2-Acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)- phenylcarbamoylsulfanyl]propionic Acid and Its Derivatives as a Novel Class of Glutathione Reductase Inhibitors

• Published in: Journal of medicinal chemistry 2005-08, Vol.48 (16), p.5224-5231
• Main Authors: Seefeldt, Teresa, Dwivedi, Chandradhar, Peitz, Greg, Herman, Jocqueline, Carlson, Laura, Zhang, Zhiling, Guan, Xiangming
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Carmustine - chemistry; Cysteine - analogs & derivatives; Cysteine - chemical synthesis; Cysteine - chemistry; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Glutathione Reductase - antagonists & inhibitors; Glutathione Reductase - chemistry; Kinetics; Medical sciences; Miscellaneous; NADP - chemistry; Oxidoreductases; Pharmacology. Drug treatments; Solubility; Structure-Activity Relationship; Thiocarbamates - chemical synthesis; Thiocarbamates - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050030i

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)phenylcarbamoylsulfanyl]propionic acid and its derivatives as irreversible GR inhibitors. The K i and k inact values of 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)phenylcarbamoylsulfanyl]propionic acid, the most potent derivative of the series, are 88 μM and 0.1 min-1, respectively. Although the K i 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 μM. Additional attractive features of the inhibitor include its ready availability through a one-step synthesis and good solubility in both organic and aqueous solutions.