L-alanine Benzyl Ester Research Articles

Enantioselective Total Synthesis and Structural Revision of (－)-Isochaetominine

In this paper, the enantioselective total synthesis and structure revision of the proposed structure of isochaetom- inine 8 are described. On the basis of the stereodivergent strategy, a highly efficient five-step synthesis of the proposed struc- ture of isochaetominine 8 and its diastereomer (+)-2,3,14-tri-epi-chaetominine (12) was achieved. The method features the use of L-tryptophan and L-alanine benzyl ester as the starting materials, and a dimethyldioxirane (DMDO)-triggered tandem reac- tion as a key step. A comparison of the physical and spectral data of the natural isochaetominine with those of the diastere- omers obtained during our previous stereodivergent synthesis of chaetominine (1), allowed revising the structure of isochae- tominine as (-)-11-epi-chaetominine (18). The first enantioselective total synthesis of this natural product has been accom- plished previously in our laboratories in five steps, 31.6% overall yield from L-tryptophan. Besides, an investigation on the L-tryptophan and L-valine tert-butyl ester-based synthesis of isochaetominine C resulted in a stereodivergent synthesis of three diastereomers of isochaetominine C. Finally, it was revealed that attempted site selective epimerization at C(14) of 13B led to a bis-epimerization at both C(14) and C(11). Keywords alkaloids; isochaetominine; total synthesis; structural revision; stereodivergent synthesis; epimerization

Solvent Effects on the Protonation Constants of Some α-Amino Acid Esters in 1,4-Dioxane–Water Mixtures

The stoichiometric protonation constants of some α-amino acid esters (glycine methyl ester, glycine t-butyl ester, l-valine methyl ester, l-valine ethyl ester, l-valine t-butyl ester, l-serine methyl ester, l-serine ethyl ester, l-leucine methyl ester, l-leucine ethyl ester, l-leucine t-butyl ester, l-alanine methyl ester, l-alanine benzyl ester, l-phenylalanine methyl ester, l-phenylalanine ethyl ester, and l-phenylalanine t-butyl ester) in water and 20%, 40%, and 60% (v/v) 1,4-dioxane–water mixtures have been determined at an ionic strength of 0.10 mol⋅L−1 NaCl and at 25.0±0.1 °C under a nitrogen atmosphere. A potentiometric method was used and the calculation of the protonation constants has been carried out using the BEST computer program. The results were discussed in terms of macroscopic properties of the mixed solvent. The stoichiometric protonation constants were influenced by changes in solvent composition and their variations were discussed in terms of preferential solvation. Also, knowledge the protonation constant of α-amino acid esters will be helpful when determining the microscopic equilibrium constants of their corresponding amino acids.

Formulation studies of microemulsions for topical applications of acyclovir

Microemulsions prepared using 1-decanol, oleic acid or oleyl alcohol as oils, Transcutol and 1, 2- hexanediol as surfactant mixture and phosphate buffer pH 6.0 as aqueous phase were studied to verify the effect of the oils on pig-skin permeation and accumulation of acyclovir (ACV). Pseudoternary phase diagrams were constructed in the absence and in the presence of ACV. ACV-containing microemulsions had a restricted area of existence compared to those without the drug. A cationic charge-inducing agent, L-alanine benzyl ester, was added to the formulations to prepare positively-charged microemulsions. Full-thickness pig ear skin was used for ACV permeation experiments using positively- and negatively- charged microemulsions and a control suspension. The presence of oleyl alcohol or oleic acid increased the flux but not the drug skin accumulation compared to a control suspension, while the use of the cationic charge-inducing agent had no influence on the formulation performance. A two-fold increase in ACV accumulation was found using the microemulsions containing 1-decanol, maintaining intact the structure of the stratum corneum, as demonstrated by the DSC analysis. Microemulsions containing 1-decanol could significantly optimize drug targeting, maintaining the structure of the stratum corneum intact.

Positively charged microemulsions for topical application

The study reports pig-skin permeation and skin accumulation of miconazole nitrate (MCZ) from positively charged microemulsions containing water, 1-decanol/1-dodecanol (2:1, w/w), lecithin and/or decyl polyglucoside at different weight ratios, propylene glycol, 1,2 hexanediol and a cationic charge-inducing agent (stearylamine (ST), l-alanine benzyl ester (ALAB) or cetyltrimethylammonium bromide (CTAB)). Zeta-potential values of the positively charged microemulsions ranged from 14.2 to 37.5 mV and mean droplet size from 6.0 to 16.8 nm. In vitro pig-skin permeation of MCZ after a single 24 h application was negligible for all microemulsions; accumulation from positively charged microemulsions was nearly twice that from their negatively charged counterparts. The increased accumulation might be ascribed to the interaction between positive microemulsive systems and negatively charged skin sites; no significant difference was observed among the various cationic charge-inducing agents. Skin accumulation from the microemulsion containing most lecithin was lower than those of other microemulsions; this was ascribed to the phase transformation from microemulsion to a liquid crystal system after skin contact. These results suggest that positively charged microemulsions could be used to optimize drug targeting without a concomitant increase in systemic absorption; ALAB, an ester of a natural aminoacid, is an appropriate cationic charge-inducing agent.

