Jeong Yeongmu, Hong Sojeong, Jung Hee Jin, Ullah Sultan, Hwang YeJi, Choi Heejeong, Ko Jeongin, Lee Jieun, Chun Pusoon, Chung Hae Young, Moon Hyung Ryong
Laboratory of Medicinal Chemistry, Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Korea.
Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Korea.
Antioxidants (Basel). 2022 May 11;11(5):948. doi: 10.3390/antiox11050948.
The rate-determining role of tyrosinase makes it a critical component in the mechanism that is responsible for melanogenesis. Thirteen ()-5-(substituted benzylidene)-3-phenyl-2-thioxothiazolidin-4-one (()-BPTT) analogs were designed based on the structural features of two potent tyrosinase inhibitors, viz. (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-thioxothiazolidin-4-one (5-HMT) and ()-2-(2,4-dihydroxybenzylidene)benzo[4,5]imidazo[2,1-]thiazol-3(2)-one (compound I). The trisubstituted double bond geometry of the ()-BPTT analogs that were generated by Knoevenagel condensation was determined using vicinal H and C coupling constants in C NMR spectra. Four analogs, numbers - and inhibited mushroom tyrosinase 9 to 29 times more potently than kojic acid did. Kinetic study results indicated that these four analogs inhibited mushroom tyrosinase competitively and this was supported by docking simulation. Also, docking results using human tyrosinase suggested that analogs and might be potent human tyrosinase inhibitors. In vitro studies using B16F10 cells (a melanoma cell line) showed that analogs , , , and inhibited cellular tyrosinase and melanin production more than kojic acid did, without perceptible cytotoxicity. In particular, analog , which possesses a catechol group, exerted an extremely potent anti-melanogenic effect. In addition, analog showed strong scavenging activity against DPPH and ABTS radicals. Furthermore, analog not only reduced ROS levels, which induce melanogenesis, but it also suppressed tyrosinase and MITF (microphthalamia-associated transcription factor) protein levels and the expressions of melanogenesis-related genes. These results suggest that analog is an efficient tyrosinase inhibitor that alleviates melanogenesis by dual mechanisms of (i) the inhibition of melanogenesis-related proteins and genes and (ii) the direct inhibition of tyrosinase activity.
酪氨酸酶的限速作用使其成为黑色素生成机制中的关键组成部分。基于两种强效酪氨酸酶抑制剂，即（Z）-5-（3-羟基-4-甲氧基亚苄基）-2-硫代噻唑烷-4-酮（5-HMT）和（）-2-（2,4-二羟基亚苄基）苯并[4,5]咪唑并[2,1-]噻唑-3（2）-酮（化合物I）的结构特征，设计了13种（）-5-（取代亚苄基）-3-苯基-2-硫代噻唑烷-4-酮（（）-BPTT）类似物。通过Knoevenagel缩合生成的（）-BPTT类似物的三取代双键几何结构，利用13C NMR谱中的邻位氢和碳耦合常数来确定。4种类似物，编号为-和，对蘑菇酪氨酸酶的抑制作用比曲酸强9至29倍。动力学研究结果表明，这4种类似物对蘑菇酪氨酸酶具有竞争性抑制作用，对接模拟也支持了这一点。此外，使用人酪氨酸酶的对接结果表明，类似物和可能是有效的人酪氨酸酶抑制剂。使用B16F10细胞（一种黑色素瘤细胞系）进行的体外研究表明，类似物、、、和对细胞酪氨酸酶和黑色素生成的抑制作用比曲酸更强，且无明显细胞毒性。特别是具有儿茶酚基团的类似物，具有极强的抗黑色素生成作用。此外，类似物对DPPH和ABTS自由基表现出较强的清除活性。此外，类似物不仅降低了诱导黑色素生成的ROS水平，还抑制了酪氨酸酶和小眼畸形相关转录因子（MITF）蛋白水平以及黑色素生成相关基因的表达。这些结果表明，类似物是一种有效的酪氨酸酶抑制剂，通过（i）抑制黑色素生成相关蛋白和基因以及（ii）直接抑制酪氨酸酶活性的双重机制减轻黑色素生成。
