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1.
Phys Chem Chem Phys ; 22(11): 6154-6166, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32124897

RESUMO

The antibacterial activity of a calixarene derivative, p-tert-butylcalix[6]arene (Calix6), was assessed and was shown not to inhibit the growth of E. coli, S. aureus and B. subtilis bacteria. With the aim of gaining more insights into the absence of antibacterial activity of Calix6, the interaction of this derivative with DPPG, a bacterial cell membrane lipid, was studied. Langmuir monolayers were used as the model membrane. Pure DPPG and pure Calix6 monolayers, as well as binary DPPG:Calix6 mixtures were studied using surface pressure measurements, compressional modulus, Brewster angle and fluorescence microscopies, ellipsometry, polarization-modulation infrared reflection absorption spectroscopy and molecular dynamics simulations. Thermodynamic properties of the mixed monolayers were additionally calculated using thermodynamic parameters. The analysis of isotherms showed that Calix6 significantly affects the DPPG monolayers, modifying the isotherm profile and increasing the molecular area, in agreement with the molecular dynamics simulations. The presence of Calix6 in the mixed monolayers decreased the interfacial elasticity, indicating that calixarene disrupts the strong intermolecular interactions of DPPG hindering its organization into a compact arrangement. At low molar ratios of Calix6, the DPPG:Calix6 interactions are preferentially attractive, due to the interactions between the hydrophobic tails of DPPG and the tert-butyl groups of Calix6. Increasing the proportion of calixarene generates repulsive interactions. Calix6 significantly affects the hydrophobic tail organization, which was confirmed by PM-IRRAS measurements. Calix6 appears to be expelled from the mixed films at a biologically relevant surface pressure, π = 30 mN m-1, indicating a low interaction with the cell membrane model related to the absence of antibacterial activity.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Calixarenos/química , Calixarenos/farmacologia , Membrana Celular/efeitos dos fármacos , Membranas Artificiais , Simulação de Dinâmica Molecular , Termodinâmica
2.
Ecotoxicol Environ Saf ; 192: 110328, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32078840

RESUMO

In this study pillar[5]arene (P5) and a quinoline-functionalized pillar[5]arene (P5-6Q) which is used for detecting radioactive element, gas adsorption and toxic ions were synthesized. These materials were characterized by Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared (FTIR), elemental analysis, melting point, Mass Spectroscopy, Scanning Electron Microscopy (SEM) and Zeta Potential. The cytotoxic and genotoxic potential of P5 and P5-6Q at distinct concentrations of 12.5, 25, 50, and 100 µg/mL were also investigated by Allium ana-telophase and comet assays on Allium cepa roots and Drosophila melanogaster haemocytes. P5 and P5-6Q showed dose dependent cytotoxic effect by decreasing mitotic index (MI) and genotoxic effect by increasing chromosomal aberrations (CAs such as disturbed anaphase-telophase, polyploidy, stickiness, chromosome laggards and bridges) and DNA damage at the exposed concentrations. These changes in P5-6Q were lower than P5. Further research is necessary to clarify the cytotoxic and genotoxic action mechanisms of P5 and P5-6Q at molecular levels.


Assuntos
Calixarenos/toxicidade , Dano ao DNA , Drosophila melanogaster/efeitos dos fármacos , Cebolas/efeitos dos fármacos , Anáfase/efeitos dos fármacos , Animais , Calixarenos/química , Aberrações Cromossômicas , Ensaio Cometa , Citotoxinas/química , Citotoxinas/toxicidade , Drosophila melanogaster/genética , Hemócitos/efeitos dos fármacos , Índice Mitótico , Cebolas/genética , Raízes de Plantas/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/química , Quinolinas/toxicidade , Telófase/efeitos dos fármacos
3.
Chem Soc Rev ; 49(3): 865-907, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31957756

RESUMO

Supramolecular chemistry is a central topic in modern chemistry. It touches on many traditional disciplines, such as organic chemistry, inorganic chemistry, physical chemistry, materials chemistry, environmental chemistry, and biological chemistry. Supramolecular hosts, inter alia macrocyclic hosts, play critical roles in supramolecular chemistry. Calix[4]pyrroles, non-aromatic tetrapyrrolic macrocycles defined by sp3 hybridized meso bridges, have proved to be versatile receptors for neutral species, anions, and cations, as well as ion pairs. Compared to the parent system, octamethylcalix[4]pyrrole and its derivatives bearing simple appended functionalities, strapped calix[4]pyrroles typically display enhanced binding affinities and selectivities. In this review, we summarize advances in the design and synthesis of strapped calix[4]pyrroles, as well as their broad utility in molecular recognition, supramolecular extraction, separation technology, ion transport, and as agents capable of inhibiting cancer cell proliferation. Future challenges within this sub-field are also discussed.


