Amino Acid Esters Research Articles

Synthesis, biological evaluation and molecular docking studies of Combretastatin A-4 phosphoramidates as novel anticancer prodrugs

A new series of CA4P analogs (5a-g, 6a-g) has been designed and effectively synthesized via a one-pot reaction from Combretastatin A-4/Erianin, commercially available amino acid esters and phenyl dichlorophosphate. To establish new candidates with anticancer activity, the in vitro antiproliferative effect of these compounds was measured by the CCK8 method on different cancer cell lines such as human liver caricinoma (HepG2), cervical cancer (HeLa) and colorectal carcinoma (HCT-116). The structure-activity relationships between CA4P outgrowth-promoting activity and its analogs suggested that the biaryl structure linked with double bond in Part A and the steric effect at the position α-carbon atom in the amino acid ester moiety (Part B) are essential for affecting the in vitro proliferation inhibitory activity of CA4P analogs. Additionally, the results of biological activity and molecular docking simulation showed that the vast majority of these novel Phosphoramidate derivatives exhibited potent anti-cancer activities.

Synthesis of Fluorinated Quaternary α-Amino Acid Esters

Key words amino acid esters - fluorinated amino acids - aza-Friedel–Crafts alkylation - silver catalysis

Modulation of the binding affinity of naproxen to bovine serum albumin by conversion of the drug into amino acid ester salts

Naproxen (NAP) is one of the most widely prescribed non-steroidal anti-inflammatory drugs. Novel formulations of NAP aiming at better water-solubility, dosage, and the onset of action or new routes of application in order to minimize or prevent side effects of NAP are in the current interest of the pharmaceutical industry. Here, we report the synthesis, chemical, spectral and physicochemical characterization of a series of salts containing cations amino acid alkyl esters (AAE) and NAP anion, which potentially can be used as novel drug formulation. The [l-AAE][NAP] were obtained in three steps: preparation of the AAE hydrochlorides, neutralization of the hydrochlorides to the corresponding AAE, and formation of the target organic salts. All NAP derivatives, tested at a concentration as high as 100 μM, exhibited no toxicity against murine macrophage cell line (RAW 264.7). The binding parameters and stoichiometry of [AAE][NAP]s to bovine serum albumin (BSA) are in the range of that estimated for the parent NAP. Only l-valine isopropyl ester naproxenate characterizes with about one order of magnitude lower binding affinity for BSA, which suggests a faster diffusion rate in the circulatory system than the parent NAP and other derivatives, and therefore faster reach to the target system. Using molecular modeling seven binding pockets of BSA were probed for their suitability to binds the cation and the anion and results are discussed in correlation with the obtained thermodynamic parameters for the binding of NAP derivatives to BSA.

Ionic liquids derived from α-amino acid ester salts as potent green corrosion inhibitors for mild steel in 1M HCl

In 1 M HCl solution, three selected amino acid ester salt based ionic liquids ([AAE][Sac] ILs), namely L-Phenyl Alanine methyl ester saccharinate ([PheME][Sac]), L-Leucine methyl ester saccharinate ([LeuME][Sac]), and L-Alanine methyl ester saccharinate ([AlaME][Sac]) under static conditions were examined as potent green corrosion inhibitors for mild steel by means of electrochemical measurements, weight loss, FT-IR spectroscopy, contact angle measurement, UV–vis spectroscopy, SEM/EDAX study, quantum chemical calculations and Monte Carlo (MC) simulation studies. 1H NMR, and FTIR spectroscopy has confirmed the structure of obtained ILs. The investigations were done in the temperature range of 303–353 K. [AAE][Sac] ILs are assessed as an efficient steel corrosion inhibitors in 1 M HCl up to 333 K but have less inhibiting properties above 333 K i.e., 343 and 353 K. Among the [AAE][Sac] ILs analysed, [PheME][Sac] showed the greatest inhibition efficiency and obey the order as: [PheME][Sac] > [LeuME][Sac] > [AlaME][Sac]. Polarization measurements showed all the [AAE][Sac] ILs tested to be mixed-type inhibitors. The adsorption of the examined [AAE][Sac] ILs obeyed the Langmuir adsorption isotherm perfectly. The theoretical descriptors provided by quantum chemical calculations and advanced MC simulation also reinforced the experimental conclusions adequately.

