Synthesis and Evaluation of the Inhibitory Activity of the Four Stereoisomers of the Potent and Selective Human γ-Glutamyl Transpeptidase Inhibitor GGsTop

Bioorganic and Medicinal Chemistry Letters

4 years ago

Synthesis and Evaluation of the Inhibitory Activity of the Four Stereoisomers of the Potent and Selective Human γ-Glutamyl Transpeptidase Inhibitor GGsTop

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 (R P/S P). 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 (k on = 174 M^-1s^-1) was ca. 8-fold more potent than the D-isomer (k on = 21.5 M^-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 S P. The S P-isomers inhibited human GGT (k on = 21.5-174 M^-1s^-1), while the R P-isomers were inactive even at concentrations of 0.1 mM.

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DOI: S0960894X17309022