Aspartic Acid Analogues Research Articles

ChemInform Abstract: Diastereoselective Synthesis of (1S,2S,3R,4R)‐ and (1R,2S,3R,4S)‐ Bicyclo(2.2.1)hept‐2‐amino‐2,3‐dicarboxylic Acids: New Conformationally‐Constrained (S)‐Aspartic Acid Analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A New Conformationally Restricted Aspartic Acid Analogue with a Bicyclo[2.2.2]octane Skeleton

The bicyclo[2.2.2] octane cage in (2R,3S)-3-benzamido-3-methoxycarbonylbicyclo­[2.2.2]octane-2-carboxylic acid, C18H21NO5, has approximate D3 symmetry and the three six-membered rings of this fragment all deviate slightly from ideal boat conformations. The values determined for the torsion angles about the N—Cα(ϕ) and Cα—CO(ψ) bonds correspond to a semi-extended conformation for the amino acid residue. The crystal structure is stabilized by two inter­molecular hydrogen bonds (O—H⋯O and N—H⋯O) involving the carboxylic acid, the benzamido and the methyl ester groups.

A Conformationally Restricted Aspartic Acid Analogue

In the title compound, (1R,2R,3S,4S)-3-benzamido-3-methoxycarbonylbicyclo[2.2.1]heptane-2-carboxylic acid, C17H19NO5, the norbornyl group shows distortion from C2v(mm2) symmetry of the parent hydrocarbon. The values determined for the torsion angles about the N—Cα (ϕ) and Cα—CO (ψ) bonds correspond to a semi-extended conformation for the amino acid residue. The structure is stabilized by an intermolecular O—H⋯O hydrogen bond between the carboxyl and amide groups and an intramolecular N—H⋯O hydrogen bond involving the benzamido and the carboxylic acid groups.

Diastereoselective synthesis of (1S,2S,3R,4R) and (1R,2S,3R,4S)-bicyclo[2.2.1]hept-2-amino-2,3-dicarboxylic acids: New conformationally-constrained (S)-aspartic acid analogues

Abstract The title compounds were prepared from key intermediates readily obtained by the stereoselective Diels-Alder reaction of ( Z )-2-phenyl-4-[( S )-2,2-dimethyl-1,3-dioxolan-4-ylmethylene]-5(4H)-oxazolone, a chiral az-lactone derived from ( R )-glyceraldehyde and cyclopentadiene.

Therapeutic effects of D-aspartic acid beta-hydroxamate (DAH) on Friend erythroleukemia.

D-aspartic acid beta-hydroxamate (DAH), an aspartic acid analogue, exerts anti-tumoral activity against murine leukemia L5178Y both in vitro and in vivo. We show here that DAH displays activity against Friend leukemia cells (FLC) in vitro: a concentration of 2 mM results in a total inhibition of cell growth. DAH is also active in vivo against Friend virus (FV-P)-induced erythroleukemia. Treatment with DAH, given for 95 days as a single daily i.p. injection to DBA/2 mice 3 days following FV-P inoculation, induced a marked increase of 212% in the mean survival time (MST) of treated animals. Since FV-P-induced erythroleukemia is characterized by the proliferation of mature erythroid precursors, we examined the effect of DAH treatment on erythroid colony-forming cells (CFU-E) and observed that the number of CFU-E per spleen was 30 times lower in DAH-treated mice than in the controls. To gain further insight into the early effects of DAH treatment on the early phase of Friend disease, we examined the effects of short DAH treatment on spleen size, hematocrit and viremia in FV-P-infected mice. DAH treatment initiated 3 days post infection (p.i.) inhibited splenomegaly, prevented virus-induced polycythemia, and reduced serum viremia. Late DAH treatment (18 days p.i.) induced regression of FVP-induced disease as evidenced by reduction of spleen weight.

ChemInform Abstract: Enantioselective Synthesis of (2S,3S)‐ and (2R,3R)‐Pyrrolidine‐2,3‐ dicarboxylic Acids: Conformationally Constrained (S)‐ and (R)‐Aspartic Acid Analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Enantioselective synthesis of (2S,3S)- and (2R,3R)-pyrrolidine-2,3-dicarboxylic acids: Conformationally constrained (S)- and (R)-aspartic acid analogues

The title compounds were prepared from the key intermediate 2 and its enantiomer at C2, derived from chiral synthons 1- ( R) and 1- ( S), respectively, by ethoxycarbonylation, desulfonylation and conversion to carboxylic acid.

