scholarly journals Inhibition of Acetylcholinesterase by Coumarin-Linked Amino Acids Synthetized via Triazole Associated with Molecule Partition Coefficient

2021 ◽  
Author(s):  
Bianca de Sousa ◽  
João Leite ◽  
Tiago Mendes ◽  
Eduardo Varejão ◽  
Anna Chaves ◽  
...  
Keyword(s):  
Amino Acids ◽  
Inhibitory Activity ◽  
Molar Mass ◽  
Aromatic Amino Acids ◽  
Van Der Waals Volume ◽  
Enzymatic Inhibition ◽  
Ache Inhibitors ◽  
High Enzyme ◽  
The Impact

A previous study for the identification of acetylcholinesterase (AChE) inhibitors demonstrated that the hybrid between tyrosol, the 1,2,3-triazole nucleus, and the coumarin group, namely 7-({1-[2-(4-hydroxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}methoxy)-4-methyl-2H-chromen-2-one (10), has a high enzyme inhibitory activity. Here, we synthesized analogues of 10 via triazole with pharmacophoric groups represented by tyrosine, phenylalanine, tryptophan, and glycine in addition to evaluating the impact of coumarin-linked amino acids on AChE inhibition. We obtained eight triazoles, six of which are undescribed. In general, the presence of carboxylic acid decreased the inhibitory activity, while aromatic amino acids increased enzymatic inhibition compared to glycine. The derivative containing tyrosine, structurally most similar to 10, presented the lowest inhibition percentage, indicating that phenolic hydroxyl is not the preponderant factor for inhibition. Molecular docking was not enough to explain in vitro experiments. On the other hand, MlogP (logP calculated by the Moriguchi method) was related positively to enzymatic inhibition. To increase the hydrophobicity of the molecules, we tested the esterified triazole derivatives comparatively with the enzyme. The compound ethyl 2-(4-(((4-methyl-2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)acetate (6) presented an increment of inhibitory activity of 46.97 ± 1.75% at 100 μmol L-1. We also associated the best activity with the lowest van der Waals volume and molar mass values.

scholarly journals Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Paulo L. Pfitzinger ◽  
Laura Fangmann ◽  
Kun Wang ◽  
Elke Demir ◽  
Engin Gürlevik ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Tumor Stage ◽  
Ache Inhibitors ◽  
Impact On Survival ◽  
The Impact ◽  
Ache Expression ◽  
Cholinergic Activation

Abstract Background Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. Methods We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/−physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. Results We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. Conclusion For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.

In Vitro adsorption Spectrum of Plasma Amino Acids by Coated Charcoal Hemoperfusion

1983 ◽  
Vol 6 (5) ◽  
pp. 267-270 ◽  
Author(s):  
Z.Q. Shi ◽  
T.M.S. Chang
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Hepatic Coma ◽  
Aromatic Amino Acids ◽  
Molar Ratio ◽  
Adsorption Experiment ◽  
Preferential Adsorption ◽  
Branched Chain ◽  
Charcoal Hemoperfusion

In order to clarify wether coated charcoal hemoperfusion is capable of normalizing amino acid disturbances in hepatic coma, in vitro adsorption and in vitro hemoperfusion studies were carried out. We have found that collodion-coated activated charcoal beads preferentially removed much more aromatic acids (AAA) than branched chain amino acids (BCAA). In the in vitro adsorption experiment with 50 μM amino acid standards aqueous solution, 99% of AAAs were removed by charcoal while only 50 to 81% of BCAAs were removed. As the concentration of amino acids in solution was doubled from μM to 100 μM, BCAA removal was halved while about 90% of AAA was still being removed. In vitro hemoperfusion with heparinized blood from hepatic failure rats, the clearance and the removal of AAAs were significantly greater than those of BCAAs. Consequently, the molar ratio of BCAA over AAA was markedly improved from the initial 1.09 to 3.87 after 60 min of hemoperfusion. Thus, we have demonstrated the preferential adsorption of aromatic amino acids by collodion-coated charcoal beads. The correction of BCAA/AAA molar ratio is also demonstrated.

scholarly journals Expression of a Heterologous Glutamate Dehydrogenase Gene inLactococcus lactis Highly Improves the Conversion of Amino Acids to Aroma Compounds

2000 ◽  
Vol 66 (4) ◽  
pp. 1354-1359 ◽  
Author(s):  
Liesbeth Rijnen ◽  
Pascal Courtin ◽  
Jean-Claude Gripon ◽  
Mireille Yvon
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Glutamate Dehydrogenase ◽  
Aroma Compounds ◽  
In Vitro Tests ◽  
Limiting Factor ◽  
Keto Acid ◽  
Cheese Curd ◽  
The Impact

