Novel Furocoumarin Derivatives Stimulate Melanogenesis in B16 Melanoma Cells by Up-Regulation of MITF and TYR Family via Akt/GSK3β/β-Catenin Signaling Pathways

Abstract

The extracts of Ficuscarica L. and Psoralen corylifolia L. are traditional Uygur medicines for the treatment of vitiligo, and its active ingredients furocoumarins, were are found to be the most effective agents against this skin disorder nowadays. Therefore, a series of novel easter derivatives (8a–8p) of furocoumarin were designed and synthesized based on our previous research to improve this activity in the present study. The synthesized derivatives were biologically evaluated for melanin synthesis in murine B16 cells and the SAR (structure-activity relationship) was summarized. Eight derivatives were more potent than positive control (8-MOP, 8-methoxypsoralan), especially compounds 8n (200%) and 8o (197%), which were nearly 1.5-fold potency when compared with 8-MOP (136%). Furthermore, the signaling pathway by which 8n activates the melanin biosynthesis was defined. Our results showed that it not only elevated the melanin content, but also stimulated the activity of tyrosinasein a concentration-dependent manner. Increasing of phosphorylation of Akt (also named PKB, protein kinase B) and non-activated GSK3β (glycogen synthase kinase 3 beta), which inhibited the degradation of β-catenin were observed through Western blot analysis. The accumulation of β-catenin probably led to the activation of transcription of MITF (microphthalmia-associated transcription factor) and TYR (tyrosinase) family, as well as the subsequent induction of melanin synthesis.

Psoralen Derivatives with Enhanced Potency

“…However, few comprehensive structure-activity relationship (SAR) studies on psoralen exist to assess such claims. The pertinent studies report only a few compounds at a time, making it difficult to establish any generalizable principles (16,(22)(23)(24)(25). Moreover, applying modern medicinal chemistry approaches to screen a library of psoralens could identify derivatives with unprecedented potencies and minimal undesired offtarget effects.…”

Inhibitory Effects of Essential Oil from Zanthoxylum coreanum Nakai on Melanin Production: Protection Against Re-Pigmentation after Laser Treatment

“…Kojic acid and Lascorbic acid, well-known tyrosinase inhibitors, were used as positive controls, as previously described. 14,15 B16F10 cells treated with ZCN showed reduced melanin production at the concentrations of 0.00125%-0.01%, although a significant positive correlation between essential oil concentration and melanin production was not observed ( Fig. 2A).…”

“…B16F10 cells characteristically release melanin. The release of melanin was assessed as previously described, 14 with slight modification. Cells were seeded in six-well plates.…”

Biological Activity of Endophytic Fungi from the Roots of the Medicinal Plant Vernonia anthelmintica

“…Tyrosinase activity was performed using the method of Chao et al [31]. First, the B16 cells were seeded in a six-well plate at a concentration of 2 × 10 5 cells per well and incubated for 24 h. Test samples were then added to each well and incubated for 24 h. Cells were then washed twice with ice-cold PBS and lysed using 1% Triton X-100 solution containing 1% sodium deoxycholate for 30 min at −80 • C. The lysates were centrifuged at 12,000× g for 15 min.…”

“…The crude extracts of endophytic fungi were evaluated for their effects on the synthesis of melanin pigments and intracellular tyrosinase activity in B16 cells. This method was carried out as described by Niu et al [31] and Rustamova et al [27]. After 48 h of treatment with crude extracts at 50 µg/mL, melanin content in B16 cells was determined ( Figure 3).…”