Assuntos
Calixarenos/química , Calixarenos/metabolismo , Porfirinas/química , Porfirinas/metabolismo , Ânions/química , Apoptose , Cátions/química , Permeabilidade da Membrana Celular , Cristalização , Modelos Moleculares , Estrutura Molecular , Compostos Orgânicos/química , Relação Estrutura-Atividade , Termodinâmica
4.
Chemistry ; 26(14): 3022-3025, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-31944456

RESUMO

This work describes a calix[6]arene-based wheel that binds, in non-polar media, a stilbazolium salt to yield a mixture of pseudorotaxane orientational isomers. The isomer's abundance ratio evolves with time and can be reversibly tuned by adjusting the temperature. The spectroscopic properties, and notably the emission spectrum, of the bound guest depend on its orientation inside the non-palindromic wheel, suggesting such a system as a switch with spectroscopic readout.


Assuntos
Calixarenos/química , Corantes Fluorescentes/química , Fenóis/química , Rotaxanos/química , Cinética , Estrutura Molecular , Espectrometria de Fluorescência , Estereoisomerismo , Temperatura , Termodinâmica
5.
Spectrochim Acta A Mol Biomol Spectrosc ; 224: 117390, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31336324

RESUMO

A quinoline functionalized pillar[5]arene, QPA has been prepared and its interaction with biologically relevant ions and molecules in aqueous solution has been demonstrated. The sensor molecule, QPA has shown selectivity towards Fe3+ among eleven metal ions studied. The Fe3+ complex of QPA (FeQPA) selectively interacts with F- among halides by ∼4 fold fluorescence enhancement. Further, FeQPA has shown selectivity towards arginine and lysine among twenty naturally occurring amino acids. The binding of QPA with Fe3+ has been confirmed by MALDI-TOF and 1H NMR titrations.


Assuntos
Aminoácidos Básicos/análise , Calixarenos/química , Fluoretos/análise , Ferro/análise , Quinolinas/química , Ferro/química , Limite de Detecção , Espectrometria de Fluorescência , Água/química
6.
Nat Commun ; 10(1): 5762, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848349

RESUMO

Perfluorinated alkyl substances, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), are toxic materials that are known to globally contaminate water, air, and soil resources. Strategies for the simultaneous detection and removal of these compounds are desired to address this emerging health and environmental issue. Herein, we develop a type of guanidinocalix[5]arene that can selectively and strongly bind to PFOS and PFOA, which we use to demonstrate the sensitive and quantitative detection of these compounds in contaminated water through a fluorescent indicator displacement assay. Moreover, by co-assembling iron oxide nanoparticle with the amphiphilic guanidinocalix[5]arene, we are able to use simple magnetic absorption and filtration to efficiently remove PFOS and PFOA from contaminated water. This supramolecular approach that uses both molecular recognition and self-assembly of macrocyclic amphiphiles is promising for the detection and remediation of water pollution.


Assuntos
Ácidos Alcanossulfônicos/análise , Calixarenos/química , Caprilatos/análise , Fluorcarbonetos/análise , Tensoativos/química , Poluentes Químicos da Água/análise , Absorção Fisico-Química , Ácidos Alcanossulfônicos/isolamento & purificação , Caprilatos/isolamento & purificação , Monitorização de Parâmetros Ecológicos/métodos , Poluição Ambiental/prevenção & controle , Compostos Férricos/química , Filtração/instrumentação , Filtração/métodos , Fluorcarbonetos/isolamento & purificação , Nanopartículas de Magnetita/química , Água/análise , Água/química , Poluentes Químicos da Água/isolamento & purificação , Poluição Química da Água/prevenção & controle
7.
Chem Commun (Camb) ; 55(95): 14275-14278, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31720595

RESUMO

The amelioration of antibacterial efficacy along with the reduced minimum inhibitory concentration (MIC) of sanguinarine (SGR) drug have been demonstrated through the uptake of SGR by p-sulfonatocalix[6]arene functionalized silver nanoparticles. The large upward pKa shift and enhanced stability of SGR resulting from the favorable supra-nanomolecular strategy are deciphered into an improved antibacterial drug against different pathogenic micro-organisms including multi drug resistant bacteria.