ABSTRACT The first step of amino acid degradation in lactococci is a transamination, which requires an α-keto acid as the amino group acceptor. We have previously shown that the level of available α-keto acid in semihard cheese is the first limiting factor for conversion of amino acids to aroma compounds, since aroma formation is greatly enhanced by adding α-ketoglutarate to cheese curd. In this study we introduced a heterologous catabolic glutamate dehydrogenase (GDH) gene into Lactococcus lactis so that this organism could produce α-ketoglutarate from glutamate, which is present at high levels in cheese. Then we evaluated the impact of GDH activity on amino acid conversion in in vitro tests and in a cheese model by using radiolabeled amino acids as tracers. The GDH-producing lactococcal strain degraded amino acids without added α-ketoglutarate to the same extent that the wild-type strain degraded amino acids with added α-ketoglutarate. Interestingly, the GDH-producing lactococcal strain produced a higher proportion of carboxylic acids, which are major aroma compounds. Our results demonstrated that a GDH-producing lactococcal strain could be used instead of adding α-ketoglutarate to improve aroma development in cheese.

An In-Frame Deletion of Six Amino Acids and a Point Mutation in the Disintegrin Domain of ADAMTS-13 Associates with a Case of Congenital Thrombotic Thromocytopenic Purpura.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 854-854
Author(s):  
Zhenyin Tao ◽  
Leticia Nolasco ◽  
Bernardo Aubrey ◽  
Lawrence Rice ◽  
Joel F. Moake ◽  
...  
Keyword(s):  
Amino Acids ◽  
Point Mutation ◽  
Active Form ◽  
White Blood Cells ◽  
In Vitro Mutagenesis ◽  
Severe Thrombocytopenia ◽  
Direct Dna Sequencing ◽  
Disintegrin Domain ◽  
The Impact

Abstract Thrombotic thrombocytopenic purpura (TTP) is characterized by severe thrombocytopenia, hemolytic anemia, and diffuse and non-focal neurological findings. Microthrombi found in these patients are predominantly composed of platelets and von Willebrand factor (VWF). Recent studies suggest that the systemic thrombosis in TTP is mostly due to the congenital or acquired deficiency of the VWF-cleaving metalloprotease ADAMTS-13, which cleaves the ultra-large and hyperreactive VWF to smaller and less active form found in plasma. Most congenital cases of TTP have so far been identified in children. Here, we report a 60-year-old Caucasian man with a history of chronic relapsing TTP over thirty years, requiring plasma transfusion every 24 days in recent years. Repeat assays showed no ADAMTS13 activity in patient’s plasma under both static and flow conditions without inhibitors being detected. We therefore examined the possible genetic defects in the ADAMTS-13 gene of this patient. Genomic DNA was extracted from patient’s white blood cells and exons of ADAMTS-13 gene were amplified by polymerase chain reaction. The amplified DNA fragments were then screened for mutations by direct DNA sequencing. We identified a deletion of 18 base pairs from G1095 to G1112 (GTGCTCCAAGGGTCGCTG) in the exon10 of ADAMTS-13 gene, resulting in a deletion of six amino acids (C366 to C371) in the disintegrin domain of the metalloprotease. A point mutation (W365C) occurred immediately before the deletion due to a nucleotide realignment. The patient is heterozygote for the deletion. This is the first report of a deletion mutant (without frame shift and truncations) in the disintegrin region that has previously been demonstrated as critical for the ADAMTS-13 function by in vitro mutagenesis, epitope mapping of autoantibody to the metalloprotease in patients with adult acquired TTP, and identification of natural occurring mutations in patients with congenital TTP. Our ongoing studies are to determine the impact of these two mutations on the synthesis, release, and cleavage of ADAMTS-13.

scholarly journals Structure/Function Analysis of the Vaccinia Virus F18 Phosphoprotein, an Abundant Core Component Required for Virion Maturation and Infectivity

2010 ◽  
Vol 84 (13) ◽  
pp. 6846-6860 ◽  
Author(s):  
Nadi T. Wickramasekera ◽  
Paula Traktman
Keyword(s):  
Amino Acids ◽  
Structure Function ◽  
Protein Interactions ◽  
Function Analysis ◽  
Aromatic Amino Acids ◽  
Protein Protein Interactions ◽  
Core Component ◽  
Virion Morphogenesis

ABSTRACT Poxvirus virions, whose outer membrane surrounds two lateral bodies and a core, contain at least 70 different proteins. The F18 phosphoprotein is one of the most abundant core components and is essential for the assembly of mature virions. We report here the results of a structure/function analysis in which the role of conserved cysteine residues, clusters of charged amino acids and clusters of hydrophobic/aromatic amino acids have been assessed. Taking advantage of a recombinant virus in which F18 expression is IPTG (isopropyl-β-d-thiogalactopyranoside) dependent, we developed a transient complementation assay to evaluate the ability of mutant alleles of F18 to support virion morphogenesis and/or to restore the production of infectious virus. We have also examined protein-protein interactions, comparing the ability of mutant and WT F18 proteins to interact with WT F18 and to interact with the viral A30 protein, another essential core component. We show that F18 associates with an A30-containing multiprotein complex in vivo in a manner that depends upon clusters of hydrophobic/aromatic residues in the N′ terminus of the F18 protein but that it is not required for the assembly of this complex. Finally, we confirmed that two PSSP motifs within F18 are the sites of phosphorylation by cellular proline-directed kinases in vitro and in vivo. Mutation of both of these phosphorylation sites has no apparent impact on virion morphogenesis but leads to the assembly of virions with significantly reduced infectivity.

