Choi Moon-Hee, Yang Seung-Hwa, Kim Da-Song, Kim Nam Doo, Shin Hyun-Jae, Liu Kechun
Department of Chemical Engineering, Graduate School of Chosun University, Gwangju 61452, Korea.
VORONOI BIO Inc., Incheon 21984, Korea.
Int J Mol Sci. 2021 Apr 20;22(8):4264. doi: 10.3390/ijms22084264.
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 S2 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.
槲皮素是一种著名的植物黄酮醇和抗氧化剂；然而，关于天然槲皮素作为一种通过抑制酪氨酸酶实现皮肤美白剂的功效和安全性存在一些争议。几位研究人员已合成槲皮素衍生物作为低毒性抗氧化剂和美白剂。然而，迄今为止尚未报道合适的槲皮素衍生物。在本研究中，使用槲皮素和油基溴通过S2反应合成了一种新型槲皮素衍生物。使用体外酶动力学、分子对接和猝灭研究；细胞系实验；以及体内斑马鱼模型研究评估了槲皮素衍生物作为抗黑素生成剂的结构与活性之间的关系。新型3,7 - 二油基槲皮素（OQ）在>100 µg/mL（125 µM）时表现出低细胞毒性浓度水平，其毒性比天然槲皮素低五倍。抑制机制表明，OQ是一种竞争性抑制剂，类似于天然槲皮素。在B16F10黑色素瘤细胞系中，酪氨酸酶、酪氨酸酶相关蛋白1（TRP - 1）、酪氨酸酶相关蛋白2（TRP - 2）以及小眼畸形相关转录因子的表达受到抑制。酪氨酸酶、TRP - 1和TRP - 2的mRNA转录水平呈剂量依赖性下降。在斑马鱼模型中使用槲皮素衍生物证实了黑色素的形成。因此，OQ可能是开发新型皮肤美白剂的宝贵资源。
