title: 2-Acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)- phenylcarbamoylsulfanyl]propionic acid and its derivatives as a novel class of glutathione reductase inhibitors.
abstract: 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 muM 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 IC(50) value of 646 microM. Additional attractive features of the inhibitor include its ready availability through a one-step synthesis and good solubility in both organic and aqueous solutions.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Seefeldt
authors.forename: Chandradhar
authors.initials: C
authors.lastname: Dwivedi
authors.forename: Greg
authors.initials: G
authors.lastname: Peitz
authors.forename: Jocqueline
authors.initials: J
authors.lastname: Herman
authors.forename: Laura
authors.initials: L
authors.lastname: Carlson
authors.forename: Zhiling
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiangming
authors.initials: X
authors.lastname: Guan
mesh_terms: D002330:Carmustine / Q000737:chemistry; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D007700:Kinetics; D009249:NADP / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C503900:2-acetylamino-3-(4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)phenylcarbamoylsulfanyl)propionic acid; D013859:Thiocarbamates; D009249:NADP; D005980:Glutathione Reductase; D003545:Cysteine; D002330:Carmustine