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1.
Org Biomol Chem ; 22(18): 3584-3588, 2024 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-38623862

RESUMEN

Asp-based lactam cyclic peptides are considered promising drug candidates. However, using Fmoc solid-phase peptide synthesis (Fmoc-SPPS) for these peptides also causes aspartimide formation, resulting in low yields or even failure to obtain the target peptides. Here, we developed a diaminodiacid containing an amide bond as a ß-carboxyl-protecting group for Asp to avoid aspartimide formation. The practicality of this diaminodiacid has been illustrated by the synthesis of lactam cyclic peptide cyclo[Lys9,Asp13] KIIIA7-14 and 1Y.


Asunto(s)
Amidas , Ácido Aspártico , Lactamas , Péptidos Cíclicos , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Lactamas/química , Lactamas/síntesis química , Amidas/química , Amidas/síntesis química , Ácido Aspártico/química , Ácido Aspártico/síntesis química , Ácido Aspártico/análogos & derivados , Técnicas de Síntesis en Fase Sólida , Estructura Molecular
2.
Biochim Biophys Acta Biomembr ; 1864(1): 183817, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34767780

RESUMEN

Here, carbon nanodots synthesized from ß-alanine (Ala-CDs) and detonation nanodiamonds (NDs) were assessed using (1) radiolabeled excitatory neurotransmitters L-[14C]glutamate, D-[2,33H]aspartate, and inhibitory ones [3H]GABA, [3H]glycine for registration of their extracellular concentrations in rat cortex nerve terminals; (2) the fluorescent ratiometric probe NR12S and pH-sensitive probe acridine orange for registration of the membrane lipid order and synaptic vesicle acidification, respectively; (3) suspended bilayer lipid membrane (BLM) to monitor changes in transmembrane current. In nerve terminals, Ala-CDs and NDs increased the extracellular concentrations of neurotransmitters and decreased acidification of synaptic vesicles, whereas have not changed sufficiently the lipid order of membrane. Both nanoparticles, Ala-CDs and NDs, were capable of increasing the conductance of the BLM by inducing stable potential-dependent cation-selective pores. Introduction of divalent cations, Zn2+ or Cd2+ on the particles` application side (cis-side) increased the rate of Ala-CDs pore-formation in the BLM. The application of positive potential (+100 mV) to the cis-chamber with Ala-CDs or NDs also activated the insertion as compared with the negative potential (-100 mV). The Ala-CD pores exhibited a wide-range distribution of conductances between 10 and 60 pS and consecutive increase in conductance of each major peak by ~10 pS, which suggest the clustering of the same basic ion-conductive structure. NDs also formed ion-conductive pores ranging from 6 pS to 60 pS with the major peak of conductance at ~12 pS in cholesterol-containing membrane. Observed Ala-CDs and NDs-induced increase in transmembrane current coincides with disturbance of excitatory and inhibitory neurotransmitter transport in nerve terminals.


Asunto(s)
Corteza Cerebral/metabolismo , Nanopartículas/química , Sinapsis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Vesículas Sinápticas/química , Alanina/síntesis química , Alanina/química , Animales , Ácido Aspártico/síntesis química , Ácido Aspártico/química , Ácido Aspártico/farmacología , Carbono/química , Carbono/farmacología , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacología , Cationes/farmacología , Corteza Cerebral/efectos de la radiación , Colesterol/química , Ácido Glutámico/síntesis química , Ácido Glutámico/química , Ácido Glutámico/farmacología , Membrana Dobles de Lípidos/química , Nanodiamantes/química , Neurotransmisores/química , Neurotransmisores/farmacología , Ratas , Sinapsis/química , Transmisión Sináptica/fisiología , Vesículas Sinápticas/efectos de los fármacos , Vesículas Sinápticas/metabolismo , Ácido gamma-Aminobutírico/síntesis química , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/farmacología
3.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-34445521

RESUMEN

Poly(aspartamide) derivatives, one kind of amino acid-based polymers with excellent biocompatibility and biodegradability, meet the key requirements for application in various areas of biomedicine. Poly(aspartamide) derivatives with stimuli-responsiveness can usually respond to external stimuli to change their chemical or physical properties. Using external stimuli such as temperature and pH as switches, these smart poly(aspartamide) derivatives can be used for convenient drug loading and controlled release. Here, we review the synthesis strategies for preparing these stimuli-responsive poly(aspartamide) derivatives and the latest developments in their applications as drug carriers.