Assuntos
Antibacterianos/farmacologia , Benzofenantridinas/farmacologia , Calixarenos/química , Escherichia coli/efeitos dos fármacos , Isoquinolinas/farmacologia , Nanopartículas Metálicas/química , Fenóis/química , Prata/química , Staphylococcus aureus/efeitos dos fármacos , Células A549 , Animais , Antibacterianos/química , Benzofenantridinas/química , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Sinergismo Farmacológico , Humanos , Isoquinolinas/química , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Propriedades de Superfície
8.
Chem Commun (Camb) ; 55(95): 14387-14390, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31723950

RESUMO

We designed a tandem stimuli-responsive assembly based on a guanidinium-modified calix[5]arene (GC5A-6C) and eosin Y modified hyaluronic acid (EY-HA), which showed hyaluronidase-triggered disassembly and ATP-activated release of EY. Both hyaluronidase and ATP are tumor biomarkers, and therefore, the present system shows potential in precision delivery with respect to tumor phototheranostics.


Assuntos
Trifosfato de Adenosina/metabolismo , Calixarenos/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Guanidina/metabolismo , Ácido Hialurônico/metabolismo , Hialuronoglucosaminidase/metabolismo , Trifosfato de Adenosina/química , Biomarcadores Tumorais/química , Biomarcadores Tumorais/metabolismo , Calixarenos/química , Amarelo de Eosina-(YS)/química , Guanidina/química , Humanos , Ácido Hialurônico/química , Hialuronoglucosaminidase/química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/metabolismo , Polímeros/química , Polímeros/metabolismo , Nanomedicina Teranóstica , Microambiente Tumoral
9.
Inorg Chem ; 58(21): 14720-14727, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31613605

RESUMO

Although alkaline earth metal cations play an important role in our daily life, little attention has been paid to the field of fast quantitative analysis of their content due to a lack of satisfactory precision and a fast and convenient means of detection. In this study, we have designed a set of molecular tweezers based on the calix[4]arene chemosensor L, which was found to exhibit high selectivity and sensitivity toward Ca2+, Sr2+, and Ba2+ (by UV-vis and fluorescence methods) with low detection limits of the order of 10-7 to 10-8 M and high association constants (of the order of 106). More significantly, sensor L not only can recognize Ca2+, Sr2+, and Ba2+ but also can further discriminate between these three cations via the differing red shifts in their UV-vis spectra (560 nm for L·Ca2+, 570 nm for L·Sr2+, and 580 nm for L·Ba2+ complex) which is attributed to their different atomic radii. A rare synergistic effect for the recognition mechanism has been demonstrated by 1H NMR spectroscopic titration. Sensor L constructed a high shielding field by the cooperation of Tris with alkaline earth metal ion after complex. Additionally, the presence of acetoxymethyl group in sensor L results in enhancement of cell permeability, and as a consequence, sensor L exhibited excellent sensing and imaging (in vivo) in living cells and in zebrafish.


Assuntos
Bário/análise , Cálcio/análise , Calixarenos/química , Metais Alcalinoterrosos/química , Imagem Óptica , Compostos Organometálicos/química , Fenóis/química , Estrôncio/análise , Animais , Sobrevivência Celular , Células HeLa , Humanos , Compostos Organometálicos/síntese química , Células Tumorais Cultivadas , Peixe-Zebra
10.
Soft Matter ; 15(41): 8197-8200, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31613305

