Glutamic Acid Analogues Research Articles

Synthesis of phosphonic analog of glutamic acid

A scheme for the synthesis of phosphonic analog of glutamic acid starting from tert-butyl N-tert-butoxycarbonylaspartate I was developed. The latter was obtained from aspartic acid by the previously described method [1, 2]. The carboxy group of compound I was acylated with ethyl chloroformate and reduced with sodium borohydride in methanol to give tertbutyl-(S)-N-(tert-butoxycarbonyl)homoserine (S)-II [2]. The latter was converted to the bromide (S)-III via the reaction with triphenylphosphine and bromotrichloromethane [3]. Bromide III was introduced into the Arbuzov reaction with trimethylsilyldiethylphosphite to yield phosphonate IV, deprotection of which with diluted hydrochloric acid resulted in the phosphorus analog of glutamic acid V.

Synthesis of amino acids of cyclopropylglycine series

The review covers methods of synthesis of amino acids of the cyclopropylglycine series published in the past decade. Main methods of synthesis of cyclopropylglycines are based on the carbene and ylide addition to alkenes, enzymatic reactions, the Kulinkovich cyclopropanation of esters and amides, MIRC reactions, the modification of cyclopropanecarbaldehydes by the Strecker reaction, and other transformations of functional groups of cyclopropanes. Particular attention is given to 2-carboxycyclopropylglycines and 3,4-methanoprolines. These compounds have attracted interest as conformationally rigid cyclopropane-containing analogs of glutamic acid and proline and also as components of physiologically active peptides. The physiological properties of cyclopropylglycines are briefly characterized.

Phosphonic analogues of glutamic acid as irreversible inhibitors of Staphylococcus aureus endoproteinase GluC: An efficient synthesis and inhibition of the human IgG degradation

Endoproteinase GluC (V8 protease) is one of many virulence factors released by the Staphylococcus aureus species in vivo. The V8 protease is able to hydrolyze some serpins and all classes of mammalian immunoglobulins. The application of specific and potent inhibitors of V8 protease may lead to the development of new antibacterial agents. Herein, we present the synthesis and the inhibitory properties of novel peptidyl derivatives of a phosphonic glutamic acid analogue. One of the compounds Boc-Phe-Leu-GluP(OC6H4)2 displayed an apparent second-order inhibition rate value of 8540M−1s−1. The Boc-Phe-Leu-GluP(OC6H4)2 compound with the highest inhibitory potency showed the ability to prevent V8-mediated human IgG proteolysis in vitro.

Synthesis of conformationally restricted glutamate and glutamine derivatives from carbonylation of orthopalladated phenylglycine derivatives.

A new method for the regioselective synthesis of 2-alkoxycarbonyl- and 2-(aminocarbonyl)phenylglycinate methyl esters has been developed. The reaction of the orthopalladated complex [Pd(μ-Cl)(C6H4(CH(CO2Me)NMe2)-2)]2 (1) with nucleophiles HNu under a CO atmosphere results in the selective incorporation of the C(O)Nu moiety to the phenyl ring and formation of the carbonyl species ortho-C6H4(C(O)Nu)(CH(CO2Me)NMe2) (2a–j) (Nu = OR, NHR, NR2). Compounds 2a–j are conformationally restricted analogues of glutamic acid and glutamine and are interesting due to their biological and pharmacological properties. The reaction of [Pd(μ-Cl)(C6H4(CH(CO2Me)NHTf)-2)]2 (3) with nucleophiles in a CO atmosphere results, however, in the formation of the cyclic isoindolinone or the open 2-carboxyphenylglycine methyl esters, with the reaction outcome being driven by the choice of the solvent.

α-Amino-β-fluorocyclopropanecarboxylic acids as a new tool for drug development: Synthesis of glutamic acid analogs and agonist activity towards metabotropic glutamate receptor 4

Herein we describe the diastereoselective synthesis of glutamic acid analogs and the evaluation of their agonist activity towards metabotropic glutamate receptor subtype 4 (mGluR4). These analogs are based on a monofluorinated cyclopropane core substituted with an α-aminoacid function. The potential of this new building block as a tool for the development of a novel class of drugs is demonstrated with racemic analog 11a that displayed the best agonist activity with an EC50 of 340nM.

