Novel Quercetin Derivative of 3,7-Dioleylquercetin Shows Less Toxicity and Highly Potent Tyrosinase Inhibition Activity

• Main Authors: Moon-Hee Choi, Seung-Hwa Yang, Da-Song Kim, Nam Doo Kim, Hyun-Jae Shin, Kechun Liu
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: International Journal of Molecular Sciences
• Subjects: quercetin derivatives; 3,7-dioleylquercetin; tyrosinase inhibitor; anti-melanogenesis; zebrafish; enzyme kinetics
• Online Access: https://www.mdpi.com/1422-0067/22/8/4264

Quercetin is a well-known plant flavonol and antioxidant; however, there has been some debate regarding the efficacy and safety of native quercetin as a skin-whitening agent via tyrosinase inhibition. Several researchers have synthesized quercetin derivatives as low-toxicity antioxidants and whitening agents. However, no suitable quercetin derivatives have been reported to date. In this study, a novel quercetin derivative was synthesized by the S_N2 reaction using quercetin and oleyl bromide. The relationship between the structures and activities of quercetin derivatives as anti-melanogenic agents was assessed using in vitro enzyme kinetics, molecular docking, and quenching studies; cell line experiments; and in vivo zebrafish model studies. Novel 3,7-dioleylquercetin (OQ) exhibited a low cytotoxic concentration level at >100 µg/mL (125 µM), which is five times less toxic than native quercetin. The inhibition mechanism showed that OQ is a competitive inhibitor, similar to native quercetin. Expression of tyrosinase, tyrosinase-related protein 1 (TRP-1) and tyrosinase-related protein 2 (TRP-2), and microphthalmia-associated transcription factor was inhibited in B16F10 melanoma cell lines. mRNA transcription levels of tyrosinase, TRP-1, and TRP-2 decreased in a dose-dependent manner. Melanin formation was confirmed in the zebrafish model using quercetin derivatives. Therefore, OQ might be a valuable asset for the development of novel skin-whitening agents.