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Abstract：
Tyrosinase plays a key role in the melanin biosynthesis since it catalyzes the transformation of tyrosine into L-dopaquinone. A large number of studies have also shown that molecules to efficiently inhibit the activity of tyrosinase would be potentially used in treating many depigmentation-related disorders. In this study, we targeted a series of structure-based 3-aryl substituted xanthone derivatives in which diverse functional groups were respectively attached on 3-aromatic ring moiety as new tyrosinase inhibitors. The results demonstrated that all obtained compounds had potent tyrosinase inhibitory activities with IC50 values at micromolar range. Especially, compound 4t was found to be the most active tyrosinase inhibitor with the IC50 value of 11.3 µM, uncovering that the introduction of the proper hydroxyl group in the 3-aromatic ring was beneficial for enhancing the inhibitory potency against tyrosinase. Moreover, the inhibition mechanism and inhibition kinetics studies revealed that compound 4t presented such inhibitory effect by acting as the reversible and competitive-uncompetitive mixed-II type inhibitor. Further molecular docking simulation showed that 3-aromatic ring of compound 4t was inserted into the narrow regions of binuclear copper-binding site at the bottom of the enzyme binding pocket, while the xanthone skeleton was positioned at the surface of tyrosinase. Taken together, these data suggested that such type of molecules might be utilized for the development of new and promising candidate for the treatment of depigmentation-related disorders.
摘要：
酪氨酸酶在黑色素生物合成中起关键作用,因为它催化酪氨酸转化为L-多巴醌。大量研究还表明,有效抑制酪氨酸酶活性的分子将潜在地用于治疗许多色素脱失相关疾病。在这项研究中,我们针对一系列基于结构的3-芳基取代的黄吨酮衍生物,其中不同的官能团分别连接在3-芳环部分作为新的酪氨酸酶抑制剂.结果表明，所有获得的化合物都具有有效的酪氨酸酶抑制活性，IC50值在微摩尔范围内。尤其是,发现化合物4t是活性最高的酪氨酸酶抑制剂，IC50值为11.3µM，发现在3-芳环中引入适当的羟基有利于增强对酪氨酸酶的抑制能力。此外，抑制机制和抑制动力学研究表明，化合物4t通过充当可逆和竞争性非竞争性混合II型抑制剂而表现出这种抑制作用。进一步的分子对接模拟表明,化合物4t的3-芳环插入酶结合袋底部双核铜结合位点的狭窄区域,而黄原酮骨架位于酪氨酸酶的表面。一起来看,这些数据表明,这类分子可用于开发治疗色素脱失相关疾病的新的有希望的候选药物.