RESUMO

A series of supramolecular assemblies based on multi-charged calixarene (SC4A), bis(p-calixarene) (BSC4A) and pillararene (CP5A) modified gold nanoparticles (AuNP) was constructed to realize colorimetric sensing of both succinylcholine (SuCh) and butyrylcholinesterase (BChE). With the high binding affinity of BSC4A and CP5A towards SuCh, BSC4A-AuNPs and CP5A-AuNPs could assemble with micromolar level SuCh as SuCh-BSC4A/CP5A-AuNPs. More interestingly, the enzymatic hydrolysis of SuCh by BChE could lead to the disassembly of SuCh-BSC4A/CP5A-AuNPs and provide a sensitive time-dependent color change from blue to red which could be observed by the naked eye and used to monitor BChE activity. As BChE activity is an important biomarker for diseases and poor health conditions, this novel supramolecular tandem colorimetric sensing strategy may have potential use for early diagnosis of diseases.


Assuntos
Butirilcolinesterase/análise , Calixarenos/química , Corantes/química , Ouro/química , Nanopartículas Metálicas/química , Técnicas Biossensoriais/métodos , Colorimetria , Concentração de Íons de Hidrogênio , Cinética , Succinilcolina/análise , Propriedades de Superfície
11.
ACS Appl Mater Interfaces ; 11(42): 38497-38502, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31556585

RESUMO

A charge-reversal amphiphilic pillar[5]arene, P5NH-DCA, bearing 10 charge-reversal headgroups is reported. It targets the cell membrane of cancer cells and selectively destroys the cancer cells by disrupting the membrane. In the acidic tumor microenvironment, the headgroup charge of P5NH-DCA reversed from negative to positive owing to hydrolysis of the acid-labile amide group. The hydrolyzed product bearing multiple positive charges can bind to the cell membrane and then disrupt the membrane of cancer cells with high efficiency. However, under the neutral microenvironment of healthy cells, the negatively charged P5NH-DCA remains stable and the cytotoxicity is considerably reduced. The strategy killing the cancer cells by membrane disruption may represent a new route of cancer chemotherapy.


Assuntos
Calixarenos/química , Membrana Celular/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Calixarenos/farmacologia , Calixarenos/uso terapêutico , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Microscopia Confocal , Neoplasias/tratamento farmacológico
12.
Carbohydr Polym ; 223: 115071, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31427015

RESUMO

Methylimidazolium side groups were grafted via ether linkage to dextran and the self-assembly of these polymers with 4-sulfonato-calix[n]arenes (SCXn) was studied in aqueous solutions. Dynamic light scattering and zeta potential measurements revealed the mixing ratio ranges of the constituents where stable nanoparticles could be created. The macrocycle size of SCXn and the molecular mass of the polymer barely affected the nanoparticle diameter, but the lowering of the imidazolium degree of substitution substantially diminished the stability of the associates. The pH change from neutral to acidic also unfavourably influenced the self-organization owing mainly to the decrease of the SCXn charge. Cryogenic transmission electron microscopy images proved the spherical morphology of the nanoproducts in which the stoichiometry of the constituents was always close to the one corresponding to charge compensation. The flexible and positively charged dextran-chains are compacted by the polyanionic SCXn. Coralyne, a pharmacologically important alkaloid was efficiently embedded by self-assembly in the produced nanoparticles reaching 99% association efficiency.


Assuntos
Benzenossulfonatos/química , Calixarenos/química , Dextranos/química , Portadores de Fármacos/química , Imidazóis/química , Nanopartículas/química , Alcaloides de Berberina/química , Dextranos/síntese química , Concentração de Íons de Hidrogênio , Imidazóis/síntese química
13.
Int J Biol Macromol ; 139: 75-84, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369782

RESUMO

Resorcinarenes are macrocyclic molecules that can bind different molecules in a supramolecular fashion. There are some sulfonated water-soluble derivatives that have been investigated to bind proteins avoiding fibrillation. The interaction with enzymes such as catalase (CAT) allows the interpretation of the possible effects of the use of resorcinarenes on human health or environmental applications. The interaction of five sulfonated resorcinarenes with different chemical structures was investigated by using different biophysical methods. The results of the spectroscopic experiments (fluorescence, synchronous fluorescence, and Uv-vis spectrophotometry) show different degrees of structural change, indicating that the binding of the macrocycles that were studied causes alterations on the conformation of CAT. The resorcinarenes reduce the activity of CAT in different extent, two macrocycles (named Na4EtRA and Na4PrRA, according to ethyl or propyl moieties at the lower pendant group) exhibit significant inhibition capacity (until ca. 70%). The study about inhibition types reveals a non-competitive mechanism for all the studied resorcinarenes. The docking calculations reveal that the macrocycles bond mainly to two domains of the CAT structure, which are not related with the active site.