Rac-3-exo-Ammonio-7-anti-carboxytricyclo[2.2.1.0.2,6]heptane-3-endo-carboxylate monohydrate

The racemic title compound, C9H11NO4·H2O, a tricyclic rearranged amino­norbornane dicarb­oxy­lic acid, is a conformationally rigid analogue of glutamic acid and exists as an ammonium-carboxyl­ate zwitterion, with the bridghead carb­oxy­lic acid group anti-related. In the crystal, N—H⋯O and O—H⋯O hydrogen bonds involving the ammonium, carb­oxy­lic acid and water donor groups with both water and carboxyl O-atom acceptors give a three-dimensional framework structure.

Process Development for a Key Synthetic Intermediate of LY2140023, a Clinical Candidate for the Treatment of Schizophrenia

To fuel clinical development of the experimental CNS medicine LY2140023, we developed a scalable route for the multistep synthesis of a pivotal synthetic intermediate. The core of the conformationally restricted glutamic acid-based amino acid analogue was built via a Rh-catalyzed cyclopropanation of thiophene. Regioselective functionalization of the remaining double bond was achieved by a hydroboration/oxidation sequence followed by a Bucherer–Bergs reaction to give a hydantoin with the targeted l-glutamic acid configuration. Subsequent resolution, oxidation state, and protecting group manipulations gave the key intermediate in an overall nine-step scalable streamlined route starting from thiophene.

Analysis of Electrical Brain Waves in Neurotoxicology: Gamma- Hydroxybutyrate

Advances in computer technology have allowed quantification of the electroencephalogram (EEG) and expansion of quantitative EEG (qEEG) analysis in neurophysiology, as well as clinical neurology, with great success. Among the variety of techniques in this field, frequency (spectral) analysis using Fast Fourier Transforms (FFT) provides a sensitive tool for time-course studies of different compounds acting on particular neurotransmitter systems. Studies presented here include Electrocorticogram (ECoG) analysis following exposure to a glutamic acid analogue - domoic acid (DOM), psychoactive indole alkaloid - ibogaine, as well as cocaine and gamma-hydroxybutyrate (GHB). The ECoG was recorded in conscious rats via a tether and swivel system. The EEG signal frequency analysis revealed an association between slow-wave EEG activity delta and theta and the type of behavioral seizures following DOM administration. Analyses of power spectra obtained in rats exposed to cocaine alone or after pretreatment with ibogaine indicated the contribution of the serotonergic system in ibogaine mediated response to cocaine (increased power in alpha1 band). Ibogaine also lowered the threshold for cocaine-induced electrographic seizures (increased power in the low-frequency bands, delta and theta). Daily intraperitoneal administration of cocaine for two weeks was associated with a reduction in slow-wave ECoG activity 24 hrs following the last injection when compared with controls. Similar decreased cortical activity in low-frequency bands observed in chronic cocaine users has been associated with reduced metabolic activity in the frontal cortex. The FFT analyses of power spectra relative to baseline indicated a significant energy increase over all except beta2 frequency bands following exposure to 400 and 800 mg/kg GHB. The EEG alterations detected in rats following exposure to GHB resemble absence seizures observed in human petit mal epilepsy. Spectral analysis of the EEG signals combined with behavioral observations may prove to be a useful approach in studying chronic exposure to drugs of abuse and treatment of drug dependence.

ChemInform Abstract: Michael Addition of 2,2-Difluoroketene Silyl Acetal. Preparation of 4, 4-Difluoroglutamic Acid and 5,5-Difluorolysine.

2,2-Difluoroketene silyl acetal, generated in situ by treating methyl difluoroiodoacetate with Zn followed by chlorosilane, readily reacted with α,β-unsaturated carbonyl compounds or acetals to give the 1,4-addition products, preferentially. The difluoro analogs of glutamic acid and lysine were prepared through the present reaction.

ChemInform Abstract: Heterocyclic Excitatory Amino Acids. Synthesis and Biological Activity of Novel Analogues of AMPA.

The novel acidic amino acids 6a-c, 7, and 8 have been synthesized via 1,3-dipolar cycloadditions, using nitrile oxides and alkynes. The prepared compounds are heterocyclic analogues of glutamic acid with differing chain lengths. One of these compounds, (RS)-2-amino-3-(3-carboxy-5-methyl-4- isoxazolyl)propionic acid (ACPA, 8), was shown in [3H]AMPA binding studies to be more active than AMPA itself (IC50 = 20 nM compared to IC50 = 79 nM for AMPA). No affinity for NMDA receptors (NMDA-sensitive [3H]glutamic acid binding) was found, and only weak affinity in [3H]kainic acid binding (IC50 = 6.3 microM) was detected. The excitatory activity in rat cortical wedge also showed that ACPA was more potent than AMPA (EC50 = 1.0 microM compared to EC50 = 3.5 microM for AMPA). The depolarizing effect of ACPA could be fully antagonized by the selective non-NMDA antagonist 6-cyano-7-nitro-quinoxazoline-2,3-dione (CNQX), but was unaffected by the selective NMDA antagonist D-2-amino-5-phosphonovaleric acid (AP5).