Reductive Alkylation of Amines with Carboxylic Ortho Esters

AbstractWe have demonstrated for the first time that carboxylic ortho esters could be used as an alkylating agent in the reductive alkylation of amines. A variety of amines, including amino acid esters, were alkylated affording mono‐alkylated products with high selectivity in practical to high yields using standard heterogeneous catalysts. By applying acyclic ortho esters alkylation was completed at room temperature.magnified image

Production of L-alanyl-L-glutamine by immobilized Escherichia coli expressing amino acid ester acyltransferase.

Production of Ala-Gln by the E. coli expressing α-amino acid ester acyltransferase was a promising technical route due to its high enzyme activity, but the continuous production ability still needs to improve. Therefore, the immobilized E. coli expressing α-amino acid ester acyltransferase was applied for the continuous production of Ala-Gln. Four materials were selected as embedding medium for the whole cell entrapment of recombinant bacteria. Calcium alginate beads were found to be the most proper entrapment carrier for production of Ala-Gln. The temperature, pH, and repeatability of the immobilized cell were compared with free cells. Results showed that immobilization cell could maintain a wider range of temperature/pH and better stability than free cell (20-35°C/pH8.0-9.0, and 25°C/pH8.5, respectively). On this basis, continuous production strategy was put forward by filling the immobilized cell in the tubular reactor with multiple control conditions. The Ala-Gln by immobilization cell achieved the productivity of 2.79mg/(min*mL-CV) without intermittent time. Consequently, these findings suggest that the immobilization technique has potential applications in the production of Ala-Gln by biotechnological method. KEY POINTS: • Immobilization helps to achieve high efficiency production of Ala-Gln. • Immobilized cells have better stability than free cells. • Sodium alginate is the most suitable immobilized material.

Pharmacokinetics of gemcitabine and its amino acid ester prodrug following intravenous and oral administrations in mice

Gemcitabine is an intravenously administered anti-cancer nucleoside analogue. Systemic exposure following oral administration of gemcitabine is limited by extensive first-pass metabolism via cytidine deaminase (CDA) and potentially by saturation of nucleoside transporter-mediated intestinal uptake. An amino acid ester prodrug of gemcitabine, 5′-l-valyl-gemcitabine (V-Gem), was previously shown to be a substrate of the intestinally expressed peptide transporter 1 (PEPT1) and stable against CDA-mediated metabolism. However, preliminary studies did not evaluate the in vivo oral performance of V-Gem as compared to parent drug. In the present study, we evaluated the pharmacokinetics and in vivo oral absorption of gemcitabine and V-Gem following intravenous and oral administrations in mice. These studies revealed that V-Gem undergoes rapid systemic elimination (half-life < 1 min) and has a low oral bioavailability (<1%). Most importantly, the systemic exposure of gemcitabine was not different following oral administration of equimolar doses of gemcitabine (gemcitabine bioavailability of 18.3%) and V-Gem (gemcitabine bioavailability of 16.7%). Single-pass intestinal perfusions with portal blood sampling in mice revealed that V-Gem undergoes extensive activation in intestinal epithelial cells and that gemcitabine undergoes first-pass metabolism in intestinal epithelial cells. Thus, formulation of gemcitabine as the prodrug V-Gem does not increase systemic gemcitabine exposure following oral dosing, due, in part, to the instability of V-Gem in intestinal epithelial cells.

High-throughput assay for determining enantiomeric excess of chiral diols, amino alcohols, and amines and for direct asymmetric reaction screening.

