Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BioTechnologia (Pozn) ; 105(1): 69-81, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38633893

RESUMO

In molecular biological studies, considerable attention is paid to macrocyclic nanoscale compounds known as calix[4]arenes. An imperative concern in biochemical membranology and molecular biotechnology is the exploration of effectors capable of modifying the intensity of redox reactions within the inner mitochondrial membrane and influencing the activity of its Ca2+ transport systems. The simulation model development is relevant to formalize and generalize the experimental data and assess the conformity of experimental results with theoretical predictions. Experiments were carried out on a suspension of isolated rat myometrial mitochondria. The synthesized thiacalix[4]arene C-1193, containing four sulfur atoms, was employed. Demonstrations of time-dependent and concentration-dependent (0.01-10 µM) inhibition of Ca2+ accumulation and reactive oxygen species (ROS) formation by mitochondria in the presence of C-1193 were observed. While C-1193 inhibited the oxidation of NADH and FADH2, it did not induce mitochondrial swelling. The thiacalix[4]arene also inhibited the synthesis of nitric oxide, with a Ki of 5.5 ± 1.7 nM, positioning it as a high-affinity blocker of endogenous NO generation in mitochondria. These results are the basis for the possible application of the synthesized thiacalix[4]arene as a tool in researching biochemical processes in mitochondria. A simulation model employing functional hybrid Petri nets was developed, reproducing the functional activity of mitochondria, including simultaneous NADH oxidation, ROS formation, NO synthesis, and Ca2+ accumulation. The derived equations formalize and describe the time dependencies of the listed processes in the medium under the influence of thiacalix[4]arene C-1193.

2.
Bioorg Med Chem Lett ; 77: 129019, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36216030

RESUMO

Calix[4]arenes bearing photoactive α-ketophosphonic acid groups at the upper rim of the macrocycle were synthesized and evaluated as inhibitors of glutathione S-transferases. Irradiation at 365 nm increased the inhibition effects of some macrocyclic compounds on GSTP1-1 by more than two orders of magnitude. Calix[4]arene bis-α-ketophosphonic acids substituted at the lower rim by n-propyl or n-butyl groups showed IC50 values in the low micromolar range. Kinetics of the irreversible inhibition was described by pseudo-first-order rate constants dependent on inhibitor concentration. The values of second-order rate constants were higher for glutathione S-transferase from human placenta than for the enzyme from equine liver. Molecular docking suggested that photoactive macrocyclic compounds cover the active site of glutathione S-transferase, providing the possibility to modify the catalytically important amino acid residues during irradiation.


Assuntos
Calixarenos , Animais , Cavalos , Humanos , Simulação de Acoplamento Molecular , Calixarenos/química , Glutationa Transferase , Transferases , Glutationa
3.
J Colloid Interface Sci ; 624: 270-278, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-35660896

RESUMO

Shape-persistent macrocycles enable superior control on molecular self-assembly, allowing the preparation of well-defined nanostructures with new functions. Here, we report on anionic amphiphilic calixarenes of conic shape and their self-assembly behavior in aqueous media for application in intracellular delivery of peptides. Newly synthesized calixarenes bearing four phosphonate groups and two or four long alkyl chains were found to form micelles of âˆ¼ 10 nm diameter, in contrast to an analogue with short alkyl chains. These amphiphilic calixarenes are able to complex model (oligo-lysine) and biologically relevant (HIV-1 nucleocapsid peptide) cationic peptides into small nanoparticles (20-40 nm). By contrast, a control anionic calixarene with short alkyl chains fails to form small nanoparticles with peptides, highlighting the importance of micellar assembly of amphiphilic calixarenes for peptide complexation. Cellular studies reveal that anionic amphiphilic calixarenes exhibit low cytotoxicity and enable internalization of fluorescently labelled peptides into live cells. These findings suggest anionic amphiphilic macrocycles as promising building blocks for the preparation of peptide delivery vehicles.


Assuntos
Calixarenos , Nanopartículas , Ânions , Calixarenos/química , Micelas , Nanopartículas/química , Peptídeos/química
4.
ACS Infect Dis ; 6(4): 687-702, 2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32045204

RESUMO

The nucleocapsid protein (NC) is a highly conserved protein that plays key roles in HIV-1 replication through its nucleic acid chaperone properties mediated by its two zinc fingers and basic residues. NC is a promising target for antiviral therapy, particularly to control viral strains resistant to currently available drugs. Since calixarenes with antiviral properties have been described, we explored the ability of calixarene hydroxymethylphosphonic or sulfonic acids to inhibit NC chaperone properties and exhibit antiviral activity. By using fluorescence-based assays, we selected four calixarenes inhibiting NC chaperone activity with submicromolar IC50 values. These compounds were further shown by mass spectrometry, isothermal titration calorimetry, and fluorescence anisotropy to bind NC with no zinc ejection and to compete with nucleic acids for the binding to NC. Molecular dynamic simulations further indicated that these compounds interact via their phosphonate or sulfonate groups with the basic surface of NC but not with the hydrophobic plateau at the top of the folded fingers. Cellular studies showed that the most soluble compound CIP201 inhibited the infectivity of wild-type and drug-resistant HIV-1 strains at low micromolar concentrations, primarily targeting the early steps of HIV-1 replication. Moreover, CIP201 was also found to inhibit the flipping and polymerization activity of reverse transcriptase. Calixarenes thus form a class of noncovalent NC inhibitors, endowed with a new binding mode and multitarget antiviral activity.