Asunto(s)
Ácido Aspártico/análogos & derivados , Portadores de Fármacos/síntesis química , Polímeros/síntesis química , Ácido Aspártico/síntesis química , Ácido Aspártico/química , Preparaciones de Acción Retardada , Portadores de Fármacos/química , Concentración de Iones de Hidrógeno , Polímeros/química , Temperatura
4.
J Pept Sci ; 27(6): e3311, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33605058

RESUMEN

The helix-sense reversal of poly(ß-phenylpropyl l-aspartate) (3PLA) in the solid state was studied by synchrotron wide-angle X-ray diffraction and small-angle X-ray scattering. The direct determination of the characteristic helical pitch before and after the transition revealed that the transition takes place reversibly between the two α-helices having opposite screw-sense during the heating and cooling cycle. While the hexagonal packing remains unaltered, the helix-sense inversion causes discontinuous changes in the molecular arrangement and, by extension, the crystalline dimension. In this study, another transition was detected at a higher temperature from the left-handed α-helix to the π-helix, the molecular chirality being unaffected.


Asunto(s)
Ácido Aspártico/química , Polímeros/química , Ácido Aspártico/síntesis química , Estructura Molecular , Polímeros/síntesis química , Sincrotrones , Difracción de Rayos X
5.
Nat Commun ; 11(1): 982, 2020 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-32080186

RESUMEN

Although peptide chemistry has made great progress, the frequent occurrence of aspartimide formation during peptide synthesis remains a formidable challenge. Aspartimide formation leads to low yields in addition to costly purification or even inaccessible peptide sequences. Here, we report an alternative approach to address this longstanding challenge of peptide synthesis by utilizing cyanosulfurylides to mask carboxylic acids by a stable C-C bond. These functional groups-formally zwitterionic species-are exceptionally stable to all common manipulations and impart improved solubility during synthesis. Deprotection is readily and rapidly achieved under aqueous conditions with electrophilic halogenating agents via a highly selective C-C bond cleavage reaction. This protecting group is employed for the synthesis of a range of peptides and proteins including teduglutide, ubiquitin, and the low-density lipoprotein class A. This protecting group strategy has the potential to overcome one of the most difficult aspects of modern peptide chemistry.


Asunto(s)
Péptidos/química , Péptidos/síntesis química , Técnicas de Síntesis en Fase Sólida/métodos , Ácido Aspártico/análogos & derivados , Ácido Aspártico/síntesis química , Ácido Aspártico/química , Ácidos Carboxílicos/química , Cianuros/química , Lipoproteínas LDL/síntesis química , Lipoproteínas LDL/química , Pliegue de Proteína , Ubiquitina/química
6.
Curr Opin Chem Biol ; 55: 111-118, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32086167

RESUMEN

The field of organic chemistry has recently witnessed a rapid rise in the use of chemoenzymatic strategies for the synthesis of complex molecules. Under this paradigm, biocatalytic methods and contemporary synthetic methods are used synergistically in a multistep approach toward a target molecule. In light of the unparalleled regioselectivity and stereoselectivity of enzymatic transformations and the reaction diversity of contemporary organic chemistry, chemoenzymatic strategies hold enormous potential for streamlining access to important bioactive molecules. This review covers recent demonstrations of chemoenzymatic approaches in chemical synthesis, with special emphasis on the preparation of medicinally relevant natural products.


