Khatib Soliman, Nerya Ohad, Musa Ramadan, Shmuel Maayan, Tamir Snait, Vaya Jacob
Laboratory of Natural Medicinal Compounds, Migal-Galilee Technological Center, PO Box 831, Kiryat Shmona 11016, Israel.
Bioorg Med Chem. 2005 Jan 17;13(2):433-41. doi: 10.1016/j.bmc.2004.10.010.
Compounds, which inhibit tyrosinase, could be effective as depigmenting agents. We have introduced a group of mono-, di-, tri- and tetra-substituted hydroxychalcones as effective tyrosinase inhibitors, showing that the most important factor determining tyrosinase inhibition efficiency is the position of the hydroxyl group(s) rather their number. The aim of the present study was to investigate the contribution of the different functional groups of the tetrahydroxychalcones to their inhibitory potency, with a view to optimizing the design of whitening agents. Four tetrahydroxychalcones were evaluated, the commercially available Butein and other three were synthesized, and their inhibitory effect on tyrosinase was tested. Results showed that a 2,4-substituted resorcinol subunit on ring B contributed the most to inhibitory potency. Changing the resorcinol substitute to position 3,5- or placing it on ring A significantly diminished the inhibitory effect of the compounds. A catechol subunit on ring A acted as a metal chelator (in the presence of copper ions) and as a competitive inhibitor (in the presence of tyrosinase), while a catechol on ring B oxidized to o-quinone (in the presence of both copper ions and tyrosinase). Three of the compounds also demonstrated antioxidant activity, which may contribute to the prevention of pigmentation. An examination of correlations between inhibitory activity and physical properties of the chalcones tested (such as dissociation energy and molecular planarity) showed positive correlation with the moment dipole value in the Y-axis, which may be used as an indicator of the inhibitory potential of new molecules. The present study revealed two very active tyrosinase inhibitors, 2,4,3',4'-hydroxychalcone and 2,4,2',4'-hydroxychalcone (with IC50 of 0.2 and 0.02 microM, respectively). Structure-related activity studies added some understanding of the role and contribution of different functional groups associated with tyrosinase inhibitors.
抑制酪氨酸酶的化合物可作为有效的色素脱失剂。我们已引入一组单取代、二取代、三取代和四取代的羟基查尔酮作为有效的酪氨酸酶抑制剂，结果表明，决定酪氨酸酶抑制效率的最重要因素是羟基的位置而非其数量。本研究的目的是研究四羟基查尔酮不同官能团对其抑制效力的贡献，以期优化美白剂的设计。对四种四羟基查尔酮进行了评估，其中包括市售的紫铆因以及另外三种合成的四羟基查尔酮，并测试了它们对酪氨酸酶的抑制作用。结果表明，B环上的2,4-二取代间苯二酚亚基对抑制效力的贡献最大。将间苯二酚取代基移至3,5-位或置于A环上会显著降低化合物的抑制作用。A环上的儿茶酚亚基在存在铜离子时充当金属螯合剂，在存在酪氨酸酶时充当竞争性抑制剂，而B环上的儿茶酚在同时存在铜离子和酪氨酸酶时会氧化为邻醌。其中三种化合物还表现出抗氧化活性，这可能有助于预防色素沉着。对所测试查尔酮的抑制活性与物理性质（如离解能和分子平面性）之间的相关性进行研究发现，其与Y轴上的偶极矩值呈正相关，该偶极矩值可作为新分子抑制潜力的指标。本研究发现了两种活性很强的酪氨酸酶抑制剂，即2,4,3',4'-羟基查尔酮和2,4,2',4'-羟基查尔酮（IC50分别为0.2和0.02微摩尔）。与结构相关的活性研究增进了对与酪氨酸酶抑制剂相关的不同官能团的作用和贡献的理解。