Assuntos
Fármacos Anti-HIV/farmacologia , Calixarenos/farmacologia , HIV-1/química , Chaperonas Moleculares/antagonistas & inibidores , Proteínas do Nucleocapsídeo/antagonistas & inibidores , Organofosfonatos/farmacologia , Animais , Calixarenos/classificação , HIV-1/efeitos dos fármacos , Concentração Inibidora 50 , Camundongos , Camundongos Transgênicos , Simulação de Dinâmica Molecular , Ligação Proteica
5.
Org Biomol Chem ; 12(48): 9811-21, 2014 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-25335911

RESUMO

The action of calix[4]arenes C-91, C-97, C-99, C-107 and C-160 on solvent-containing planar bilayer membranes made of cholesterol and egg phosphatidylcholine (egg PC) or synthetic 18-carbon-tail phospholipid DOPC has been investigated in a voltage-clamp mode. Within the range of calix[4]arenes tested, a steady-state voltage-dependent transmembrane current was achieved only after addition of calix[4]-arene C-99 (calix[4]arene-bis-hydroxymethylphosphonic acid) from the side of the membrane the positive potential was applied to. This current exhibited anion selectivity passing more chloride at negative potentials applied from the side of the membrane to which calix[4]arene C-99 was introduced. The kinetics and temperature-dependence determined for calix[4]arene C-99-mediated ionic transport suggest a carrier mode of facilitated diffusion.


Assuntos
Calixarenos/química , Bicamadas Lipídicas/química , Ânions/química , Colesterol/química , Cinética , Conformação Molecular , Óvulo/química , Fosfatidilcolinas/química , Temperatura
6.
Bioorg Med Chem Lett ; 23(20): 5619-23, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24012179

RESUMO

Сalix[4]arenes bearing methylenebisphosphonic or hydroxymethylenebisphosphonic acid fragments at the wide rim of the macrocycle were studied as inhibitors of PTP1B. Some of the inhibitors showed IC50 values in the micromolar range and good selectivity in comparison with other protein tyrosine phosphatases such as TC-PTP, PTPß, LAR, and CD45. Kinetic studies indicated that the calix[4]arene derivatives influence PTP1B activity as slow-binding inhibitors. Based on molecular docking results, the binding modes of the macrocyclic bisphosphonates in the active centre of PTP1B are discussed.


Assuntos
Calixarenos/química , Difosfonatos/química , Inibidores Enzimáticos/química , Fenóis/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Sítios de Ligação , Difosfonatos/síntese química , Difosfonatos/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
7.
Bioorg Med Chem Lett ; 20(2): 483-7, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20015646

RESUMO

Inhibition of Yersinia protein tyrosine phosphatase by calix[4]arene mono-, bis-, and tetrakis(methylenebisphosphonic) acids as well as calix[4]arene and thiacalix[4]arene tetrakis(methylphosphonic) acids have been investigated. The kinetic studies revealed that some compounds in this class are potent competitive inhibitors of Yersinia PTP with inhibition constants in the low micromolar range. The binding modes of macrocyclic phosphonate derivatives in the enzyme active center have been explained using computational docking approach. The results obtained indicate that calix[4]arenes are promising scaffolds for the development of inhibitors of Yersinia PTP.


Assuntos
Calixarenos/química , Inibidores Enzimáticos/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Sítios de Ligação , Calixarenos/farmacologia , Simulação por Computador , Inibidores Enzimáticos/farmacologia , Cinética , Organofosfonatos/química , Proteínas Tirosina Fosfatases/metabolismo , Yersinia/efeitos dos fármacos
8.
Org Lett ; 8(4): 549-52, 2006 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-16468708

RESUMO

[structure: see text] Chiral calix[4]arene alpha-aminophosphonic acids were obtained through diastereoselective Pudovik-type addition of sodium ethyl phosphites to the chiral calixarene imines, removal of chiral auxiliary groups, and mild dealkylation of phosphonate fragments. The diacids obtained show inhibitory activity toward porcine kidney alkaline phosphatase that depends considerably on the absolute configuration of the alpha-carbon atoms.


Assuntos
Fosfatase Alcalina/antagonistas & inibidores , Calixarenos/síntese química , Calixarenos/farmacologia , Rim/enzimologia , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Fosfitos/química , Fosfatase Alcalina/metabolismo , Animais , Calixarenos/química , Calixarenos/farmacocinética , Estrutura Molecular , Organofosfonatos/química , Organofosfonatos/farmacocinética , Estereoisomerismo , Suínos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...