esters (3a–3g) were synthesized and evaluated for their anti-inflammatory and antioxidant activity. Compounds 2e, 2i, 3b and 3d showed potent anti-inflammatory and antioxidant activity, amongst them, 3d demonstrated the most photoprotective effects on UVB-irradiated human skin keratinocyte (HaCaT) cells (IC50 = 5.13 µM) through efficiently scavenging free radicals and dose-dependently reducing reactive oxygen species (ROS) and apoptosis generation, as well as effectively promoting wound healing. 3d protected HaCaT cells against oxidative stress, inflammation and cellular damage by the activation of Nrf2/HO-1 signaling and inhibition of NF-κB pathway, further significantly improving wound healing. In acute UVB-induced skin injury mouse model, 3d significantly reduced the level of pro-inflammatory factors, improved the effect of UVB radiation on the activity of antioxidant enzymes, and maintained normal metabolic capacity. In conclusion, 3d may be a potential candidate for developing cosmetics with UVB protective effect.