ChemInform Abstract: Synthesis of Two Cyclic Analogs of Glutamic Acid: cis- and trans- Pyrrolidine-2,4-dicarboxylic Acids.

Abstract The tosyl ester 2 of tetraethyl 1-acetamido-4-hydroxybutane- 1,1,3,3-tetracarboxylate gave 4-methylene glutammic acid in 90% yield by refluxing with concentrated HC1. Treatment of 2 with NaOEt, then with refluxing concentrated HC1 gave a 54% yield of cis and trans -pyrrolidine-2,4-dicarboxylic acids 4 and 5, separated by anion exchange chromatography An analytical resolution of 4 and 5 enantiomers by chiral derivatization and GPC is described.

ChemInform Abstract: Asymmetric Synthesis of Enantiomerically Pure Phosphonic Analogues of Glutamic Acid and Proline.

ChemInform Abstract: Asymmetric Synthesis of Enantiomerically Pure Phosphonic Analogues of Glutamic Acid and Proline.

ChemInform Abstract: A New Access to Alkyl-α-ketoglutaric Acids, Precursors of Glutamic Acid Analogues by Enzymatic Transamination. Application to the Synthesis of (2S,4R)-4-Propyl-glutamic Acid.

Abstract 4-Alkyl-2-alkylidene-glutaric acids are easily obtained by a Claisen-Johnson rearrangement, providing a short access to 4-alkyl-α-ketoglutaric acids. These compounds are substrates of the glutamic oxalacetic transaminase (GOT), allowing the enzymatic synthesis of biologically important analogues of l -glutamate. A new analogue, (2S,4R)-4-propyl-glutamic acid, is described.

Constrained cycloalkyl analogues of glutamic acid: stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and its 6-phosphonic acid analogue

A new stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2.6-dicarboxylic acid (LY354740) 1, a potent and selective 2mGluR agonist, has been accomplished in four steps with an overall yield of 27% starting from the enantiopure (+)-( R)-2-( p-tolylsulfinyl)cyclopent-2-enone 3. The key steps include asymmetric cyclopropanation of 3 with (dimethylsulfuranylidene)acetate (EDSA) and removal of the chiral p-tolylsulfinyl auxiliary from the cycloadduct ent- 4c upon treatment with iso-propylmagnesium chloride. The stereoselective hydantoin formation from the bicyclic ketone 6 formed (Bucherer–Bergs reaction) and subsequent hydrolysis completed the synthesis of 1. The same reaction sequence has been applied in the first synthesis of enantiopure (+)-2-amino-6-phosphonobicyclo[3.0.1]hexane-2-carboxylic acid 2, a structural 6-phosphono analogue of 1. The starting bicyclic ketophosphonates 9–11 have been obtained by asymmetric cyclopropanation of (−)-( S)- 3 with phosphoryl sulfonium ylides, producing only two endo-isomers. The major endo-isomer (+)- 11a containing the 6-diisopropoxyphosphoryl group has been converted in three steps into (+)- endo- 2 in 46% overall yield.

Rational design and synthesis of potent and long-lasting glutamic acid-based dipeptidyl peptidase IV inhibitors

A series of (2 S)-cyanopyrrolidines with glutamic acid derivatives at the P2 site have been prepared and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV). The structure–activity relationships (SAR) led to the discovery of potent 3-substituted glutamic acid analogues, providing enhanced chemical stability and excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. Compound 13f exhibited the ability to both significantly decrease the glucose excursion and inhibit plasma DPP-IV activity.

Synthesis of conformationally restricted glutamic acid analogs based on the spiro[3.3]heptane scaffold

A library of isomeric glutamic acid analogs based on the spiro[3.3]heptane skeleton is designed. Two members of the library, ( R)- and ( S)-2-amino-spiro[3.3]heptane-2,6-dicarboxylic acid hydrochlorides, were synthesized. The stereochemistry of the synthesized amino acids was determined using 1H– 1H-NOESY of their diastereomeric derivatives. The aminocarboxylate moiety and the carboxylic group in the synthesized glutamic acid analogs are ‘fixed’ in space relative to each other due to the rigid spirocyclic scaffold and therefore, they can be used to probe topologies of different glutamate receptors.

