Intramolecular Nonbonded S...N Interaction in Rabeprazole

Abstract

Intramolecular nonbonded S · · · X (XϭS, O, N, etc.) interactions have been observed in a large number of organosulfur compounds controlling the conformation of small and large molecules. [1][2][3][4][5][6][7][8][9][10][11][12] Some of these compounds showed the strong bioactivity, and we suggested that the intramolecular nonbonded S · · · X interactions play an important role on the mechanism of several biological effects.1,2,6-12) For example, the clear S · · · O close contact in the complex crystalline structure of carbonic anhydrase I and acetazolamide was recognized.12) The same nonbonded interaction was observed in the crystalline structure of acyliminothiadiazoline, which has potent angiotensin II receptor antagonistic activity. 6,11) It is estimated that the ring structure consisted of the intramolecular nonbonded S · · · X interactions was more flexible than that of covalent bonding, and this flexibility increased the binding affinity of the active compound to the flexible pocket of the enzyme or the receptor. These results prompted us to disclose the new roles of intramolecular nonbonded S · · · X interactions in other drugs. Herein, we focus on rabeprazole, [13][14][15][16] and discuss the intramolecular nonbonded S · · · N interaction in rabeprazole and its role.Sodium rabeprazole (1) is one of the inhibitors of the gas-13,14) As a result of the investigations on the mechanism of action of these inhibitors, it has been expected that 1 will be activated by protonation in the parietal cell (intermediate 2), converted into the sulfenamide 5 via the spiro sulfoxide 3 and sulfenic acid 4, and the active principle 5 can react with the accessible cysteines of the gastric (H ϩ -K ϩ )-ATPase followed by the inhibition of the enzyme (compound 6), as shown in Chart 1. 14,[17][18][19][20] In this reaction cascade, the key step is the formation of the putative spiro sulfoxide 3 arising from nucleophilic attack of the pyridine nitrogen on the activated 2-position of the benzimidazole moiety.18) The fact that the nucleophilic attack of the pyridine nitrogen smoothly proceeds despite the week nucleophilicity is very interest, and made us guess that the intramoleculer nonbonded S · · · N interaction influenced this step. Because, if such intramoleculer nonbonded S · · · N interaction is possible in rabeplazole, the 4-membered quasiring in 2 containing the rabeplazole structure would be formed and bring the nitrogen atom of pyridine close to the electrophilic position of benzimidazole moiety, as shown in Fig. 1. Therefore, in order to make clear the presence of the intramoleculer nonbonded S · · · N interaction in 1, we characterized the crystal structures of derivatives of 1 at first, since 1 itself could hardly be crystallized. 21)The reactions of 1 with various electrophiles in the presence of amines gave the corresponding derivatives of 1 in 36-92% yields, as shown in Chart 2. The resultant derivatives 7a-d were recrystallized from suitable solvents to obtain the corresponding crystals available for X-ray crystal...

Coherent Multidimensional Vibrational Spectroscopy of Biomolecules: Concepts, Simulations, and Challenges

“…[167] Analytic energy gradient in the presence of multi-pole field was implemented in the Gaussian 03 code [168] to compute the higher derivatives. [169,170] The LAS were calculated for a grid of electrostatic multipole coefficients C by diagonalizing the local Hamiltonian operator expanded in a harmonic basis set. The ARNOLDI matrix diagonalization algorithm was employed in these vibrational configuration interactions (vibrational CI) calculations.…”

Theoretical study of the smiles rearrangement in the activation mechanism of proton pump inhibitors

“…Hayashi et al have already suggested the existence of a N … S interaction in neutral rabeprazole, based on crystallographic distances. [23] These authors synthesized several derivatives of rabeprazole, which presented N … S distances around 0.27-0.28 nm ∇ 2 ρ envelope map of c5 in Fig. 3 can help to understand the N … S interaction.…”

Kohärente mehrdimensionale Schwingungsspektroskopie von Biomolekülen: Konzepte, Simulationen und Herausforderungen

“…[167] Analytische Energiegradienten in Gegenwart von Multipolfeldern wurden auch in Gaussian 03 [168] implementiert, um höhere Ableitungen berechnen zu können. [169,170] Durch Diagonalisierung des in einen harmonischen Basissatz entwickelten lokalen Hamilton-Operators wurden die lokalen Amidzustände in einem Gitternetz von elektrostatischen Multipolkoeffizienten C ermittelt, wobei zur Berechnung der Schwingungskonfigurationswechselwirkung (Schwingungs-CI) der ARNOLDI-Algorithmus für die Matrixdiagonalisierung angewendet wurde. Die Übergangsschwingungsfrequenz vom Grundzustand in den LAS a und die Übergangsdipolmomente zwischen LAS a und b der mten Peptideinheit wurden quadratisch in C entwickelt [Gl.…”