Key Laboratory of Clinical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Department of Pharmacy, University-Town Hospital of Chongqing Medical University, Chongqing, China.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):728-742. doi: 10.1080/14756366.2022.2038591.
The linking of ethacrynic acid with ethylenediamine and 1,4-butanediamine gave EDEA and BDEA, respectively, as membrane-permeable divalent pro-inhibitors of glutathione -transferase (GST). Their divalent glutathione conjugates showed subnanomolar inhibition and divalence-binding to GSTmu (GSTM) (PDB: 5HWL) at ∼0.35 min. In cisplatin-resistant SK-OV-3, COC1, SGC7901 and A549 cells, GSTM activities probed by 15 nM BDEA or EDEA revealed 5-fold and 1.0-fold increases in cisplatin-resistant SK-OV-3 and COC1 cells, respectively, in comparison with the susceptible parental cells. Being tolerable by HEK293 and LO2 cells, BDEA at 0.2 μM sensitised resistant SK-OV-3 and COC1 cells by ∼3- and ∼5-folds, respectively, released cytochrome c and increased apoptosis; EDEA at 1.0 μM sensitised resistant SK-OV-3 and A549 cells by ∼5- and ∼7-fold, respectively. EDEA at 1.7 μg/g sensitised resistant SK-OV-3 cells to cisplatin at 3.3 μg/g in nude mouse xenograft model. BDEA and EDEA are promising leads for probing cellular GSTM and sensitising cisplatin-resistant ovarian cancers.
乙二醛与乙二胺和 1,4-丁二胺的连接分别得到乙二醛二乙胺（EDEA）和乙二醛二丁胺（BDEA），它们是谷胱甘肽 -S- 转移酶（GST）的膜通透性二价前抑制剂。它们的二价谷胱甘肽缀合物对 GSTmu（GSTM）（PDB：5HWL）表现出亚纳摩尔抑制作用和二价结合，结合常数约为 0.35 min。在顺铂耐药的 SK-OV-3、COC1、SGC7901 和 A549 细胞中，用 15 nM 的 BDEA 或 EDEA 探测 GSTM 活性，与敏感亲本细胞相比，顺铂耐药的 SK-OV-3 和 COC1 细胞分别增加了 5 倍和 1.0 倍。BDEA 在 0.2 μM 时对 HEK293 和 LO2 细胞是耐受的，分别使耐药 SK-OV-3 和 COC1 细胞的敏感性增加了约 3 倍和 5 倍，释放细胞色素 c 并增加细胞凋亡；EDEA 在 1.0 μM 时使耐药 SK-OV-3 和 A549 细胞的敏感性分别增加了约 5 倍和 7 倍。EDEA 在 1.7 μg/g 时使耐药 SK-OV-3 细胞对裸鼠异种移植模型中 3.3 μg/g 的顺铂的敏感性增加。BDEA 和 EDEA 是探测细胞 GSTM 和增敏顺铂耐药卵巢癌的有前途的先导化合物。
