Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety.

Sanggwon Lee,Chaeun Park,Hyung Ryong Moon,Inkyu Choi,Pusoon Chun,Dongwan Kang,Il Young Ryu,Hee Jin Jung,Sultan Ullah,Heejeong Choi,Yujin Park,Yeji Hwang,Yeongmu Jeong,Sojeong Hong

doi:10.3390/ijms22115616

Sanggwon Lee, Chaeun Park + Show 12 more

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https://doi.org/10.3390/ijms22115616

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Abstract

We previously reported (E)-β-phenyl-α,β-unsaturated carbonyl scaffold ((E)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (E)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds 1c (IC50 = 18.09 ± 0.25 μM), 1h (IC50 = 4.14 ± 0.10 μM), and 2a (IC50 = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC50 = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition.

Highlights

Melanin plays an important role by protecting the skin from harmful ultraviolet rays
We synthesized urolithin derivatives 1a–1j using the Hurtley reaction [69], as previously described with minor modification [44]
Methylation of the phenolic hydroxyl groups of 1a, 1c, 1g, and 1h using methyl iodide and K2 CO3 produced urolithin derivatives 1b, 1d, 1i, and 1j, respectively and the demethylation of the phenolic methyl ether in 1g and 1h using AlCl3 furnished urolithin derivatives 1e, and 1f, respectively

Summary

Introduction

Melanin plays an important role by protecting the skin from harmful ultraviolet rays. Abnormal accumulation of melanin leads to skin diseases, such as Riehl melanosis, melasma, and senile lentigo [1]. Numerous approaches have been made to reduce abnormal melanin accumulation by suppressing tyrosinase expression [2], maturation [3,4], and catalytic activity [5] and enhancing its degradation [6]. Due to its fewer side effects, arbutin is more widely used as a whitening agent than hydroquinone, and its anti-melanogenic effect is known to be due to the inhibition of tyrosinase. Skin-lightening agents used clinically, including arbutin and hydroquinone, do not have strong whitening effects. There is considerable need for new tyrosinase inhibitors with high efficacies but less or no side effects

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