scholarly journals Molecular design and virtual docking of oligopeptides for binding and elimination interleukin-6 from blood plasma

2019 ◽  
Vol 64 (3) ◽  
pp. 350-358
Author(s):  
T. V. Ryabzeva ◽  
D. A. Makarevich ◽  
E. M. Ermola ◽  
V. P. Golubovich ◽  
V. V. Kirkovskiy
Keyword(s):  
Amino Acids ◽  
Blood Plasma ◽  
Interleukin 6 ◽  
Molecular Design ◽  
Three Dimensional ◽  
Aromatic Amino Acids ◽  
Allergic Diseases ◽  
Molecular Structures ◽  
Autoimmune Pathology

Binding of interleukin-6 (IL-6) is the perspective target for the anti-inflammatory therapy in many pathological conditions (sepsis, autoimmune pathology, allergic diseases). The aim of this work was to develop and study the binding IL-6 oligopeptides. To achieve the goal, were set and successfully solved the following tasks: studying three-dimensional models of molecular structures of IL-6 incombination with the R-IL-6 and gp130, prediction and virtual synthesis low molecular weight oligopeptides; evaluating the free energy of IL-6 binding for identity the most effective oligopeptide; studying the changing the concentration of IL-6 inthe model solution after contact with experimental oligopeptides. In the article presents the binding IL-6 energy of 62 peptides, designed using the PyMol. Energy was calculated in the Chimera program using the AutodockVina application. There are also presented results of in vitro experiments interacting 7 sextapeptides, 2 tetrapeptides, and 3 tripeptides with recombinant IL-6. The effectiveness of the peptides was calculated by reducing the concentration of cytokine in solution as a percentage of the initial concentration.The free binding energy has shown that the efficiency of binding increases with an increase in the total number of amino acids and, in particular, of aromatic amino acids in the oligopeptide. Correlation analysis showed that the molecular modeling method is not absolutely effective for predicting the structure of an oligopeptide, however, it can be used as one of the preliminary steps for analyzing the interaction between molecules and studying the optimal interaction points. Two oligopeptides were identified as the most promising for further synthesis as the ligands for binding and evaluating IL-6 inhuman blood plasma.

scholarly journals Ruminal bioshynthesis of aromatic amino acids from arylacetic acids, glucose, shikimic acid and phenol

1974 ◽  
Vol 31 (3) ◽  
pp. 357-365 ◽  
Author(s):  
S. Kristensen
Keyword(s):  
Amino Acids ◽  
Acetic Acid ◽  
Phenylacetic Acid ◽  
Shikimic Acid ◽  
Aromatic Amino Acids ◽  
Hydroxyphenylacetic Acid ◽  
Arylacetic Acids ◽  
First Time ◽  
Indole 3 Acetic Acid

1. Ruminal metabolism of labelled phenylacetic acid, 4-hydroxyphenylacetic acid, indole-3-acetic acid, glucose, shikimic acid, phenol, and serine was studied in vitro by short-term incubation with special reference to incorporation rates into aromatic amino acids.2. Earlier reports on reductive carboxylation of phenylacetic acid and indole-3-acetic acid in the rumen were confirmed and the formation of tyrosine from 4-hydroxyphenylacetic acid was demonstrated for the first time.3. The amount of phenylalanine synthesized from phenylacetic acid was estimated to be 2 mg/1 rumen contents per 24 h, whereas the amount synthesized from glucose might be eight times as great, depending on diet.4. Shikimic acid was a poor precursor of the aromatic amino acids, presumably owing to its slow entry into rumen bacteria.5. A slow conversion of phenol into tyrosine was observed.

Palladium(ii) complexes bearing 1-iminothiolate-3,5-dimethylpyrazoles: synthesis, cytotoxicity, DNA binding and enzymatic inhibition studies

2020 ◽  
Vol 44 (45) ◽  
pp. 19891-19901
Author(s):  
Thales Reggiani de Moura ◽  
Renan Diego Zanetti ◽  
Debora Eduarda Soares Silva ◽  
Renan Lira de Farias ◽  
Antonio Eduardo Mauro ◽  
...  
Keyword(s):  
Dna Binding ◽  
Inhibitory Activity ◽  
In Silico ◽  
Cathepsin B ◽  
Topoisomerase Iiα ◽  
Enzymatic Inhibition ◽  
Inhibition Studies

This work describes the enzymatic inhibitory activity of four novel Pd(ii) complexes towards topoisomerase IIα and cathepsins B and L. In silico studies agree well with the enhanced in vitro cathepsin B inhibition induced by compound 4 (58% at 10 μM).

Sign in / Sign up

Export Citation Format

Share Document