Determining enantiomeric excess (e.e.) in chiral compounds is key to development of chiral catalyst auxiliaries and chiral drugs. Here we describe a sensitive and robust fluorescence-based assay for determining e.e. in mixtures of enantiomers of 1,2- and 1,3-diols, chiral amines, amino alcohols, and amino-acid esters. The method is based on dynamic self-assembly of commercially available chiral amines, 2-formylphenylboronic acid, and chiral diols in acetonitrile to form fluorescent diastereomeric complexes. Each analyte enantiomer engenders a diastereomer with distinct fluorescence wavelength/intensity originating from enantiopure fluorescent ligands. In this assay, enantiomers of amines and amine derivatives assemble with diol-type ligands containing a binaphthol moiety (BINOL and VANOL), whereas diol enantiomers form complexes with the enantiopure amine-type fluorescent ligand tryptophanol. The differential fluorescence is utilized to determine the amount of each enantiomer in the mixture with an error of <1% e.e. This method enables high-throughput real-time evaluation of enantiomeric/diastereomeric excess (e.e./d.e.) and product yield of crude asymmetric reaction products. The procedure comprises high-throughput liquid dispensing of three components into 384-well plates and recording of fluorescence using an automated plate reader. The approach enables scaling up the screening of combinatorial libraries and, together with parallel synthesis, creates a robust platform for discovering chiral catalysts or auxiliaries for asymmetric transformations and chiral drug development. The procedure takes ~4-6 h and requires 10-20 ng of substrate per well. Our fluorescence-based assay offers distinct advantages over existing methods because it is not sensitive to the presence of common additives/impurities or unreacted/incompletely utilized reagents or catalysts.

EFFICIENT SYNTHESIS OF NOVEL TRICYCLIC BENZOXAZINE DERIVATIVE VIA RING OPENING OF EPOXIDE ALONG THE MP AND DFT STUDIES OF STRUCTURAL, SPECTROSCOPIC (IR, RAMAN, UV-VIS), THERMODYNAMIC, ORBITALS AND NLO PROPERTIES OF DESIRED TRICYCLIC BENZOXAZINE DERIVATIVE

Ring opening of 2-nitro phenyl glycidyl ether by chelated amino acid ester enolate provides access to desired novel benzoxazine derivative just over a few steps. Theoretical study on the molecular structure of 2,2,2-trifluoro-N-(1-oxo-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]ox-azin-2-yl) acetamide (S11) is presented by using second order Moller Plesset (MP2) as well as density functional theory (DFT) level calculations. The calculated vibrational frequencies were assigned into normal modes of vibration by the use of potential energy distribution (PED). The positive charge on all hydrogen atoms were obtained by charge distribution calculations using Mulliken, electrostatic and natural charge distributions. Similar electrophilic and nucleophilic regions were observed from the calculated electrostatic potential surface calculations. The time dependent density functional theory (TD-DFT) calculations were performed to obtain electronic transitions within the molecule. The frontier molecular orbital (FMO) analysis was leading to the possible charge transfer within the molecule. The natural bond orbital (NBO) analysis provided information regarding the interaction between the donor and acceptor in bond. The statistical thermodynamic functions (dipole moment, internal energy, enthalpy, Gibbs free energy, entropy, heat capacities and partition functions) were calculated at the range of temperature from 10-500 K

Design, synthesis and antiproliferative activity of new amine, amino acid and dipeptide-coupled benzamides as potential sigma-1 receptor

N-Alkyl-2-(substitutedbenzamido) benzamides and methyl 2-(2-(substitutedbenzamido) benzamido) alkanoates were prepared by either the reaction of amines or amino acid esters with benzoxazine derivatives or the DCC coupling of 2-substitutedbenzamido benzoic acid with amines or amino acid esters. Methyl 2-(2-(4-chlorobenzamido)benzamido alkanoates were used as the key intermediate for the preparation of dipeptide-coupled benzamides via azide and DCC coupling methods. The investigated compounds were subjected to in silico molecular docking as agonist for human σ1 receptor through their binding energies and analysis of ligand–receptor interactions and prediction study to their physicochemical properties and drug-likeness scores. Moreover, compounds with the highest binding affinity toward the target were screened against breast MCF-7 and liver A549 cancer cell lines to test their cytotoxic activities. Compounds 11a, 3a, 8c, 12a and 13b showed potent cytotoxic activity for the tested compounds against MCF-7 cell line with low IC50 values, especially for 11a (5.3 µM compared to the standard drug 5-FU 5.8 µM). Based on the identification of this hit candidate, new potent σ1 receptor with anti-cancer activity could be designed.

