2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)-phenylcarbamoylsulfanyl]propionic acid and its derivatives as a novel class of glutathione reductase inhibitors
2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)-phenylcarbamoylsulfanyl]propionic acid and its derivatives as a novel class of glutathione reductase inhibitors
复制标题
DOI：
10.1021/jm050030i
复制
发表时间：
2005-08-11
影响因子：
7.3
通讯作者：
Guan, XM
中科院分区：
文献类型：
--
作者：
Seefeldt, T;Dwivedi, C;Guan, XM
谷胱甘肽还原酶（GR）催化氧化型谷胱甘肽还原为还原型谷胱甘肽。该酶是抗疟药物开发的一个有吸引力的靶标。药剂、降低疟疾耐药性的药剂和抗癌药剂。此外，酶的抑制已被用作各种目的的研究工具。在本文中，我们提出了2-乙酰氨基-3-[4-(2-乙酰氨基-2-羧乙基硫基羰基氨基)苯基氨基甲酰基硫基丙酸及其衍生物作为不可逆GR抑制剂的合理设计。该系列中最有效的衍生物2-乙酰氨基-3-[4-(2-乙酰氨基-2-羧乙基硫基羰基氨基)苯基氨基甲酰基硫基丙酸的K-i和k(无活性)值分别为88,μM和0.1 min(-1)。尽管该抑制剂的 Ki 值在微摩尔范围内，但它比 N,N-双(2-氯乙基)-N-亚硝基脲更有效，N,N-双(2-氯乙基)-N-亚硝基脲是目前最常用的不可逆 GR 抑制剂，据报道 IC50 值为 646,μM。该抑制剂的其他吸引人的特性包括通过一步合成即可轻松获得，并且在有机溶液和水溶液中均具有良好的溶解度。
Glutathione reductase (GR) catalyzes the reduction of oxidized glutathione to reduced glutathione. The enzyme is an attractive target for the development of antimalarial. agents, agents to decrease malarial drug resistance and anticancer agents. In addition, inhibition of the enzyme has been employed as a tool in research for various purposes. In this paper, we present a rational design of 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)phenylcarbamoylsulfanyllpropionic acid and its derivatives as irreversible GR inhibitors. The K-i and k(inact) values of 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)phenylcarbamoylsulfanyllpropionic acid, the most potent derivative of the series, are 88,mu M and 0.1 min(-1), respectively. Although the Ki value of the inhibitor is in the micromolar range, it is more potent than N,N-bis(2-chloroethyl)-N-nitrosourea, which is currently the most commonly employed irreversible GR inhibitor with a reported IC50 value of 646,mu M. Additional attractive features of the inhibitor include its ready availability through a one-step synthesis and good solubility in both organic and aqueous solutions.