219507-00-3Relevant articles and documents
Design, synthesis and evaluation of transition-state analogue inhibitors of Escherichia coli γ-glutamylcysteine synthetase
Tokutake, Nobuya,Hiratake, Jun,Katoh, Makoto,Irie, Takayuki,Kato, Hiroaki,Oda, Jun'ichi
, p. 1935 - 1953 (2007/10/03)
Phosphinic acid-, sulfoximine- and sulfone-based transition-state analogues were synthesized and evaluated as inhibitors of Escherichia coli γ-glutamylcysteine synthetase. These compounds have a carboxyl function at the β-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 β-carboxyl function plays a key role in the recognition of the inhibitors by the enzyme. The sulfoximine with (S)-β-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 39nM and an inactivation rate of 6750M-1s-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. Copyright (C) 1998 Elsevier Science Ltd.