A short synthesis of (S)-3-(dimethylphosphono)-2- ((9-fluorenyl)methoxycarbamoyl)propionic acid, a protected phosphonic acid analogue of aspartic acid

The synthesis, from serine, of a phosphonic acid analogue of aspartic acid protected in a form suitable for peptide synthesis, is described.

The actions of a conformationally restricted analogue of aspartic acid on mammalian spinal neurones

The effects of the 4 stereoisomers of 1-aminocyclopentane-1,2-dicarboxylic acid (CPA), a conformationally restricted analogue of aspartic acid, have been examined on spinal dorsal horn neurones of the rat in vivo. Unlike the corresponding 1,3-dicarboxylate compounds which are glutamate analogues and markedly excitatory, the CPA isomers had no evident excitatory actions of their own. Three were weak and non-specific antagonists of other amino acid-induced excitations, while the (+)- trans isomer had a slight potentiating effect.

NMDA receptor agonists derived from ibotenic acid. Preparation, neuroexcitation and neurotoxicity

The two heterocyclic aspartic acid and glutamic acid analogues derived from ibotenic acid, (RS)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)acetic acid (AMAA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) have previously been shown to be selective agonists at N-methyl-D-aspartic acid (NMDA) and AMPA receptors, respectively. Two analogous series of AMAA and AMPA derivatives have now been synthesized and characterized in receptor binding studies and neuropharmacological experiments. AMAA was shown to be a very potent NMDA agonist in cortical tissue preparations, slightly more active than NMDA, whereas N-methyl-AMAA was less potent and N,N-dimethyl-AMAA almost inactive. (RS)-3-Hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-4-carboxylic acid (4-HPCA), a bicyclic analogue of AMAA, exhibited weak NMDA agonist effects similar to those of quinolinic acid. The relative potency as AMPA receptor agonists of AMPA, N-methyl-AMPA, N,N-dimethyl-AMPA and (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA), a bicyclic analogue of AMPA, was distinctly different from that of the AMAA series of compounds as NMDA agonists. The pharmacological and toxicological profiles of AMAA and 4-HPCA, compared with those of quinolinic acid, are consistent with heterogeneity of NMDA receptors.

Complexes of aminophosphonates. II. Transition metal complexes of aminophosphonic acid analogues of aspartic acid and glutamic acid

The stoichiometries and stability constants of the proton, cobalt(II), nickel(Il), copper(II) and zinc(II) complexes of 2-amino-3-phosphonopropionic acid (β-P-Asp), 3-amino-3-phosphonopropionic acid (α-P- Asp) and 2-amino-4-phosphonobutanoic acid (γ-P- Glu) have been determined pH-metrically at 25 °C and at an ionic strength of 0.2 mol dm −3 (KCl). [p ]From the stability data and the spectral parameters of the complexes, it has been established that, similarly as for the aminocarboxylate analogues, the metal ion bonding mode is basically bidentate with P-Glu and tridentate with P-Asp. However, the more basic character of the -PO 3 2− group than that of the -COO - group leads to an enhanced formation of various protonated complexes. PO 3 2−/COO − substitution in the α-position results in a more marked ambidentate character of P-Asp in the copper(II) complexes than does that in the β-position.

Conjugation of aspartic acid with 4-bromophenylacetic acid, an auxin analogue of aspartic acid

Tobacco mesophyll protoplasts conjugate the auxins indoleacetic acid and naphthaleneacetic acid with aspartic acid very efficiently. This conjugation was found to be correlated with the toxicity of these molecules to protoplast-derived cells grown at low densities. Among a series of halogenated phenylacetic acids, 4-bromophenylacetic was toxic to cells grown at low densities although not able to stimulate proliferation at high cell densities, as opposed to indoleacetic acid and naphthaleneacetic acid. [ 14C-car☐yl]-4-bromophenylacetic acid was conjugated with aspartic acid by tobacco protoplasts. Although 4-bromophenylacetic acid is not an auxin, this molecule shares with auxins some of their properties.

