Design, synthesis and evaluation of transition-state analogue inhibitors of Escherichia coli gamma-glutamylcysteine synthetase.
Phosphinic acid-, sulfoximine- and sulfone-based transition-state analogues were synthesized and evaluated as inhibitors of Escherichia coli gamma-glutamylcysteine synthetase. These compounds have a carboxyl function at the beta-carbon to the tetrahedral central hetero atom so as to mimic the carboxyl group of the attacking cysteine in the transition state. The phosphinic acid- and the sulfoximine-based compounds were found to be potent ATP-dependent inactivators, both showing a slow-binding kinetics with overall affinities and second-order inactivation rates of one to two orders of magnitude greater than those of L-buthionine (SR)-sulfoximine (L-BSO). The sulfone was a simple reversible inhibitor without causing ATP-dependent enzyme inactivation, but its affinity toward the enzyme was still five times greater than that of L-BSO, indicating that the beta-carboxyl function plays a key role in the recognition of the inhibitors by the enzyme. The sulfoximine with (S)-beta-carbon to the sulfur was synthesized stereoselectively, and the two diastereomers with respect to the chiral sulfur atom were separated as a cyclic sulfoximine derivative. The sulfoximine with R-configuration around the sulfur served as an extremely powerful ATP-dependent inactivator with an overall inhibition constant of 39 nM and an inactivation rate of 6750 M-1 s-1, which correspond to 1260-fold higher affinity and almost 1400-fold greater inactivation rate as compared with L-BSO. The sulfoximine with (S)-sulfur was a simple reversible inhibitor with an inhibition potency comparable to that of the sulfone. The synthesis and inhibition profile of the N-phosphoryl sulfoximine is also described.
Tokutake
N
N
Institute for Chemical Research, Kyoto University, Japan.
Hiratake
J
J
Katoh
M
M
Irie
T
T
Kato
H
H
Oda
J
J
D002087:Butyrates / Q000138:chemical synthesis* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology*; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D063065:Organophosphonates / Q000138:chemical synthesis; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*
C116530:2-amino(4-(2-carboxybutyl)sulfonyl)butanoic acid; C116531:2-amino-4-(2-carboxybutyl-(N-phosphoryl)sulfonimidoyl)butanoic acid; C116529:2-amino-4-(2-carboxybutylsulfonimidoyl)butanoic acid; D002087:Butyrates; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D005721:Glutamate-Cysteine Ligase