Alparslan Mustafa Muhlis, Danış Özkan
Department of Medicinal Biochemistry, Faculty of Medicine, Çukurova University, Adana, Turkey.
Department of Chemistry, Faculty of Arts and Sciences, Marmara University, Istanbul, Turkey.
Arch Pharm (Weinheim). 2015 Sep;348(9):635-42. doi: 10.1002/ardp.201500151. Epub 2015 Jul 22.
Glutathione S-transferases (EC: 2.5.1.18, GSTs) are phase II detoxification enzymes that catalyze the conjugation of various electrophilic compounds to glutathione (GSH), thus usually producing less reactive and more water soluble compounds. However, there is evidence that elevated expression of GSTs, especially GSTP1, is involved in the resistance of tumor cells against chemotherapeutic agents. In this study, we synthesized and investigated the inhibitory effects of differently substituted 3-arylcoumarin derivatives on human placental GST, identified as GSTP1-1, using 1-chloro-2,4-dinitrobenzene as a substrate. A known potent inhibitor of GST, ethacrynic acid was used as a positive control. Among the tested compounds, 6,7-dihydroxy substituted coumarin derivatives exhibited the highest inhibitory activity (IC50 = 13.50-20.83 μM). These results suggest that 6,7-dihydroxy-3-arylcoumarins may represent a new promising scaffold to discover potent GST inhibitors.
谷胱甘肽S-转移酶（EC：2.5.1.18，GSTs）是II期解毒酶，可催化各种亲电化合物与谷胱甘肽（GSH）结合，从而通常产生反应性较低且水溶性更高的化合物。然而，有证据表明GSTs，尤其是GSTP1的表达升高与肿瘤细胞对化疗药物的耐药性有关。在本研究中，我们合成并研究了不同取代的3-芳基香豆素衍生物对人胎盘GST（鉴定为GSTP1-1）的抑制作用，以1-氯-2,4-二硝基苯为底物。已知的强效GST抑制剂依他尼酸用作阳性对照。在测试的化合物中，6,7-二羟基取代的香豆素衍生物表现出最高的抑制活性（IC50 = 13.50 - 20.83 μM）。这些结果表明，6,7-二羟基-3-芳基香豆素可能是发现强效GST抑制剂的一种新的有前景的骨架。