Determination of absolute configuration of optically active 1-aminoalkanephosphonic acids by chemical correlations

Abstract The absolute configurations of optically active phosphonic analogues of serine, β-chloroalanine, phenylalanine, tyrosine and 2-aziridinephosphonic acid have been established via chemical correlations with phosphonic analogues of alanine or aspartic acid of known configuration.

Modulation of fluoropyrimidine metabolism in L1210 cells by l-alanosine

l-Alanosine, an analogue of aspartic acid which inhibits the conversion of inosine monophosphate to adenosine monophosphate (AMP), was evaluated in L1210 cells as a modulator of 5-fluorouracil (FUra) and 5-fluorouridine (FUrd) metabolism. l-Alanosine resulted in increased intra-cellular levels of 5-phosphoribosyl-1-pyrophosphate (PRPP), enhanced FUra metabolism to ribonucleotide derivatives, and resulted in more FUra residues incorporated into RNA. Sequential addition of l-alanosine and FUra also resulted in synergistic cytotoxicity as determined by soft agar cloning. Adenine antagonized these biochemical and biological effects of l-alanosine. l-Alanosine also augmented the rate at which FUrd was metabolized and was also associated with a greater incorporation of the FUra residues into RNA. Cytotoxicity after sequential l-alanosine and FUrd was also synergistic. The mechanism by which l-alanosine altered the metabolism of FUrd, however, was different from the way in which it enhanced FUra metabolism in that aspartic acid and not adenine was able to reverse the effects of l-alanosine on FUrd metabolism and cytotoxicity. l-Alanosine appeared to augment the RNA-directed activity of FUra and FUrd in that there was no correlation between the enhanced metabolism and cytotoxicity of these two fluoropyrimidines and either levels of fluorodeoxyuridylate (FdUMP) which inhibits thymidylate (TMP) synthetase or inhibition of the ability of cells to incorporate deoxyuridylate into acid-precipitable material.

Response of Schaffer collateral-CA1 pyramidal cell synapses of the hippocampus to analogues of acidic amino acids

Analogues of the putative excitatory transmitters aspartic acid and glutamic acid were tested for antagonism against stimulus-evoked activation of Schaffer collateral-CA1 pyramidal cell synapses in slices of rat hippocampus. Responses to the analogues, applied via the superfusing medium, were extracellularly recorded. The compounds examined included d- and l-α-aminodicar☐ylic acids, diamonodicar☐ylic acids, phosphonate analogues of acidic amino acids, d and l-γ-glutamyl glycine, and the cis- and trans-isomers of piperidine 2,3-, and 2,4-dicar☐ylic acid. Many of these compounds are known to be potent and selective antagonists for excitatory amino acids and a few excitatory pathways. In this hippocampal pathway most of these analogues showed relatively low and similar potency. The most potent antagonist uncontaminated with agonist activity was d-α-aminosuberate, with an apparent antagonist dissociation constant ( K d of 3 mM. Only 5 of the analogues, 3 of the piperidine dicar☐ylates, kainic acid, and l-α-aminopimelic acid, reduced the amplitude of the extracellularly recorded field potentials more than 30% at 0.5 mM. However, all of the others reduced the potential by more than 30% at 5 mM. Most analogues also evoked extracellular responses whoch can be attributed to depolarization of the pyramidal neurons. Agonist activity was particularly strong among the most potent analogues. These results contrast with the responses documented by others for the N-methyl- d-aspartate receptor of the dorsal-ventral root excitatory pathway of the spinal cord in which the higher homologues tested here were the most potent antagonists, and the d-isomers were more potent than the l-isomoers. It also contrasts with the response of the perforant path synapses to granule cells of the dentate gyrus in which the portion derived from the lateral entorhinal cortex is sensitive to l-2-amino-4-phosphonobutyric acid. Thus the Schaffer-CA1 pyramidal cell synaptic field utilizes a novel excitatory transmitter receptor which interacts detectably but only weakly with a variety of acidic amino acids with potent specific inhibitory action for receptors elsewhere in the central nervous system.