Cooperative Catalysis in Amination of β-Hydroxy Carboxylic Acid Esters

Key words cooperative catalysis - ruthenium catalysis - Brønsted acid catalysis - hydroxy esters - benzylamines - amino acid esters

Modifications on the heterocyclic base of ganciclovir, penciclovir, acyclovir - syntheses and antiviral properties

АBSTRACTEsters of the antiherpetic drugs ganciclovir, penciclovir with the bile acids (cholic, chenodeoxycholic and deoxycholic) and amino acid esters of acyclovir were generated and evaluated for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The antiviral assays demonstrated that modified analogs of ACV and PCV are less active compared to the initial substances against HSV-1and HSV-2. CC50 for ganciclovir-deoxycholate corresponded to the CC50 of the other analogs and its activity is lower than ganciclovir. Obtained results show that tested modification do not improve bioavailability of nucleoside analogs in cells.

Synthesis and Biological Activities of Some New Benzotriazinone Derivatives Based on Molecular Docking; Promising HepG2 Liver Carcinoma Inhibitors.

In one-pot strategy, diazotization of methyl anthranilate 5 followed by addition of amino acid ester hydrochloride, we have prepared methyl-2-(4-oxobenzotriazin-3(4H)-yl)alkanoates 6a–c. Starting with hydrazides 7a,b, N-alkyl-2-(4-oxobenzotriazin-3(4H)-yl)alkanamides 9–10(a–h) and methyl-2-(2-(4-oxobenzotriazin-3(4H)-yl)alkanamido)alkanoates 11–12(a–e) were prepared via azide coupling. Hydrazones 13–15 were prepared via condensation of hydrazides 7a,b with 4-methoxybenzaldehyde, 4-dimethylaminobenzaldehyde, and/or arabinose. Molecular docking was done for synthesized compounds using MOE 2008-10 software. The compounds 9a, 12a, 12c, 13a, 13b, and 14b have the most pronounced strong binding affinities toward the target E. coli Fab-H receptor, whereas compounds 3, 11e, 12e, and 13a have the most pronounced strong binding affinities toward the target vitamin D receptor. The in vitro antibacterial activities of the highest binding affinity docked compounds were tested against E. coli, Staphylococcus aureus, and Salmonella spp. Majority of the tested compounds showed effective positive results against E. coli, while they were almost inactive against Staphylococcus aureus and Salmonella spp. The in vitro cytotoxic activities of the highest binding affinity-docked compounds were tested against the human liver carcinoma cell line (HepG2). Some compounds showed potent cytotoxic activity with low IC50 values, especially for 3 (6.525 μM) and 13a (10.97 μM) than that for standard drug doxorubicin (2.06 μM).

Pd-Catalyzed Asymmetric N-Allylation of Amino Acid Esters with Exceptional Levels of Catalyst Control: Stereo-Divergent Synthesis of ProM-15 and Related Bicyclic Dipeptide Mimetics.

A general and powerful method for the stereo‐controlled Pd‐catalyzed N‐allylation of amino acid esters is reported, as a previously largely unsolved synthetic challenge. Employing a new class of tartaric acid‐derived C 2‐symmetric chiral diphosphane ligands the developed asymmetric amination protocol allows the conversion of various amino acid esters to the N‐allylated products with highest levels of enantio‐ or diastereoselectivity in a fully catalyst‐controlled fashion and predictable configuration. Remarkably, the in situ generated catalysts also exhibit outstanding levels of activity (ligand acceleration). The usefulness of the method was demonstrated in the stereo‐divergent synthesis of a set of new conformationally defined dipeptide mimetics, which represent new modular building blocks for the development of peptide‐inspired bioactive compounds.

