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Synthesis and evaluation of the inhibitory activity of the four stereoisomers of the potent and selective human γ-glutamyl transpeptidase inhibitor GGsTop.

Authors
  • Watanabe, Bunta1
  • Tabuchi, Yukiko2
  • Wada, Kei3
  • Hiratake, Jun2
  • 1 Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. Electronic address: [email protected] , (Japan)
  • 2 Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. , (Japan)
  • 3 Department of Medical Sciences, University of Miyazaki, Miyazaki 889-1692, Japan. , (Japan)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Nov 01, 2017
Volume
27
Issue
21
Pages
4920–4924
Identifiers
DOI: 10.1016/j.bmcl.2017.09.017
PMID: 28985998
Source
Medline
Keywords
License
Unknown

Abstract

2-Amino-4-{[3-(carboxymethyl)phenoxy](methoxy)phosphoryl}butanoic acid (GGsTop) is a potent, highly selective, nontoxic, and irreversible inhibitor of γ-glutamyl transpeptidase (GGT). GGsTop has been widely used in academic and medicinal research, and also as an active ingredient (Nahlsgen) in commercial anti-aging cosmetics. GGsTop consists of four stereoisomers due to the presence of two stereogenic centers, i.e., the α-carbon atom of the glutamate mimic (l/d) and the phosphorus atom (RP/SP). In this study, each stereoisomer of GGsTop was synthesized stereoselectively and their inhibitory activity against human GGT was evaluated. The l- and d-configurations of each stereoisomer were determined by a combination of a chiral pool synthesis and chiral HPLC analysis. The synthesis of the four stereoisomers of GGsTop used chiral synthetic precursors that were separated by chiral HPLC on a preparative scale. With respect to the configuration of the α-carbon atom of the glutamate mimic, the l-isomer (kon=174M-1s-1) was ca. 8-fold more potent than the d-isomer (kon=21.5M-1s-1). In contrast, the configuration of the phosphorus atom is critical for GGT inhibitory activity. Based on a molecular modeling approach, the absolute configuration of the phosphorus atom of the active GGsTop isomers was postulated to be SP. The SP-isomers inhibited human GGT (kon=21.5-174M-1s-1), while the RP-isomers were inactive even at concentrations of 0.1mM.

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