Jun-ichi Mizoguchi

Supramolecular Complexation and Enantiodifferentiating Photocyclodimerization of 2-Anthracenecarboxylic Acid with 4-Aminoprolinol Derivatives as Chiral Hydrogen-Bonding Templates

The photochirogenesis of 2-anthracenecarboxylic acid (AC) complexed to a hydrogen-bonding template (TKS159) was investigated to obtain mechanistic information on how chirogenesis is achieved for the dimerization of AC. Complexation of AC to TKS159 leads to the shielding of one of the two surfaces of the prochiral AC molecule. The two diastereomeric AC-TKS complexes, i.e., re-AC-TKS and si-AC-TKS, were characterized by changes in the UV-vis, fluorescence, and circular dichroism spectra and excited-state lifetimes. The ee is not simply determined by the diastereomeric ratio of the re- and si-AC-TKS complexes but also depends on the relative lifetimes of the diastereomeric complexes. The relative population of the re and si complexes was calculated from the enantiomeric excess (ee) for the products, taking into account the relative lifetimes of the two complexes. These studies established a protocol that can be used to reveal the mechanism for photochirogenesis by investigating the ground state and the excited state behavior of supramolecular systems.

In Vitro Activity of a Novel Antimicrobial Agent, TG44, for Treatment of Helicobacter pylori Infection

ABSTRACT Due to concerns about the current therapeutic modalities for Helicobacter pylori infection, e.g., the increased emergence of drug-resistant strains and the adverse reactions of drugs currently administered, there is a need to develop an anti-H. pylori agent with higher efficacy and less toxicity. The antibacterial activity of TG44, an anti-H. pylori agent with a novel structural formula, against 54 clinical isolates of H. pylori was examined and compared with those of amoxicillin (AMX), clarithromycin (CLR), and metronidazole (MNZ). Consequently, TG44 inhibited the growth of H. pylori in an MIC range of 0.0625 to 1 μg/ml. The MIC ranges of AMX, CLR, and MNZ were 0.0078 to 8 μg/ml, 0.0156 to 64 μg/ml, and 2 to 128 μg/ml, respectively. The antibacterial activity of TG44 against AMX-, CLR-, and MNZ-resistant strains was nearly comparable to that against drug-susceptible ones. In a pH range of 3 to 7, TG44 at 3.13 to 12.5 μg/ml exhibited potent bactericidal activity against H. pylori in the stationary phase of growth as early as 1 h after treatment began, in contrast to AMX, which showed no bactericidal activity at concentrations of up to 50 μg/ml at the same time point of treatment. TG44 at 25 μg/ml exhibited no antibacterial activity against 13 strains of aerobic bacteria, suggesting that its antibacterial activity against H. pylori is potent and highly specific. The present study indicated that TG44 possesses antibacterial activity which manifests quickly and is potentially useful for eradicating not only the antibiotic-susceptible but also the antibiotic-resistant strains of H. pylori by monotherapy.

Cross- versus Homo-Photocyclodimerization of Anthracene and 2-Anthracenecarboxylic Acid Mediated by a Chiral Hydrogen-Bonding Template. Factors Controlling the Cross-/Homo-Selectivity and Enantioselectivity

Competitive cross-/homo-photocyclodimerization of anthracene (AN) and 2-anthracenecarboxylic acid (AC) mediated by a chiral hydrogen-bonding template (TKS) was investigated under various conditions. The cross-photocyclodimerization was favored by a factor of 4-5 at all temperatures and wavelengths examined to afford the AC-AN cross-dimer in 80-84% yield even at AN/AC = 1 and in 98% yield at AN/AC = 10. The enantiomeric excesses (ees) obtained were 27-47% for the homo-dimers and 21-24% for the cross-dimer. The absolute configuration of the cross-dimer was determined by comparing the experimental and theoretical circular dichroism spectra and further correlated with the re/si enantiotopic-face selectivity upon AC-TKS complexation in the ground state. Detailed analyses of the complexation behavior and the fluorescence lifetime and cyclodimerization rate of excited re/si complexes revealed that the products ee is critically controlled not only by the relative abundance of the re/si complexes in the ground and excited states but also by their relative photocyclodimerization rate. Crucially, the ground-state thermodynamics and the excited-state kinetics are not synergistic but offsetting in enantiotopic-face selectivity, and the latter overwhelms the former to give the homo- and cross-dimers in modest ees. Finally, some practical strategies for enhancing the enantioselectivity in chiral template-mediated photochirogenesis have been proposed.