Kinetics, mechanism and density functional theory calculations on base hydrolysis of α-amino acid esters catalyzed by [Pd(AEMP)(H2O)2]2+ (AEMP = 2-(2-aminoethyl)-1-methylpyrrolidine)

Pd(AEMP)Cl2 (AEMP = 2-(2-aminoethyl)-1-methylpyrrolidine) was synthesized and characterized by spectral and thermal measurements.[Pd(AEMP)(H2O)2]2+ reacts with amino acid esters (L) to form mixed ligand [Pd(AEMP)L]2+ complexes. The kinetics of the base hydrolysis of [Pd(AEMP)L]2+ was studied by a pH-stat technique and the corresponding rate constants are reported. The coordinated glycine methyl ester is hydrolyzed efficiently, whereas the coordinated methionine- and histidine- methyl esters undergo hydrolysis with a much lower catalytic activity. The catalytic effect is controlled by the mode of coordination of the ester to the Pd(II) complex. Possible mechanisms for these reactions are considered. Activation parameters were determined experimentally for the hydrolysis of the coordinated glycine methyl ester. DFT calculations (B3LYP/def2svp) were applied to gain further insight into the possible mechanism of the base hydrolysis of the amino acid esters. The calculations are discussed in reference to the reported experimental data.

Enantioselectivity of a tartaric acid amide linked zinc bisporphyrinate towards amino acid esters

We have designed and synthesized a new chiral zinc bisporphyrinate ([Zn2(D-BTABis)]) and investigated its enantioselectivity towards amino acid esters. Our studies reveal the binding of D-type of amino acid esters to this chiral zinc bisporphyrinate is more favorable than L-type of amino acid esters, the corresponding enantioselectivity (α) is 8.4 for the phenylalanine ethyl esters. NMR studies suggest these guests are monodentate ligands in the host-guest complexes. Further DFT calculations rationalize the CD results and enantioselectivity. When the chiral host interacts with the D-enantiomers of these guests, the steric repulsion interactions between the linker and the guest are weaker, and the tartaryl group adopts the conformation A with a larger positive torsion angle. These cause the complexes with D-type of amino acid esters are more energetically favorable than those with L-type of amino acid esters. Our studies provide one good bisporphyrin system for enantiodiscrimination of monodentate guests.

Novel skin permeation enhancers based on amino acid ester ionic liquid: Design and permeation mechanism

This study developed novel ionic liquids (ILs) based on amino acids. We first screened 15 methyl amino acid ester hydrochlorides ([AAC1]Cl) for their skin permeation enhancements using 5-Fluorouracil (5-Fu) and Hydrocortisone (HC) as model drugs. Glycine methyl ester hydrochloride ([GlyC1]Cl), L-proline methyl ester hydrochloride ([L-ProC1]Cl), and L-leucine methyl ester hydrochloride ([L-LeuC1]Cl) were selected, and their ester sites were modified with different carbon chains (C8 and C12). The resulting ILs showed improved permeation to the two drugs. TEWL and CLSM assays revealed the moderation effects of the modified ILs on skin barrier function, whereas L-proline dodecyl ester hydrochloride ([ProC12]Cl) and L-leucine dodecyl ester hydrochloride ([L-LeuC12]Cl) exhibited the strongest activities. Permeation mechanisms were further investigated by ATR-FTIR, solid-NMR, SEM, and TEM analyses. The results suggested that [L-ProC12]Cl and [L-LeuC12]Cl combined the advantages of amino acid esters and IL solvent and could interact with the intercellular lipid domain by the multi-functions of lipid fluidization and lipid extraction, which were observed in a dosage- and time-dependent manner. Additionally, pathological examination suggested that the amino acid ester-based ILs (AAE-ILs) had good biocompatibility. In conclusion, this study has generated novel chemical penetration enhancers (CPEs) based on AAE-ILs and may be potentially utilized in drug transdermal delivery systems (TDDSs).

