In vitro anti-melanogenisis effect of sesquiterpene lactones from roots of Saussurea lappa and their analogues

In this study, nine sesquiterpene lactones from Saussurea lappa root extracts including costunolide (1), α-, β-, γ-cyclocostunolide (2, 3, 4), santamarine (5), reynosin (6), arbuscirin A (7), dehydrocostus lactone (8), and 11β, 13-dehydrocostus lactone (9) were screened on melanin production, which was focused on extracellular melanogenesis in B16 melanoma cells [1]. Among tested compounds, only compound 2 significantly decreased extracellular melanin content in a concentration-dependent manner, with an IC₅₀ value of 5.75 μM. Particularly, at 10 μM melanin content is 1.6-fold lower than arbutin as the skin lightening agent at 730 μM. Until now, the structure-activity relationship of sesquiterpene lactones on anti-melanogenesis has not been reported. To clarify their structure-activity relationship (SAR) profiles, 12 sesquiterpene lactone analogues were synthesized and evaluated the potential for melanin production. The results showed that all analogues did not display any significant for this activity. Furthermore, compound 2 had no effect on mushroom tyrosinase inhibitory activity. This indicated that decreasing melanin was not caused by tyrosinase inhibition, which might affect protein expression at a post-translational modification.

These results provide the first SAR profile of sesquiterpene lactones and indicate that a double bond at C3-4 is the most effective position on anti-melanogenesis for eudesmanolide-skeleton. In addition, the C1-substituent with hydroxyl, ketone and ester moieties markedly decreased this activity. For the findings, therefore, suggest that α-cyclocostunolide (2) might represent a lead compound in the therapy of skin disorders.

Fig. 1 Summary of SAR of the eudesmanolide skeleton for melanin inhibitory activity

• References

• 1 Choodej S, Pudhom K, Yamauchi K, Mitsunaga T. Inhibition of melanin production by sesquiterpene lactones from Saussurea lappa and their analogues. Med Chem Res. 2019 23 April online.