Assuntos
Calixarenos/química , Calixarenos/metabolismo , Catalase/metabolismo , Fígado/enzimologia , Fenilalanina/análogos & derivados , Ácidos Sulfônicos/química , Água/química , Animais , Calixarenos/farmacologia , Catalase/química , Bovinos , Simulação de Acoplamento Molecular , Fenilalanina/química , Fenilalanina/metabolismo , Fenilalanina/farmacologia , Ligação Proteica , Conformação Proteica , Solubilidade
14.
Org Biomol Chem ; 17(32): 7482-7492, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31364652

RESUMO

A calix[4]arene scaffold, blocked in the cone conformation and decorated at the upper rim with two acylguanidine units, effectively catalyzes the cleavage of phosphodiester bonds of HPNP and BNPP under neutral pH conditions. The catalyst performance is discussed in terms of acceleration over background hydrolysis and effective molarity (EM). The combination of potentiometric acid-base titrations with pH-rate profiles for HPNP and BNPP cleavage in the presence of 2·2HCl additives points to a marked synergic action of an acylguanidine/acylguanidinium catalytic dyad in 2H+, via general base-electrophilic bifunctional catalysis. Acceleration factors over background larger than 3 orders of magnitude are obtained. The connection of the guanidine/guanidinium dyad to the calixarene scaffold by means of carbonyl joints has a double advantage: (i) the acidity of the guanidinium moiety is enhanced by the electron-withdrawing carbonyl group and maximum conversion into the catalytically active form 2H+ occurs at almost neutral pH, lower than the pH needed for the monoprotonated form 1H+ devoid of carbonyl groups; (ii) the EM value for HPNP cleavage with 2H+ is definitely higher than that with 1H+, suggesting a highly preorganized catalyst that perfectly fits in a strainless ring-shaped transition state in the catalyzed process. DFT calculations also provide useful insights into the reaction mechanisms and transition states.


Assuntos
Calixarenos/química , DNA/química , Guanidinas/química , Organofosfatos/química , Fenóis/química , RNA/química , Catálise , Simulação por Computador , Teoria da Densidade Funcional , Hidrólise , Cinética , Conformação Molecular
15.
Int J Nanomedicine ; 14: 5817-5829, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440049

RESUMO

Purpose: Acetylcholinesterase (AChE) plays a critical role in the transmission of nerve impulse at the cholinergic synapses. Design and synthesis of AChE inhibitors that increase the cholinergic transmission by blocking the degradation of acetylcholine can serve as a strategy for the treatment of AChE-associated disease. Herein, an operational targeted drug delivery platform based on AChE-responsive system has been presented by combining the unique properties of enzyme-controlled mesoporous silica nanoparticles (MSN) with clinical-used AChE inhibitor. Methods: Functionalized MSNs were synthesized by liquid phase method and characterized by using different analytical methods. The biocompatibility and cytotoxicity of MSNs were determined by hemolysis experiment and MTT assay, respectively. Comparison of AChE activity between drug-loading system and inhibitor was developed with kits and by ELISA method. The efficacy of drug-loaded nanocarriers was investigated in a mouse model. Results: Compared with AChE inhibitor itself, the inhibition efficiency of this drug delivery system was strongly dependent on the concentration of AChE. Only AChE with high concentration could cause the opening of pores in the MSN, leading to the controlled release of AChE inhibitor in disease condition. Critically, the drug delivery system can not only exhibit long duration of drug action on AChE inhibition but also reduce the hepatotoxicity in vivo. Conclusion: In summary, AChE-responsive drug release systems have been far less explored. Our results would shed lights on the design of enzyme controlled-release multifunctional system for enzyme-associated disease treatment.