Asunto(s)
Productos Biológicos/síntesis química , Enzimas/metabolismo , Ácido Aspártico/análogos & derivados , Ácido Aspártico/síntesis química , Biocatálisis , Isoquinolinas/síntesis química , Ácido Kaínico/síntesis química , Conformación Molecular , Podofilotoxina/síntesis química , Quinolinas/síntesis química , Quinolonas/síntesis química , Estereoisomerismo
7.
Chem Phys Lipids ; 226: 104832, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31560875

RESUMEN

Bone diseases are notoriously difficult diseases to treat due to the comparatively low blood flows in bone tissue. Therefore, targeting delivery of drugs to bone may not only enhance the treatment efficacy, but also reduce the quantity of drug administered. In order to increase the distribution of paclitaxel (PTX) in bone, in this study, a series of novel dendritic aspartic acid derivatives were designed and synthesized as liposome ligands to deliver PTX to bone effectively. The liposomes were prepared by thin film hydration method and its particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis were also characterized. All the aspartic acid-coated liposomes showed more than 60% binding rates to hydroxyapatite (HAP), especially the PTX-Asp8-Lip exhibited dramatic binding rates (> 97%) after 24 h. Moreover, the bone-targeting study in vivo indicated that all liposomes could improve the accumulation of PTX in bone, among which, the PTX-Asp8-Lip showed the best affinity due to the increase of aspartic acid residues exposed on the liposome surface. These results provided a novel and effective entry to the development of bone-targeting drugs.


Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Ácido Aspártico/química , Huesos/efectos de los fármacos , Liposomas/química , Paclitaxel/farmacocinética , Animales , Antineoplásicos Fitogénicos/química , Ácido Aspártico/síntesis química , Huesos/metabolismo , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Humanos , Liposomas/síntesis química , Estructura Molecular , Paclitaxel/química , Tamaño de la Partícula , Ratas , Ratas Sprague-Dawley , Propiedades de Superficie , Distribución Tisular
8.
J Am Chem Soc ; 141(46): 18624-18629, 2019 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-31656070

RESUMEN

The catalytic, enantioselective N-oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic-acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine N-oxides further document the utility of this approach. Demonstration of the asymmetric N-oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.


Asunto(s)
Piridinas/química , Ácido Aspártico/síntesis química , Ácido Aspártico/química , Catálisis , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Enlace de Hidrógeno , Péptidos/síntesis química , Péptidos/química , Piridinas/síntesis química , Estereoisomerismo
9.
Analyst ; 143(21): 5285-5294, 2018 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-30280722

RESUMEN

The development of a fluorescence method for the selective ratiometric detection of Al3+ ions in pure aqueous solutions and live cells is still a significant challenge. In the present study, we synthesized a new type of fluorescent probe using an Al3+-triggered self-assembly based on the dipeptide receptor and an aggregation-induced emission fluorophore. The fluorescent probe (1) bearing cyanostilbene with excitation by visible light detected Al3+ ions sensitively in pure aqueous buffered solution by ratiometric red-emission at 600 nm. 1 provided a highly selective ratiometric detection of Al3+ among 16 metal ions in aqueous solution. 1 exhibited sensitive ratiometric response to Al3+ in aqueous buffered solutions at pH ranging from 5 to 7.4. The detection limit (145 nM, R2 = 0.999) for Al3+ ions in pure aqueous solution was much lower than the maximum allowable level of Al3+ in drinking water demanded by the Environmental Protection Agency (EPA). The probe provided an efficient approach to detect low concentrations of Al3+ in ground water, tap water, and live cells by ratiometric red-emissions at 600 nm. The binding study using dynamic light scattering, NMR, IR, and TEM revealed that the complex between 1 and Al3+ self-assembled to form nanoparticles, resulting in the enhancement of the emission at 600 nm and a concomitant decrease in the emission at 535 nm.


Asunto(s)
Aluminio/análisis , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Benzotiazoles/química , Colorantes Fluorescentes/química , Aluminio/química , Ácido Aspártico/síntesis química , Ácido Aspártico/toxicidad , Benzotiazoles/síntesis química , Benzotiazoles/toxicidad , Línea Celular Tumoral , Fluorescencia , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/toxicidad , Agua Subterránea/análisis , Humanos , Límite de Detección , Microscopía Fluorescente/métodos , Nanopartículas/química , Tamaño de la Partícula , Espectrometría de Fluorescencia/métodos , Agua/química
10.
J Med Chem ; 61(17): 7741-7753, 2018 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-30011368