Inhibitors of Glutamine Synthetase and their Potential Application in Medicine

Glutamine synthetase (E.C. 6.3.1.2) - an enzyme catalyzing formation of glutamine from glutamate and ammonium ion, is one of the most important enzymes in nitrogen metabolism. Due to glutamine synthetase activity, inorganic nitrogen is incorporated in the cell metabolism and is further used in biosynthesis of several highly important metabolites. The first part of the review presents the long-dating research on inhibitors of glutamine synthetase which started with the discovery of methionine sulfoximine in 1949. Since that time several inhibitors of this enzyme, classified in the following groups: derivatives of methionine sulfoximine, phosphorus containing analogues of glutamic acid, bisphosphonates and miscellaneous inhibitors, have been developed and described. Analysis of their structure-activity relationships is presented in some detail. The second part of the paper is dedicated to potential medical application of glutamine synthetase inhibitors, which proved to act as effective anti-tuberculosis agents with high selectivity towards the pathogenic bacteria. Moreover, it was also shown that glutamine synthetase inhibitors could be successfully applied in cancer therapy.

Domoic Acid Impairment of Cardiac Energetics

Excitatory mediated neuronal injury has been shown to involve a complex cascade of events. However, the associated cardiac damage reported in humans and marine animals following exposure to excitotoxins has not been well characterized. We hypothesized that the excitotoxin domoic acid can traverse cardiac cell membranes and elicit a deleterious effect on cardiac mitochondrial energetics. Domoic acid (0.05-0.25 microM; 10 min) treatment of isolated rat cardiac mitochondria produced a marked decrease of both mitochondrial flavin adenine dinucleotide (FAD)- and nicotinamide adenine linked respiratory control indices (p < 0.001). Enzymatic assays of the mitochondrial electron transport chain (complexes I-V) and the mitochondrial matrix marker enzyme citrate synthase, showed marked concentration-dependent impairment in activity and integrity following exposure to domoic acid (p < 0.01). Similar mitochondrial effects were seen following exposure to the glutamic acid analog, kainic acid (0.5-2 microM). Domoic acid (0.05-10 microM; 40 min) was shown by competitive enzyme-linked immunosorbent assay to traverse the cellular membrane of H9c2 rat cardiac myoblasts. Exposure of intact H9c2 cells to domoic acid (10 microM; 24 h) impaired complex II-III activity but did not compromise cellular viability as assessed using cell quantification or lactate dehydrogenase leakage assays. Assessment of reactive oxygen species (superoxide and hydrogen peroxide) production in both isolated cardiac mitochondria and H9c2 cardiomyocytes failed to show any significant differences following exposure to domoic acid (0.05-5 microM). This is the first study to demonstrate a direct effect of domoic acid on cardiac mitochondrial energetics. However, the absence of substantial damage to intact cardiomyocytes raises questions regarding direct toxicological effects on cardiac energetics or viability under conditions of natural domoic acid exposure.

Synthesis of Novel Pyrrolo[3,4‐d]pyrazole‐dicarboxylic Acids and Evaluation of Their Interaction with Glutamate Receptors

Chiral pyrazoline amino acids (3aR,4S,6aR)-1a and (3aR,4S,6aR)-1b, and (3aS,6S,6aS)-2a and (3aS,6S,6aS)-2b, which are conformationally constrained analogues of glutamic and homoglutamic acid, respectively, were prepared via a strategy based on the 1,3-dipolar cycloaddition of a nitrile imine to methyl N-Boc-3,4-didehydro-(S)-prolinate. The new 'amino acids' were tested for activity at ionotropic glutamate receptors. Solely the derivative (3aR,4S,6aR)-1a, which is structurally related to the previously described 4,5-dihydroisoxazole analogue (S)-CIP-A, turned out to be a potent and selective agonist for the AMPA receptors. The biological activity is due to the interaction with the orthosteric glutamate binding site.

Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A 4 hydrolase

Leukotriene B 4 (LTB 4) is a potent pro-inflammatory mediator that has been implicated in the pathogenesis of multiple diseases, including psoriasis, inflammatory bowel disease, multiple sclerosis and asthma. As a method to decrease the level of LTB 4 and possibly identify novel treatments, inhibitors of the LTB 4 biosynthetic enzyme, leukotriene A 4 hydrolase (LTA 4-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA 4-h, arylamide of glutamic acid 4f, starting from the corresponding glycinamide 2. Analogs of 4f are then described, focusing on compounds that are both active and stable in whole blood. This effort culminated in the identification of amino alcohol 12a and amino ester 6b which meet these criteria.