Acute effects of N-methyl-DL-aspartate on the release of pituitary gonadotropins and prolactin in the adult female rhesus monkey

The acute effects of an aspartic acid analogue, N-methyl- dl-aspartate (NMA), upon the release of several anterior pituitary hormones were examined in adult female rhesus monkeys. Intravenous injection of NMA (15 mg/kg body weight) induced a large and rapid rise in plasma levels of luteinizing hormone, follicle stimulating hormone, and prolactin. Thyroid stimulating hormone concentrations were not altered. Thus, in primates, as in rodents, systemically administered NMA is capable of eliciting pituitary hormone secretion, although the site of its action in the rhesus monkey remains to be established.

The binding of [3H]AMPA, a structural analogue of glutamic acid, to rat brain membranes.

Binding of [3H]AMPA to rat brain membranes was investigated. The binding was saturable and reversible at physiological pH. Computer-aided Scatchard analysis of the binding data, as determined by using L-glutamic acid (L-GLU) to define nonspecific binding, suggested the presence of two independent binding sites, with KDS of 9 and 2440 nM, respectively. Additional freezing, thawing and washing sequences gave membranes with only one binding site, with a KD of 278 nM. [3H]AMPA binding exhibited the highest level in striatal membranes. A series of analogues of GLU and aspartic acid (ASP) were tested as inhibitors of [3H]AMPA binding. L-ASP and compounds which interact predominantly with N-methyl-D-aspartic acid (NMDA) receptor sites were inactive as inhibitors of [3H]AMPA binding, whereas L-GLU and compounds which interact predominantly with glutamic acid diethyl ester receptor sites were inhibitors with the same order of potency as that shown by the excitatory action in vivo. The result suggests that [3H]AMPA might represent binding to an excitatory GLU receptor.

Aminophosphonic and aminophosphinic acid analogues of aspartic acid

4-Oxoazetidin-2-ylphosphonates and phosphinates, obtained from Arbusov reactions of 4-acetoxyazetidin-2-one and 4α-acetoxy-3β-phthalimido-2-one with a variety of phosphites and phosphonites, were hyrdolysed to β-phosphono- and β-phosphino β-alanine (phosphono- and phosphinoaspartic acid) derivatives. In model studies for their incorporation in peptides, conditions for the selective removal of protecting groups for carboxylic acids, phosphonic and phosphinic acids, and amines, in derived di- and tri-peptides were investigated. Alanyl and alanyl alanyl peptide incorporation into bacteria was studied.

1H and 31P NMR studies of rotational isomerism in phosphorus analogues of aspartic acid, 3‐amino‐3‐phosphonatopropionic and 3‐amino‐3‐(methylphosphinato) propionic acids

AbstractBy the use of the 1H1H and 1H31P coupling constants in two analogues of aspartic acid i.e. 3‐amino‐3‐phosphonatopropionic and 3‐amino‐3‐(methylphosphinato) propionic acids, it was shown that the six parameter formulation for the evaluation of mole fractions of three staggered ethanic rotamers is not necessarily better than the two parameter formulation in this system. The results allowed the recommendation of the following values for the two vicinal proton parameters i.e. J(HH)g=2.3, J(HH)t=13.9 and for the two vicinal proton‐phosphorus parameters i.e. J(HP)g=4.2, J(HP)t=33.0 Hz.

Synthesis of aza homologues of folic acid.

Folic acid analogues containing an additional nitrogen atom between the phenyl ring and the carbonyl group of the side chain were synthesized. None of the compounds showed significant inhibitory activity against human lymphoblastic leukemia cells (CCRF-CEM) in culture or against Lactobacillus casei (ATCC 7469) growth. Against L1210 leukemia in mice, the aza homologue of folic acid, 4, and the aspartic acid analogue, 14, showed no increase in life span over control animals. These compounds were more toxic in vivo than the corresponding methotrexate analogues. Compound 4 supported the growth of Streptococcus faecium (ATCC 8043), and its tetrahydro derivative supported the growth of Pediococcus cerevisiae (ATCC 8081). These results strongly suggest that 4 can substitute for folate derivatives as cofactors for serine transhydroxymethylase, thymidylate synthetase, and dihydrofolate reductase.