RESUMEN

Aspartate (Asp) derivatives are privileged compounds for investigating the roles governed by excitatory amino acid transporters (EAATs) in glutamatergic neurotransmission. Here, we report the synthesis of various Asp derivatives with (cyclo)alkyloxy and (hetero)aryloxy substituents at C-3. Their pharmacological properties were characterized at the EAAT1-4 subtypes. The l- threo-3-substituted Asp derivatives 13a-e and 13g-k were nonsubstrate inhibitors, exhibiting pan activity at EAAT1-4 with IC50 values ranging from 0.49 to 15 µM. Comparisons between (dl- threo)-19a-c and (dl- erythro)-19a-c Asp analogues confirmed that the threo configuration is crucial for the EAAT1-4 inhibitory activities. Analogues (3b-e) of l-TFB-TBOA (3a) were shown to be potent EAAT1-4 inhibitors, with IC50 values ranging from 5 to 530 nM. Hybridization of the nonselective EAAT inhibitor l-TBOA with EAAT2-selective inhibitor WAY-213613 or EAAT3-preferring inhibitor NBI-59159 yielded compounds 8 and 9, respectively, which were nonselective EAAT inhibitors displaying considerably lower IC50 values at EAAT1-4 (11-140 nM) than those displayed by the respective parent molecules.


Asunto(s)
Amoníaco-Liasas/metabolismo , Ácido Aspártico/análogos & derivados , Ácido Aspártico/farmacología , Transportador 1 de Aminoácidos Excitadores/antagonistas & inhibidores , Transportador 3 de Aminoácidos Excitadores/antagonistas & inhibidores , Transportador 4 de Aminoácidos Excitadores/antagonistas & inhibidores , Proteínas de Transporte de Glutamato en la Membrana Plasmática/antagonistas & inhibidores , Ácido Aspártico/síntesis química , Transportador 2 de Aminoácidos Excitadores , Células HEK293 , Humanos , Estructura Molecular , Relación Estructura-Actividad
11.
Anal Chem ; 90(11): 6998-7003, 2018 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-29712431

RESUMEN

Asparagine deamidation in the complementarity determining regions of recombinant monoclonal antibodies has been extensively studied and shown to have a negative impact on antigen binding. Those asparagine residues are typically exposed and thus have a higher tendency toward deamidation, depending also on local structure and environmental factors such as temperature and pH. Deamidation rates and products of a susceptible asparagine residue in the complementarity determining regions of a recombinant monoclonal antibody free in solution or in the antibody-antigen complex were studied. The results demonstrated that incubation of the antibody or its antigen complex generated a similar amount of aspartate. The expected amount of isoaspartate product was detected in free antibody, but it was completely lacking in the antibody-antigen complex.


Asunto(s)
Amidas/química , Anticuerpos Monoclonales/análisis , Asparagina/química , Ácido Aspártico/síntesis química , Anticuerpos Monoclonales/inmunología , Antígenos/inmunología , Ácido Aspártico/química , Estructura Molecular , Proteínas Recombinantes/análisis
12.
J Org Chem ; 82(24): 13643-13648, 2017 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-29115130

RESUMEN

Staphylopine was discovered and functionally evaluated as a novel type of metallophore that Staphylococcus aureus employs to acquire multiple divalent transition metals. Aspergillomarasmine A (AMA), with a similar structure to staphylopine, was recently identified as an inhibitor of metallo-ß-lactamases NDM-1 and VIM-2. Herein, we report a unified approach using Mitsunobu reaction as a key step to accomplish the concise and efficient total syntheses of staphylopine and AMA. We also elucidate the similar broad-spectrum metal chelation properties between staphylopine and AMA.


