A Potent Tyrosinase Inhibitor, (E)-3-(2,4-Dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one, with Anti-Melanogenesis Properties in α-MSH and IBMX-Induced B16F10 Melanoma Cells.

Chang Kim,Hyung Moon,Yujin Park,Sang Noh,Pusoon Chun,Hee Jung,Hae Chung,Dongwan Kang

doi:10.3390/molecules23102725

Chang Kim, Hyung Moon + Show 6 more

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https://doi.org/10.3390/molecules23102725

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Abstract

In this study, we designed and synthesized eight thiophene chalcone derivatives (1a–h) as tyrosinase inhibitors and evaluated their mushroom tyrosinase inhibitory activities. Of these eight compounds, (E)-3-(2,4-dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (1c) showed strong competitive inhibition activity against mushroom tyrosinase with IC50 values of 0.013 μM for tyrosine hydroxylase and 0.93 μM for dopa oxidase. In addition, we used enzyme kinetics study and docking program to further evaluate the inhibitory mechanism of 1c toward tyrosinase. As an underlying mechanism of 1c mediated anti-melanogenic effect, we investigated the inhibitory activity against melanin contents and cellular tyrosinase in B16F10 melanoma cells. As the results, the enzyme kinetics and docking results supports that 1c highly interacts with tyrosinase residues in the tyrosinase active site and it can directly inhibit tyrosinase as competitive inhibitor. In addition, 1c exhibited dose-dependent inhibitory effects in melanin contents and intracellular tyrosinase on α-MSH and IBMX-induced B16F10 cells. Overall, our results suggested that 1c might be considered potent tyrosinase inhibitor for use in the development of therapeutic agents for diseases associated with hyperpigment disorders.

Highlights

Melanogenesis is a process that involves melanin synthesis, transport of melanin, and release of melanosome
Our results suggest that the capacity of these compounds to inhibit tyrosinase is affected by number and location of functional groups on the phenyl ring
We examined whether 1c is cytotoxic to B16F10 melanoma cells

Summary

Introduction

Melanogenesis is a process that involves melanin synthesis, transport of melanin, and release of melanosome. Melanin, composed of pheomelanin and eumelanin, is synthesized in melanosomes of melanocytes [1]. The abnormal synthesis of melanin leads to skin conditions such as vitiligo, melasma, chloasma freckles, and inflammatory pigmentation. Melanogenic enzymes such as tyrosinase was synthesized [2,3,4,5]. Tyrosinase (EC 1.14.18.1), a multifunctional copper-containing polyphenol oxidative enzyme, is key for melanin biosynthesis and is responsible for melanization in animals and browning in plants [6]. The reactions in the melanin biosynthetic pathway involves the hydroxylation of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) and the Molecules 2018, 23, 2725; doi:10.3390/molecules23102725 www.mdpi.com/journal/molecules

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