Metal free highly efficient C–N bond formation through 1,6-addition: synthesis and photophysical studies of diaryl methyl amino acid esters (DMAAEs)

A transition-metal free, proficient strategy for the one-pot synthesis of diverse diaryl methyl amino acid esters (DMAAEs) has been established from the easily accessible chiral amino acid esters and para-quinone methides (QMs) in very good to excellent yields.

Newly synthesized 3-(4-chloro-phenyl)-3-hydroxy-2,2-dimethyl-propionic acid methyl ester derivatives selectively inhibit the proliferation of colon cancer cells.

A series of 24 compounds were synthesized based on structure modification of the model methyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate as potent HDACIs. Saponification and hydrazinolysis of the model ester afforded the corresponding acid and hydrazide, respectively. The model ester was transformed into the corresponding trichloroacetimidate or acetate by the reaction with trichloroacetonitrile and acetic anhydride, respectively. N-Alkyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropan-amides and methyl-2-[(3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoyl)amino] alkanoates were obtained by the reaction of corresponding acid or hydrazide with amines and amino acid esters via DCC and azide coupling methods. Methyl-3-aryl-3-(4-chlorophenyl)-2,2-dimethylpropanoates were obtained in good yields and short reaction time from the corresponding trichloroacetimidate or acetate by the reaction with C-active nucleophiles in the presence of TMSOTf (0.1 eq.%) via C–C bond formation. The antiproliferative and apoptotic activity were further studied with molecular docking. The 48 post-treatments showed that out of 24 compounds, 12 compounds showed inhibitory actions on HCT-116 cells, we have calculated the inhibitory action (IC50) of these compounds on HCT-116 and we have found that the IC50 values were in between 0.12 mg mL−1 to 0.81 mg mL−1. The compounds (7a & 7g) showed highest inhibitory activity (0.12 mg mL−1), whereas compound 7d showed the lowest inhibitory activity (0.81 mg mL−1). We have also examined inhibitory action on normal and non-cancerous cells (HEK-293 cells) and confirmed that action of these compounds was specific to cancerous cells. The cancerous cells were also examined for nuclear disintegration through staining with DAPI, (4′,6-diamidino-2-phenylindole) is a blue-fluorescent DNA stain, and we have found that there was loss of DAPI staining in the compound treated cancerous cells. The compounds were found to potentially act through the HSP90 and TRAP1 mediated signaling pathway. Compounds 7a and 7g showed the highest selectivity to TRAP1 which explained its superior activity.

Ketoprofen-Based Ionic Liquids: Synthesis and Interactions with Bovine Serum Albumin.

The development of ionic liquids based on active pharmaceutical ingredients (API-ILs) is a possible solution to some of the problems of solid and/or hydrophobic drugs such as low solubility and bioavailability, polymorphism and an alternative route of administration could be suggested as compared to the classical drug. Here, we report for the first time the synthesis and detailed characterization of a series of ILs containing a cation amino acid esters and anion ketoprofen (KETO-ILs). The affinity and the binding mode of the KETO-ILs to bovine serum albumin (BSA) were assessed using fluorescence spectroscopy. All compounds bind in a distance not longer than 6.14 nm to the BSA fluorophores. The estimated binding constants (KA) are in order of 105 L mol−1, which is indicative of strong drug or IL-BSA interactions. With respect to the ketoprofen-BSA system, a stronger affinity of the ILs containing l-LeuOEt, l-ValOBu, and l-ValOEt cation towards BSA is clearly seen. Fourier transformed infrared spectroscopy experiments have shown that all studied compounds induced a rearrangement of the protein molecule upon binding, which is consistent with the suggested static mechanism of BSA fluorescence quenching and formation of complexes between BSA and the drugs. All tested compounds were safe for macrophages.