A one-step synthesis of enantiopure 2-substituted 4,5-dihydro-1,4-benzodiazepine-3-ones via intramolecular azide cycloaddition

Starting from the appropriate azides bearing the ( S)-1-phenylethylamine and the l-alanine benzylester as chiral pendants, a facile and effective synthetic route to the title compounds in their enantiopure form was developed with excellent product yields obtained. Basic hydrolysis of the ester group of title compounds 3a– c gave the corresponding, readily functionalisable carboxylic acids. Catalytic reduction of 2-benzyl derivatives 3c and 3f gave 4-functionalised 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones in enantiopure forms.

Elastic positively-charged liposomes for topical administration of acyclovir

Elastic positively-charged liposomes of soya lecithin were prepared using sucrose monopalmitate as deforming agent, and l-alanine benzyl ester or stearylamine as cationic charge-inducing agent. The positive charge of the liposomes was confirmed by zeta potential measurements and their elasticity by filtration through microporous filter. Positively-charged liposomes had a higher acyclovir entrapment efficiency than negatively-charged liposomes. Elastic positively-charged liposomes containing acyclovir, applied non-occlusively to pig-ear skin, determined a skin flux similar to that of non-elastic positively-charged liposomes, prepared using soya lecithin, cholesterol and stearylamine, but higher than that of non-elastic negatively-charged liposomes or control suspension. Skin deposition of acyclovir from elastic positively-charged liposomes was higher (up to 600 nmol/cm2) than that from non-elastic positively- or negatively-charged liposomes (respectively 344 nmol/cm2, 237 nmol/cm2) and than that from elastic negatively-charged liposomes (435 nmol/cm2). The enhanced ACV accumulation within the skin obtained with elastic positively-charged liposomes might help to optimize drug targeting, creating new opportunities for well-controlled, modern, topical application of ACV in the treatment of Herpes simplex.

Analgesic doses of the enkephalin degrading enzyme inhibitor RB 120 do not have discriminative stimulus properties

The systemically active mixed inhibitor of enkephalin metabolism, N-(( S)-2-benzyl-3[( S) 2-amino-4-methylthio)butyldithio-]-1-oxopropyl)- l-alanine benzylester (RB 120), alone or in combination with 4-{[2-[[3-(1 H-indol-3-yl))-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.]dec-2-yloxy) carbonyl]amino}propyl]amino]-1-phenylethyl]amino}-4-oxo-[ R-( R*, R*)]-butanoate N-methyl- d-glucamine (CI 988; CCK 1 receptor antagonist) was investigated for discriminative and morphine generalisation effects using an operant drug discrimination paradigm in rats. Animals dosed with RB 120 (10 mg/kg) failed to develop a discriminative response. Combined CI 988 (0.3 mg/kg) and RB 120 (10 mg/kg) also failed to elicit a discriminative response. Morphine-trained animals (3.0 mg/kg) did not generalise to RB 120 (10 and 20 mg/kg). Similarly, subsequent retraining of the same animals with 1.5 mg/kg of morphine did not elicit generalisation to RB 120 (10 or 20 mg/kg). Combined RB 120 (10 or 20 mg/kg) and CI 988 (0.3 or 3.0 mg/kg) treatment produced no notable drug lever selection in rats able to discriminate morphine (1.5 mg/kg) from saline. These results suggest that RB 120 may have low abuse potential at analgesic doses.

Potentiation of opioid-induced conditioned place preference by the selective serotonin reuptake inhibitor fluoxetine

The ability of the selective serotonin reuptake inhibitor, fluoxetine, to modify the effects of morphine, N-(( S)-2-benzyl-3[( S) 2-amino-4-methylthio)butyldithio-]-1-oxopropyl)- l-alanine benzylester (RB 120; mixed inhibitor of enkephalin metabolism), and 4-{[2-[[3-(1 H-indol-3-yl))-2-methyl-1-oxo-2-[[(tricyclo[3,3,1,1] dec-2-yloxy) carbonyl] amino} propyl] amino]-1-phenylethyl] amino}-4-oxo-[ R-( R*, R*)]-butanoate N-methyl- d-glucamine (CI 988; cholecystokinin receptor subtype [CCK 2] antagonist), was assessed using conditioned place preference. RB 120 and morphine both induced significant, dose-dependent conditioned place preference, whilst CI 988 failed to elicit conditioned place preference. A subthreshold dose of fluoxetine (2.5 mg/kg) potentiated the morphine submaximal response. Notably, the combination of a subthreshold dose of fluoxetine (2.5 mg/kg) with RB 120 (5 mg/kg) or CI 988 (3 mg/kg) was devoid of any significant conditioned place preference properties. Fluoxetine may act via enhanced serotonergic activity to modulate enkephalinergic tone. Agents that increase enkephalinergic tone more directly such as RB 120 and CI 988, at submaximal doses, did not induce conditioned place preference when co-administered with fluoxetine. These data suggest that fluoxetine, in combination with CI 988 or RB 120, might prove to be a beneficial treatment strategy for opioid drug addiction, though further studies are necessary.