Asunto(s)
Ácido Aspártico/análogos & derivados , Imidazoles/síntesis química , Ácido Aspártico/síntesis química , Ácido Aspártico/química , Imidazoles/química , Estructura Molecular
13.
Bioorg Med Chem ; 25(19): 5133-5141, 2017 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-28784300

RESUMEN

The ß-lactam antibiotic resistance of Gram-negative bacteria has shown to be a critical global health problem. One of the primary reasons for the drug resistance is the existence of ß-lactamases especially metallo-ß-lactamases such as New Delhi metallo-ß-lactamase (NDM-1) and Verona Integron-encoded metallo-ß-lactamase (VIM-2). The fungal natural product Aspergillomarasmine A (AMA) has proven to be a promising inhibitor of NDM-1 and VIM-2 both in vitro and in vivo. Seven new analogues of AMA were synthesized by utilizing different strategies. The biological evaluation of these analogues was performed to study the structure-activity relationship of AMA both in vitro and in vivo. Remarkably, the lead compound 4 showed synergistic effect in combination with Meropenem to overcome the antibiotic resistance of the Gram-negative bacteria such as K. pneumoniae (BAA-2146) expressing NDM-1.


Asunto(s)
Ácido Aspártico/análogos & derivados , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/enzimología , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/metabolismo , Ácido Aspártico/síntesis química , Ácido Aspártico/química , Ácido Aspártico/farmacología , Humanos , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Resistencia betalactámica/efectos de los fármacos , Inhibidores de beta-Lactamasas/síntesis química
14.
Bioorg Med Chem ; 25(12): 3116-3126, 2017 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-28462840

RESUMEN

A new series of thirteen N-(carbobenzyloxy)-l-phenylalanine and N-(carbobenzyloxy)-l-aspartic acid-ß-benzyl ester compounds were synthesized and evaluated for antiproliferative activity against four different human cancer cell lines: cervical cancer (HeLa), lung cancer (A549), gastric cancer (MGC-803) and breast cancer (MCF-7) as well as topoisomerase I and IIα inhibitory activity. Compounds (5a, 5b, 5e, 8a, 8b) showed significant antiproliferative activity with low IC50 values against the four cancer cell lines. Equally, compounds 5a, 5b, 5e, 5f, 8a, 8d, 8e and 8f showed topoisomerase IIα inhibitory activity at 100µM with 5b, 5e, 8f exhibiting potential topoisomerase IIα inhibitory activity compared to positive control at 100µM and 20µM, respectively. Conversely compounds 5e, 5f, 5g and 8a showed weaker topoisomerase I inhibitory activity compared to positive control at 100µM. Compound 5b exhibited the most potent topoisomerase IIα inhibitory activity at low concentration and better antiproliferative activity against the four human cancer cell lines. The molecular interactions between compounds 5a-5g, 8a-8f and the topoisomerase IIα (PDB ID: 1ZXM) were further investigated through molecular docking. The results indicated that these compounds could serve as promising leads for further optimization as novel antitumor agents.


Asunto(s)
Ácido Aspártico/análogos & derivados , Ácido Aspártico/farmacología , Proteínas de Unión al ADN/antagonistas & inhibidores , Fenilalanina/análogos & derivados , Fenilalanina/farmacología , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacología , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Ácido Aspártico/síntesis química , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/metabolismo , Células HeLa , Humanos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Fenilalanina/síntesis química , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química
15.
ACS Chem Neurosci ; 8(8): 1668-1672, 2017 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-28414419

RESUMEN

Excitatory amino acid transporters clear glutamate from the synaptic cleft and play a critical role in glutamatergic neurotransmission. Their differential roles in astrocytes, microglia, and neurons are poorly understood due in part to a lack of pharmacological tools that can be targeted to specific cells and tissues. We now describe a photoswitchable inhibitor, termed ATT, that interacts with the major mammalian forebrain transporters EAAT1-3 in a manner that can be reversibly switched between trans (high-affinity) and cis (low-affinity) configurations using light of different colors. In the dark, ATT competitively inhibited the predominant glial transporter EAAT2 with ∼200-fold selectivity over the neuronal transporter EAAT3. Brief exposure to 350 nm light reduced the steady-state blocker affinity by more than an order of magnitude. Illumination of EAAT2 complexed with ATT induced a corresponding increase in the blocker off-rate monitored in the presence of glutamate. ATT can be used to reversibly manipulate glutamate transporter activity with light and may be useful to gain insights into the dynamic physiological roles of glutamate transporters in the brain, as well as to study the molecular interactions of transporters with ligands.