Assuntos
Acetilcolinesterase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Portadores de Fármacos/química , Fígado/patologia , Fosfatase Alcalina/sangue , Animais , Aspartato Aminotransferases/sangue , Calixarenos/química , Sobrevivência Celular , Doença Hepática Induzida por Substâncias e Drogas/patologia , Liberação Controlada de Fármacos , Fluoresceína/química , Hemólise , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/ultraestrutura , Fenóis/química , Porosidade , Ratos , Dióxido de Silício/química , Temperatura , Fatores de Tempo
16.
Chemistry ; 25(58): 13285-13289, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31441974

RESUMO

A calix[4]arene ligand, in which two of the phenol functions are replaced by pyrazole units has been employed to mimic the His2 -Tyr2 (His: histidine, Tyr: tyrosine) ligand sphere within the active site of the galactose oxidase (GO). The calixarene backbone forces the corresponding copper(II) complex into a see-saw-type structure, which is hitherto unprecedented in GO modelling chemistry. It undergoes a one-electron oxidation that is centered at the phenolate donor leading to a copper-coordinated phenoxyl radical like in the GO. Accordingly, the complex was tested as a functional model and indeed proved capable of oxidizing benzyl alcohol to the respective aldehyde using two phenoxyl-radical equivalents as oxidants. Finally, the results show that the calixarene platform can be utilized to arrange donor functions to biomimetic binding pockets that allow for the creation of novel types of model compounds.


Assuntos
Calixarenos/química , Galactose Oxidase/química , Oxigênio/química , Aldeídos/química , Sequência de Aminoácidos , Catálise , Domínio Catalítico , Complexos de Coordenação/química , Cobre/química , Técnicas Eletroquímicas/métodos , Ligantes , Modelos Moleculares , Estrutura Molecular , Níquel/química , Oxirredução , Fenóis/química , Ligação Proteica , Zinco/química
17.
Phys Chem Chem Phys ; 21(41): 22711-22721, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31454001

RESUMO

Peptide appended pillar[5]arene (PAP) is an artificial water channel resembling biological water channel proteins, which has shown a significant potential for designing bioinspired water purification systems. Given that PAP channels need to be incorporated at a high density in membrane matrices, it is critical to examine the role of channel-channel and channel-membrane interactions in governing the structural and functional characteristics of channels. To resolve the atomic-scale details of these interactions, we have carried out atomistic molecular dynamics (MD) simulations of multiple PAP channels inserted in a lipid or a block-copolymer (BCP) membrane matrix. Classical MD simulations on a sub-microsecond timescale showed clustering of channels only in the lipid membrane, but enhanced sampling MD simulations showed thermodynamically-favorable dimerized states of channels in both lipid and BCP membranes. The dimerized configurations of channels, with an extensive buried surface area, were stabilized via interactions between the aromatic groups in the peptide arms of neighboring channels. The conformational metrics characterizing the orientational and structural changes in channels revealed a higher flexibility in the lipid membrane as opposed to the BCP membrane although hydrogen bonds between the channel and the membrane molecules were not a major contributor to the stability of channels in the BCP membrane. We also found that the channels undergo wetting/dewetting transitions in both lipid and BCP membranes with a marginally higher probability of undergoing a dewetting transition in the BCP membrane. Collectively, these results highlight the role of channel dynamics in governing channel-channel and channel-membrane interfacial interactions, and provide atomic-scale insights needed to design stable and functional biomimetic membranes for efficient separations.


Assuntos
Aquaporinas/química , Calixarenos/química , Membrana Celular/química , Aquaporinas/metabolismo , Biomimética , Membrana Celular/metabolismo , Modelos Moleculares , Conformação Molecular , Simulação de Dinâmica Molecular
18.
Nat Commun ; 10(1): 3546, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391464