Pain-suppressive effects on various nociceptive stimuli (thermal, chemical, electrical and inflammatory) of the first orally active enkephalin-metabolizing enzyme inhibitor RB 120

RB 101 ( N-(( R, S)-2-benzyl-3[( S)(2-amino-4-methylthio)butyldithio]-1-oxopropyl)- l-phenylalanine benzyl ester) is a full inhibitor of the enkephalin-catabolizing enzymes, which induces strong naloxone-reversible antinociceptive responses after i.v. or i.p. administration, but is only slightly active after oral administration. Chemical modifications were introduced on this compound, resulting in molecules such as RB 120 ( N-(( S)-2-benzyl-3[( S)(2-amino-4-methylthio)butyldithio]-1-oxopropyl)- l-alanine benzyl ester), which was selected for a complete study, after oral administration, in various assays commonly used to select analgesics: mouse hot plate test, rat tail-flick test, electrical stimulation of the tail in rats, paw pressure test on inflamed paws in rats, acetic acid-induced writhing test and the formalin test in mice. RB 120 induced potent dose-dependent antinociceptive responses in all these tests after oral administration. The differences in antinociceptive effects induced by RB 120 in the various assays is probably related to the amount of enkephalins released and to the efficiency of peptidase inactivation in particular brain regions implicated in the control of a given nociceptive input. The goal of discovering orally active analgesics endowed with a potency similar to that of morphine but devoid of its major side-effects, seems now to have been reached with mixed neutral endopeptidase/aminopeptidase N (NEP/APN) inhibitors, although these compounds have yet to be evaluated in clinical trials.

Synthesis of Poly=1={3-O-(1=(benzyl-L=alanyl Carboxylate)ethyl]-D-glucos=6-O-carbonyl}-1=methylethylene

Abstract Poly-1- {3-O-[1-(benzyl-L-alanyl carboxylate)ethyl]-D-glucos-6-O-carbonyl} -1-methylethylene was synthesized as the lipophilic and polymeric models of N-acetylmuramyl-L-alanyl-D-isoglutamine corresponding to the minimal structure required for the immunoadjuvant activity of bacterial cell wall. N-[2-(1,2-O-isoproplidene-6-O-methacryloyl-α-D-glucofuranos-3-O-yl)propionyl]-L-alanine benzyl ester was prepared from D-glucose through eight steps as a key monomer in the synthesis. The polymerization of that monomer was carried out in benzene at 50° C by using 2,2′-azobisisobutyronitrile as a radical initiator to give poly-1-{12-O-isopropylidene-3-O-[1-(benzyl-L-alanyl carboxylate)ethyl] -α-D-glucofuranos-6-O-carbonyl} -1-methylethylene. The removal of isopropylidene groups in this polymer was carried out by treatment with trifluoroacetic acid-water (6:l v/v) to give the intended polymer. Characterizations of the polymers obtained were carried out.

Preparation of perbenzylated 2-azido-2-deoxy- d-allono-1,5-lactone and its condensation with an amino acid ester

Oxidation of 2-azido-3,4,6-tri- O-benzyl-2-deoxy- d-altropyranose ( 4) with a mixture of methyl sulfoxide and acetic anhydride gave 2-azido-3,4,6-tri- O-benzyl-2-deoxy- d-allono-1,5-lactone ( 5) with concomitant inversion of the azido group. Compound 5 was readily condensed with l-alanine benzyl ester to afford N-(2-azido-3,4,6-tri- O-benzyl-2-deoxy- d-allonoyl)- l-alanine benzyl ester ( 12) without any racemization of the l-alanine moiety.

Isolation and identification of pharmacologically active amino acids in skin and their structure‐activity relationship on the guinea‐pig ileum

1. Aqueous extracts of stratum corneum were found to cause histamine-like contractions of the guinea-pig ileum which were not antagonized by mepyramine, atropine or bromolysergic acid diethylamide.2. The compounds responsible for this contraction were isolated by chromatography and shown to be common amino acids, particularly L-serine and L-alanine which occur in abundance in the stratum corneum.3. Amino acid analogues were assayed on the guinea-pig ileum against alanine as standard. With the exception of gamma-amino butyric acid and L-alanine benzyl ester all analogues which had appreciable activity gave dose-response curves parallel to L-alanine.4. The response to L-alanine benzyl ester was abolished by mepyramine and this analogue appears to be a partial agonist on the histamine receptor.5. The effects of substitution on the equipotent molar ratios of amino acid analogues indicate that all four chemical groups attached to the alpha-carbon of L-alanine interact with the receptor.6. Our results suggest that the guinea-pig ileum contains an L-alpha-amino acid receptor.