Preparation of novel 1,2,3-triazole furocoumarin derivatives via click chemistry and their anti-vitiligo activity

Abstract

The extracts of Psoralea corylifolia L. were often used for the repigmentation of leukoderma (vitiligo) in traditional Uygur medicine thousands years ago. Nowadays, its active ingredient, furocoumarins, has been clinically applied since it exhibited strong photosensitivity. Thus, a new series of furocoumarin derivatives (8a-8o) containing 1,2,3-triazole were designed and synthesized based on our previous work. After biological evaluation for melanin contents and tyrosinase activity in B16 murine cells, the SAR was summarized. The results indicated that five compounds (8a, 8j, 8m-8o) were more potent than the positive control (8-MOP) on melanogenesis. Among them, 8a and 8o showed the best stimulating effect on tyrosinase activity as well, and were submitted for further pharmacological study of anti-vitiligo.

Fig. 1. Vitiligo with typical lesions of the face and trunk.

Fig. 2. Structures of commonly used drugs for vitiligo.

Fig. 3. The plant of the Psoralea corylifolia L.

Fig. 4. The structures of the furocoumarins used for vitiligo.

Fig. 5. The SAR of furocoumarins on vitiligo.

Scheme 1. Synthesis of furocoumarin derivatives containing 1,2,3-triazole (8a–8o). Reagents and conditions: (i) DMF, K₂CO₃, 70 °C (ii) ethyl acetoacetate, H₂SO₄, 60 °C (iii) 2-bromoacetophenone, K₂CO₃, acetone, reflux (iv) 4% KOH ethanolic solution, reflux (v) SeO₂, xylene, reflux (vi): NaBH₄, methanol, rt (vii): PBr₃, THF, 0 °C-rt (viii): NaN₃, CH₃CN, reflux (ix) a–o, CuSO₄·5H₂O, Cu, t-BuOH : H₂O = 1 : 3, 80 °C.

Fig. 6. Stimulation of melanin content of B16 cells by 8a–8o. N means negative control; P means positive control (8-MOP); the B16 cells was treated with 50 μM different furocoumarin derivatives for 48 h. After that, melanin content was measured directly. Values are expressed as the mean ± SD of three separate experiments, P < 0.05.

Fig. 7. Stimulation of tyrosinase activity of B16 cells by 8a–8o. N means negative control; P means positive control (8-MOP). B16 cells was treated with 50 μM different furocoumarin derivatives for 48 h. After that, tyrosinase activity was measured directly. The data are the mean ± SD of three experiments, P < 0.05.

Fig. 8. The concentration dependent manner of 8a, 8o on melanin synthesis and tyrosinase activity. “◆”, “■” and “×”, “▲” means the effect of 8a, 8o on melanin synthesis (in blue) and tyrosinase activity (in red) separately at different concentration in B16 cells.