Identification of phenanthridine derivatives Wnt agonists and
their effects on melanin levels
Phenanthridines have been identified as specific Wnt/β -catenin
signalling agonists. To identify more potent Wnt agonists, we designed
and synthesized phenanthridine derivatives as Wnt agonists and performed
studies on their structural optimization and structure-activity
relationships (SAR). Thus, we identified additional potent Wnt agonists,
including HCJA121, HCJA404, and compounds 1–6 (Fig. 1a, Fig.
S1).
The effects of these eight phenanthridine derivatives on the levels of
melanin were initially evaluated in B16-F10 cells treated with
Wnt3a-conditioned media, using 8-methoxypsoralan (8-MOP) (Lerner, Denton
& Fitzpatrick, 1953) as a positive control. The absorbance of the same
number of cells treated with phenanthridine derivatives at 50 μ M
indicated that HCJA121 and HCJA404 strongly promoted melanin synthesis
compared to 8-MOP (Fig. 1b). Particularly, among these compounds,
HCJA121 and HCJA404 performed the best, promoting melanogenesis in a
dose-dependent manner, with EC50 values of 4.68μ M and 7.12 μ M, respectively, which were considerably
better than that of 8-MOP (EC50 = 24.36 μ M).
Therefore, HCJA121 and HCJA404 were deemed suitable for further
bioassays, and 20 μ M was chosen as an effective treatment
concentration. The effect of HCJA121 and HCJA404 on tyrosinase was
measured by ʟ-DOPA oxidation. Compared with treatment with DMSO alone
(untreated condition), treatment with 20 μ M HCJA121 and HCJA404
resulted in an increase in tyrosinase activity in the B16 cells (Fig.
1c), which suggested that HCJA121 and HCJA404 exhibit good potential for
improving vitiligo symptoms.