Asunto(s)
Ácido Aspártico/análogos & derivados , Transportador 1 de Aminoácidos Excitadores/antagonistas & inhibidores , Transportador 3 de Aminoácidos Excitadores/antagonistas & inhibidores , Proteínas de Transporte de Glutamato en la Membrana Plasmática/antagonistas & inhibidores , Moduladores del Transporte de Membrana/farmacología , Animales , Ácido Aspártico/síntesis química , Ácido Aspártico/química , Ácido Aspártico/farmacología , Relación Dosis-Respuesta a Droga , Transportador 1 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores , Transportador 3 de Aminoácidos Excitadores/metabolismo , Proteínas de Transporte de Glutamato en la Membrana Plasmática/metabolismo , Humanos , Isomerismo , Luz , Potenciales de la Membrana/efectos de los fármacos , Moduladores del Transporte de Membrana/síntesis química , Moduladores del Transporte de Membrana/química , Estructura Molecular , Oocitos , Técnicas de Placa-Clamp , Procesos Fotoquímicos , Xenopus laevis
16.
Org Biomol Chem ; 15(11): 2341-2344, 2017 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-28244539

RESUMEN

The complex amino acid (l-threo)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate (l-TFB-TBOA) and its derivatives are privileged compounds for studying the roles of excitatory amino acid transporters (EAATs) in regulation of glutamatergic neurotransmission, animal behavior, and in the pathogenesis of neurological diseases. The wide-spread use of l-TFB-TBOA stems from its high potency of EAAT inhibition and the lack of off-target binding to glutamate receptors. However, one of the main challenges in the evaluation of l-TFB-TBOA and its derivatives is the laborious synthesis of these compounds in stereoisomerically pure form. Here, we report an efficient and step-economic chemoenzymatic route that gives access to enantio- and diastereopure l-TFB-TBOA and its derivatives at multigram scale.


Asunto(s)
Sistema de Transporte de Aminoácidos X-AG/antagonistas & inhibidores , Aminoácidos/síntesis química , Aminoácidos/metabolismo , Ácido Aspártico/análogos & derivados , Enzimas/metabolismo , Aminoácidos/química , Ácido Aspártico/síntesis química , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Estructura Molecular , Estereoisomerismo
17.
Biochem Cell Biol ; 95(2): 304-309, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28177776

RESUMEN

Salmonella can utilize fructose-asparagine (F-Asn), a naturally occurring Amadori product, as its sole carbon and nitrogen source. Conversion of F-Asn to the common intermediates glucose-6-phosphate, aspartate, and ammonia was predicted to involve the sequential action of an asparaginase, a kinase, and a deglycase. Mutants lacking the deglycase are highly attenuated in mouse models of intestinal inflammation owing to the toxic build-up of the deglycase substrate. The limited distribution of this metabolic pathway in the animal gut microbiome raises the prospects for antibacterial discovery. We report the biochemical characterization of the kinase that was expected to transform fructose-aspartate to 6-phosphofructose-aspartate during F-Asn utilization. In addition to confirming its anticipated function, we determined through studies of fructose-aspartate analogues that this kinase exhibits a substrate-specificity with greater tolerance to changes to the amino acid (including the d-isomer of aspartate) than to the sugar.


Asunto(s)
Asparagina/análogos & derivados , Ácido Aspártico/análogos & derivados , Proteínas Bacterianas/química , Fructosa/análogos & derivados , Regulación Bacteriana de la Expresión Génica , Fosfotransferasas/química , Salmonella enterica/enzimología , Asparagina/síntesis química , Asparagina/metabolismo , Ácido Aspártico/síntesis química , Ácido Aspártico/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Escherichia coli/enzimología , Escherichia coli/genética , Fructosa/síntesis química , Fructosa/metabolismo , Concentración de Iones de Hidrógeno , Cinética , Operón , Fosfotransferasas/genética , Fosfotransferasas/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Salmonella enterica/genética , Estereoisomerismo , Especificidad por Sustrato , Temperatura
18.
Angew Chem Int Ed Engl ; 55(42): 13259-13262, 2016 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-27633338

RESUMEN

The fungal secondary metabolite aspergillomarasmine A (AMA) has recently been identified as an inhibitor of metallo-ß-lactamases NDM-1 and VIM-2. Described herein is an efficient and practical route to AMA and its related compounds by a sulfamidate approach. In addition, a series of derivatives has been prepared and tested for biological activity in an effort to explore preliminary structure activity relationships. While it was determined that natural LLL isomer of AMA remains the most effective inactivator of NDM-1 enzyme activity both in vitro and in cells, the structure is highly tolerant of the changes in the stereochemistry at positions 3, 6, and 9.