RESUMO

Polyamines are essential for the growth of eukaryotic cells and can be dysregulated in tumors. Here we describe a strategy to deplete polyamines through host-guest encapsulation using a peptide-pillar[5]arene conjugate (P1P5A, P1 = RGDSK(N3)EEEE) as a supramolecular trap. The RGD in the peptide sequence allows the molecule to bind to integrin αvß3-overexpressing tumor cells. The negative charged glutamic acid residues enhance the inclusion affinities between the pillar[5]arene and cationic polyamines via electrostatic interactions and facilitate the solubility of the conjugate in aqueous media. The trap P1P5A efficiently encapsulates polyamines with association constants of 105-106 M-1. We show that P1P5A has a wide spectrum of antitumor activities, and induces apoptosis via affecting the polyamine biosynthetic pathway. Experiments in vivo show that P1P5A effectively inhibits the growth of breast adenocarcinoma xenografts in female nude mice. This work reveals an approach for suppressing tumor growth by using supramolecular macrocycles to trap polyamines in tumor cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Poliaminas/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Vias Biossintéticas/efeitos dos fármacos , Neoplasias da Mama/patologia , Calixarenos/química , Calixarenos/farmacologia , Calixarenos/uso terapêutico , Cátions/química , Cátions/metabolismo , Feminino , Humanos , Integrina alfaVbeta3/metabolismo , Células MCF-7 , Camundongos , Camundongos Nus , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Poliaminas/química , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Drug Des Devel Ther ; 13: 2283-2293, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371922

RESUMO

Background: Trazodone (TRZ) is a second-generation non-tricyclic antidepressant derived from a triazolopyridine derivative, which is mainly used to treat emotional disorders and conditions related to depressive disorders. Purpose: This study investigated the design, development and characteristics of polyvinyl chloride (PVC) membrane sensors for trazodone HCl (TRZ). Methods: The developed sensing membranes were constructed using ß-cyclodextrin (ß-CD; sensor 1), γ-cyclodextrin (γ-CD; sensor 2) or 4-tert-butylcalix[8]arene (t-BC8; sensor 3) ionophores as sensing materials in addition to ionic sites and dioctyl phthalate in the PVC matrix. Results: Sensors 1, 2 and 3 displayed fast, stable and near-Nernstian response over a relatively wide trazodone concentration range (7.0×10-6-1×10-3, 5.0×10-5-1×10-3and 8.0×10-6-1.0×10-3 M, respectively), with detection limits of 2.2×10-6, 1.5×10-5 and 2.42×10-6 M, respectively in the pH range of 3.0-6.0. The sensors demonstrated good selectivity for TRZ in the presence of different ionic compounds. The accuracy and precision of the proposed sensors were assessed by the determination of 40.7 µg/ml of TRZ, which showed average recoveries of 99.6%, 99.1% and 98.5% with mean relative standard deviations of 2.4%, 2.5% and 2.6% for sensor 1, 2 and 3 respectively. Molecular modeling was used to calculate the host-guest binding energy. The lowest free binding energy was -6.243, -5.752 and -5.7105 kcal/mol for 1:1 stoichiometry host-guest complexes of trazodone and ß-CD, γ-CD and t-BC8, respectively, which was in-line with a Nernstian response. Conclusion: The investigated methods can be applied for the determination of TRZ in pharmaceutical preparations. The results of investigated dosage-form of TRZ show good agreement with those using the US Pharmacopeia method.


Assuntos
Técnicas Biossensoriais , Calixarenos/química , Ionóforos/química , Trazodona/análise , Trazodona/química , beta-Ciclodextrinas/química , gama-Ciclodextrinas/química , Estrutura Molecular
20.
Dalton Trans ; 48(32): 12040-12049, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31292575

RESUMO

Quadruplex nucleic acids - DNA/RNA secondary structures formed in guanine rich sequences - proved to have key roles in the biology of cancers and, as such, in recent years they emerged as promising targets for small molecules. Many reports demonstrated that metal complexes can effectively stabilize quadruplex structures, promoting telomerase inhibition, downregulation of the expression of cancer-related genes and ultimately cancer cell death. Although extensively explored as anticancer agents, studies on the ability of ruthenium arene complexes to interact with quadruplex nucleic acids are surprisingly almost unknown. Herein, we report on the synthesis and characterization of four novel Ru(ii) arene complexes with 1,3-dioxoindan-2-carboxamides ligands bearing pendant naphthyl-groups designed to bind quadruplexes by both stacking and coordinating interactions. We show how improvements on the hydrolytic stability of such complexes, by substituting the chlorido leaving ligand with pyridine, have a dramatic impact on their interaction with quadruplexes and on their cytotoxicity against ovarian cancer cells.


Assuntos
Antineoplásicos/farmacologia , Calixarenos/farmacologia , Complexos de Coordenação/farmacologia , Quadruplex G , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Calixarenos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Estrutura Molecular , Rutênio/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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