Study of Novel Furocoumarin Derivatives on Anti-Vitiligo Activity, Molecular Docking and Mechanism of Action

白癜风 补骨脂素 呋喃库马林 化学 酪氨酸酶 呋喃香豆素 作用机理 药理学 对接(动物) 生物化学 生物 医学 体外 遗传学 DNA 护理部 光化学
作者
Chao Niu,Deng Zang,Haji Akber Aisa
出处
期刊:International Journal of Molecular Sciences [MDPI AG]
卷期号:23 (14): 7959-7959 被引量:10
标识
DOI:10.3390/ijms23147959
摘要

Vitiligo is a common chronic dermatological abnormality that afflicts tens of millions of people. Furocoumarins isolated from Uygur traditional medicinal material Psoralen corylifolia L. have been proven to be highly effective for the treatment of vitiligo. Although many furocoumarin derivatives with anti-vitiligo activity have been synthesized, their targets with respect to the disease are still ambiguous. Fortunately, the JAKs were identified as potential targets for the disease and its inhibitors have been proved to be effective in the treatment of vitiligo in many clinical trials. Thus, sixty-five benzene sulfonate and benzoate derivatives of furocoumarins (7a-7ad, 8a-8ag) with superior anti-vitiligo activity targeting JAKs were designed and synthesized based on preliminary research. The SAR was characterized after the anti-vitiligo-activity evaluation in B16 cells. Twenty-two derivatives showed more potent effects on melanin synthesis in B16 cells than the positive control (8-MOP). Among them, compounds 7y and 8 not only could increase melanin content, but they also improved the catecholase activity of tyrosinase in a concentration-dependent manner. The docking studies indicated that they were able to interact with amino acid residues in JAK1 and JAK2 via hydrogen bonds. Furthermore, candidate 8 showed a moderate inhibition of CXCL-10, which plays an important role in JAK-STAT signaling. The RT-PCR and Western blotting analyses illustrated that compounds 7y and 8 promoted melanogenesis by activating the p38 MAPK and Akt/GSK-3β/β-catenin pathways, as well as increasing the expressions of the MITF and tyrosinase-family genes. Finally, furocoumarin derivative 8 was recognized as a promising candidate for the fight against the disease and worthy of further research in vivo.
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