Asunto(s)
Amidas/farmacología , Antibacterianos/farmacología , Ácido Aspártico/análogos & derivados , Inhibidores Enzimáticos/farmacología , beta-Lactamasas/metabolismo , Acinetobacter/efectos de los fármacos , Acinetobacter/enzimología , Amidas/química , Antibacterianos/síntesis química , Antibacterianos/química , Ácido Aspártico/síntesis química , Ácido Aspártico/química , Ácido Aspártico/farmacología , Relación Dosis-Respuesta a Droga , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/enzimología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pseudomonas/efectos de los fármacos , Pseudomonas/enzimología , Relación Estructura-Actividad
19.
Bioorg Med Chem Lett ; 26(9): 2142-6, 2016 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-27032331

RESUMEN

A series of novel aryloxyphosphoramidate nucleoside prodrugs based on l-aspartic acid and l-glutamic acid as amino acid motif has been synthesized and evaluated for antitumoral activity. Depending on the cancer cell line studied and on the nature of the parent nucleoside compound (gemcitabine, 5-iodo-2'-deoxy-uridine, floxuridine or brivudin), the corresponding ProTides are endowed with an improved or decreased cytotoxic activity.


Asunto(s)
Antineoplásicos/farmacología , Ácido Aspártico/análogos & derivados , Glutamatos/farmacología , Nucleósidos/farmacología , Compuestos Organofosforados/farmacología , Profármacos/farmacología , Antineoplásicos/síntesis química , Ácido Aspártico/síntesis química , Ácido Aspártico/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Glutamatos/síntesis química , Humanos , Nucleósidos/síntesis química , Compuestos Organofosforados/síntesis química , Profármacos/síntesis química , Relación Estructura-Actividad
20.
ACS Chem Neurosci ; 7(5): 534-9, 2016 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-26918289

RESUMEN

Glutamate is the major excitatory neurotransmitter in the mammalian brain. Its rapid clearance after the release into the synaptic cleft is vital in order to avoid toxic effects and is ensured by several transmembrane transport proteins, so-called excitatory amino acid transporters (EAATs). Impairment of glutamate removal has been linked to several neurodegenerative diseases and EAATs have therefore received increased attention as therapeutic targets. O-Benzylated l-threo-ß-hydroxyaspartate derivatives have been developed previously as highly potent inhibitors of EAATs with TFB-TBOA ((2S,3S)-2-amino-3-((3-(4-(trifluoromethyl)benzamido)benzyl)oxy)succinic acid) standing out as low-nanomolar inhibitor. We report the stereoselective synthesis of all four stereoisomers of TFB-TBOA in less than a fifth of synthetic steps than the published route. For the first time, the inhibitory activity and isoform selectivity of these TFB-TBOA enantio- and diastereomers were assessed on human glutamate transporters EAAT1-3. Furthermore, we synthesized potent photoaffinity probes based on TFB-TBOA using our novel synthetic strategy.


Asunto(s)
Ácido Aspártico/análogos & derivados , Transportador 1 de Aminoácidos Excitadores/antagonistas & inhibidores , Transportador 3 de Aminoácidos Excitadores/antagonistas & inhibidores , Proteínas de Transporte de Glutamato en la Membrana Plasmática/antagonistas & inhibidores , Etiquetas de Fotoafinidad/síntesis química , Ácido Aspártico/síntesis química , Ácido Aspártico/farmacología , Química Farmacéutica , Relación Dosis-Respuesta a Droga , Transportador 1 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores , Transportador 3 de Aminoácidos Excitadores/metabolismo , Proteínas de Transporte de Glutamato en la Membrana Plasmática/metabolismo , Células HEK293 , Humanos , Etiquetas de Fotoafinidad/farmacología , Estereoisomerismo
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