Laboratory of Medicinal Chemistry, College of Pharmacy, Pusan National University, Busan 46241, South Korea.
Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan; Department of Anatomy, Pusan National University School of Medicine, 49 Busandaehak-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do 50612, South Korea.
Bioorg Med Chem. 2018 Nov 15;26(21):5672-5681. doi: 10.1016/j.bmc.2018.10.014. Epub 2018 Oct 19.
Pigmentation disorders are attributed to excessive melanin which can be produced by tyrosinase. Therefore, tyrosinase is supposed to be a vital target for the treatment of disorders associated with overpigmentation. Based on our previous findings that an (E)-β-phenyl-α,β-unsaturated carbonyl scaffold can play a key role in the inhibition of tyrosinase activity, and the fact that cinnamic acid is a safe natural substance with a scaffolded structure, it was speculated that appropriate cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. Thus, ten cinnamamides were designed, and synthesized by using a Horner-Emmons olefination as the key step. Cinnamamides 4 (93.72% inhibition), 9 (78.97% inhibition), and 10 (59.09% inhibition) with either a 2,4-dihydroxyphenyl, or 4-hydroxy-3-methoxyphenyl substituent showed much higher mushroom tyrosinase inhibition at 25 µM than kojic acid (18.81% inhibition), used as a positive control. Especially, the two cinnamamides 4 and 9 having a 2,4-dihydroxyphenyl group showed the strongest inhibition. Docking simulation with tyrosinase revealed that these three cinnamamides, 4, 9, and 10, bind to the active site of tyrosinase more strongly than kojic acid. Cell-based experiments carried out using B16F10 murine skin melanoma cells demonstrated that all three cinnamamides effectively inhibited cellular tyrosinase activity and melanin production in the cells without cytotoxicity. There was a close correlation between cellular tyrosinase activity and melanin content, indicating that the inhibitory effect of the three cinnamamides on melanin production is mainly attributed to their capability for cellular tyrosinase inhibition. These results imply that cinnamamides having the (E)-β-phenyl-α,β-unsaturated carbonyl scaffolds are promising candidates for skin-lighting agents.
色素沉着障碍归因于过量的黑色素，而黑色素可以由酪氨酸酶产生。因此，酪氨酸酶被认为是治疗与过度色素沉着相关疾病的重要靶点。基于我们之前的发现，即(E)-β-苯基-α，β-不饱和羰基支架可以在抑制酪氨酸酶活性中发挥关键作用，并且肉桂酸是一种具有支架结构的安全天然物质，推测适当的肉桂酸衍生物可能具有有效的酪氨酸酶抑制活性。因此，设计并合成了十种肉桂酰胺，其中关键步骤是使用霍纳-埃蒙斯（Horner-Emmons）烯烃化反应。具有 2,4-二羟基苯基或 4-羟基-3-甲氧基苯基取代基的肉桂酰胺 4（93.72%抑制率）、9（78.97%抑制率）和 10（59.09%抑制率）在 25 µM 时对蘑菇酪氨酸酶的抑制作用明显高于作为阳性对照的曲酸（18.81%抑制率）。特别是具有 2,4-二羟基苯基的两种肉桂酰胺 4 和 9 表现出最强的抑制作用。与酪氨酸酶的对接模拟表明，这三种肉桂酰胺 4、9 和 10 与酪氨酸酶的活性位点结合比曲酸更紧密。在 B16F10 鼠皮肤黑色素瘤细胞中进行的细胞实验表明，这三种肉桂酰胺均能有效抑制细胞内酪氨酸酶活性和黑色素生成，且无细胞毒性。细胞内酪氨酸酶活性与黑色素含量密切相关，表明这三种肉桂酰胺对黑色素生成的抑制作用主要归因于其对细胞内酪氨酸酶的抑制能力。这些结果表明，具有(E)-β-苯基-α，β-不饱和羰基支架的肉桂酰胺是有前途的皮肤增亮剂候选物。