Absolute configuration determination of the anti-head-to-head photocyclodimer of anthracene-2-carboxylic acid through cocrystallization with L-prolinol.

The absolute configuration has been established of the enantiopure anti-head-to-head cyclodimer of anthracene-2-carboxylic acid (AC) cocrystallized with L-propinol and dichloromethane [systematic name: (S)-2-(hydroxymethyl)pyrrolidin-1-ium (5R,6S,11R,12S)-8-carboxy-5,6,11,12-tetrahydro-5,12:6,11-bis([1,2]benzeno)dibenzo[a,e][8]annulene-2-carboxylate dichloromethane monosolvate], C5H12NO(+)·C30H19O4(-)·CH2Cl2. In the crystal structure, the AC dimer interacts with L-prolinol through a nine-membered hydrogen-bonded ring [R2(2)(9)], while the dichloromethane molecule is incorporated to fill the void space. The absolute configuration determined in this study verifies a recent assignment made by comparing theoretical versus experimental circular dichroism spectra.

Pharmacological activity and structural analysis of a benzamide (TKS159) and its optical isomers in an in vitro study and in an in vivo study in mice.

We previously conducted an in vitro study of 4-amino-5-chloro-2-methoxy-N-(1-ethyl-2-hydroxymethyl-4-pyrrolidinyl)benzamide (2S,4S)-(1, TKS159) and its three optical isomers (2S,4R)-(2), (2R,4S)-(3) and (2R,4R)-(4) with respect to their binding ability to the 5-HT(4) receptors, as well as an in vivo study on their gastric emptying-accelerating ability in rats. Consequently, we reported that steric configuration at positions 2 and 4 of the pyrrolidine ring is important in determining their pharmacological activity. The optical isomer (2R,4S)-(3) exhibited the most potent binding ability. However, the compound (2S,4S)-(1, TKS159) exhibited the most potent gastric emptying-accelerating ability in rats. A difference was thus found between binding ability and gastric emptying-accelerating ability in rats. Therefore, we conducted an in vitro study of TKS159 (1) and its three optical isomers to examine their agonistic activity on the 5-HT(4) receptors, as well as an in vivo study in mice to examine their gastric emptying-accelerating ability. Consequently, a tendency for correlation was found between the activity and the ability. TKS159 (1) exhibited the most potent pharmacological activity, well reflecting the results from the previous in vivo study in rats. Furthermore, the present in vitro and in vivo studies reverified the importance of steric configuration at positions 2 and 4 of the pyrrolidine ring. In addition, we also made an X-ray crystallographic analysis of the optical isomer (2R,4S)-(3), which has the S-configuration at position 4 similar to TKS159 (1), and discussed molecular structures in conjunction with the previously reported results from the X-ray crystallographic analysis of TKS159 (1).

New Gastroprokinetic Agent TKS159: 4‐Amino‐5‐chloro‐N‐[(2S,4S)‐1‐ethyl‐2‐hydroxymethyl‐4‐pyrrolidinyl]‐2‐methoxybenzamide

The absolute configuration of the title compound (TKS159, C 15 H 22 C1N 3 O 3 ) has been determined. The bent conformation of the molecule, in which the aromatic and pyrrolidine rings are at nearly 60° to each other, is maintained by intra- and intermolecular hydrogen bonds. A three-dimensional network of hydrogen bonds is formed among the amino, hydroxy and carbonyl groups of neighbouring molecules.