A Theoretical Investigation of Phosphonamidates and Sulfonamides as Protease Transition State Isosteres

Abstract

The conformations and electrostatic potentials of phosphonamides, phosphonamidates and sulfonamides have been compared to the tetrahedral intermediate for base-catalyzed amide hydrolysis. The wide variation in inhibition by these similar compounds is explained through differences in electrostatic effects.

Ab initio study toward designing transition-state analogues which elicit proteolytic catalytic antibodies

“…It is considered that such a large N-EPS plays an important role in stabilizing the tetrahedral intermediate of ester in the catalytic pocket. 28,29 For stabilization, the hydrogen bonding and the electrostatic interactions play a part, and the x-ray analyses suggested that these interactions between the phosphonyl oxygens (O3 and O3') of haptens and the catalytic binding site were formed in the esterolytic antibodies. 30 The most likely mechanism for the esterolytic antibodies elicited against 1 and 2 involves direct hydroxide attack from free water rather than a sidechain of the amino acid on the scissile carbonyl carbon of ester, facilitated by the specific stabilizing interactions with the oxyanionic transition state species.…”

Asymmetric Synthesis of α-Substituted-β-Amino Phosphonates and Phosphinates and β-Amino Sulfur Analogs

“…Baldoli et al 84 have reported the first stereoselective synthesis of b-sultams from The very poor acceptor ability of the sulfonamide group has been confirmed by recent theoretical studies. 87 X-rays indicate that the N-H-O À À À ÀS À À À ÀO hydrogen bond is much weaker than the N-H-O À À À ÀC hydrogen bond. 88 Furthermore, the sulfonamido bond is more flexible than the amide bond and should show significant increase in polarity, enhanced metabolic stability, and structural similarity to the tetrahedral transition state involved in the amide bond enzymatic hydrolysis, 89 which is interesting for the development of catalytic antibodies and new drugs.…”

Pseudopeptide Synthesis via Fmoc Solid-Phase Synthetic Methodology

“…The tetrahedral achiral sulfur atom bonded to the two oxygen atoms possesses geometry similar to the high energy intermediate formed during the amide-bond hydrolysis or amide-bond formation [13,14]. Therefore, the peptidosulfonamides are at the same time stable to proteolytic hydrolysis and are capable of significantly altering the polarity and Hbonding patterns of native peptide.…”