Catalytic Hydrolysis of Charged Carboxylic Acid Active Esters with Cyclic Dipeptides Carrying Hydrophobic and Nucleophilic Groups

Abstract

KEY WORDSCyclo(o-or L-Leu-L-His) I Charged Carboxylic Acid Ester I Hydrophobic Interaction I Hydrolytic Reaction IThe special arrangement of functional groups and their cooperative interactions constitute an essential part of the molecular mechanism of enzyme reactions. Cyclic peptides carrying functional groups fixed at specific positions along the molecular skeleton are suitable model compounds for enzymes in studying the structure-<:atalytic activity relationship. The specific arrangement of the functional groups in cyclic peptides can be determined by NMR and CD spectroscopy.In our previous studies, two cyclic dipeptides carrying nucleophilic groups, i.e., cyclo(o-Leu-LHis) and cyclo(o-Val-L-His), were found to show specific and effective catalyses for the hydrolyses of hydrophobic active esters, i.e., p-nitrophenyl esters of lauric acid [CH 3 (CH 2 ) 10 C00Ph(N0 2 )] and decanoic acid [CH 3 (CH2)8C00Ph(N02)]. 1 ' 2 Conformational analysis of the cyclic dipeptides mainly by NMR indicated the catalytic effectiveness to be controlled by the substrate binding due to hydrophobic interactions and the stereochemical fit of functional groups in the peptide-substrate complex to enhance the intramolecular nucleophilic attack. 2 · 3In order to design an effective catalyst on the basis of a hydrophobic interaction the hydrophobicities of the catalyst and the substrate should be maximized. However, an increase in the hydrophobicity of the substances simultaneously decreases their solubility in water, resulting in a complexity due to molecular associations. 2 In the present study, active esters with long hydrocarbon chains and positive or negative charges were prepared and subjected to catalytic hydrolysis using hydrophobic cyclic peptides. These substrates were expected to be hydrophobic but still have good solubility in water.

Highly Efficient and Enantiomer-Selective Hydrolysis of α-Amino Acid Active Ester Hydrochlorides by a Cyclic Hexapeptide Containing Histidines

“…A solution of III (7.07g, 14.5mmol) in 4.7mol dm -3 HCljdioxane (50 cm 3 ) was allowed to stand for 30 minutes at room temperature, and then the solvent was distilled off. Et 2 0 (100 cm 3 ) was added to the residue and the mixture was left overnight at -l5°C to solidify the product.…”

“…Et 2 0 (100 cm 3 ) was added to the residue and the mixture was left overnight at -l5°C to solidify the product. The solid obtained was very hygroscopic.…”

“…A solution of VIII (1.1 g, 2.15 mmol) in HCONMe 2 (8cm 3 ) was mixed with concentrated hydrochloric acid (1.92 cm 3 ) and 2 N NaN0 2 (1.1 cm 3 ) with stirring at -20°C. After 30 minutes, the solution was cooled to -30°C, and N-ethylpiperidine (5.0cm 3 , 36.4 mmol) and a solution of IX in HCONMe 2 were added.…”

“…Syntheses and purifications of these materials have been reported. 3 As p-nitrophenyl ester hydrochlorides of chiral o:-amino acid, o-and L-Val-0Ph(N0 2 )·HC1 and nand L-Leu-0Ph(N0 2 ) · HCl were used. Syntheses and purifications of these materials have been reported.…”

“…3 Cyclic dipeptides having the D-L configuration were more efficient as hydrolytic catalysts than imidazole and diastereomeric dipeptides having the L-L configuration. These findings have been discussed in terms of the effect of the spatial arrangement of functional groups on the hydrophobic binding of a substrate and intramolecular nucleophilic or general-base Cyclic dipeptides consisting of a-amino acid residues having anionic and nucleophilic side chains have been found efficient catalysts for the hydrolyses of positively charged carboxylic acid esters and p-nitrophenyl ester hydrochlorides of a-amino acids.…”