Drug Design, Development and Therapy (Feb 2019)
Amine derivatives of furocoumarin induce melanogenesis by activating Akt/GSK-3β/β-catenin signal pathway
Abstract
Deng Zang,1,2 Chao Niu,1 Haji Akber Aisa1 1Key Laboratory of Plant Resources and Chemistry in Arid Regions, State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China; 2University of Chinese Academy of Sciences, Beijing 100049, China Background: Melanogenesis, or the biosynthesis of melanin, plays a critical role in the pigmentation of skin, hair, and eyes. Reduced melanogenesis may lead to depigmentation conditions such as vitiligo. Psoralen, a furocoumarin derivative, is closely associated with melanogenesis, and its derivative 8-methoxypsoralen is used in psoralen and ultraviolet A therapy for pigmentation disorders. In a previous study, we synthesized a new series of amine derivatives of furocoumarin, of which 5-(morpholinomethyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (encoded as D206008) showed a remarkable melanogenic effect in B16 murine cells.Methods: In this study, we examined the effects of D206008 on the melanogenesis-related pathways in B16 cells. D206008 increased melanin production and tyrosinase (TYR) activity, as well as the mRNA and protein expression levels of the melanogenic enzymes TYR, TRP-1 and TRP-2, and the melanogenesis-related transcription factor microphthalmia-associated transcription factor (MITF) in a dose-dependent (0–100 µM) and time-dependent (0–48 hours) manner.Results: Mechanistically, D206008 inhibited β-catenin degradation by enhancing the phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β), which increased the accumulation of β-catenin in the cytoplasm. Nuclear translocation of β-catenin also increased in response to D206008 treatment.Conclusion: Taken together, these data indicate that D206008 promotes melanin synthesis by stimulating the nuclear translocation of β-catenin, which activates MITF transcription and eventually melanogenesis. Keywords: amine derivatives of furocoumarin, melanogenesis, Akt/GSK-3β/β-catenin
