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1.
J Am Chem Soc ; 146(19): 13580-13587, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38687470

RESUMO

CO2 reacts with simple amines in the presence of water to generate dynamic combinatorial libraries of majority (i.e., ammonium carbamates) and minority (i.e., ammonium carbonates) nonisoenergetic covalent adducts. Over the past two decades, our laboratory has reported on a new class of cavitands, namely, dyn[n]arenes, from which a polyanionic macrocycle is a highly efficient receptor for linear polyammoniums that forms [2]pseudorotaxanes in water at neutral pH. Herein, we demonstrate that the formation of [2]pseudorotaxanes shifts the equilibrium of CO2 capture by polyamines in water toward the quasi-exclusive formation of carbonate adducts, providing the first example of a switch between two competitive and reversible covalent processes triggered by host-guest interactions. In addition, this supramolecular approach to CO2 capture exhibits enhanced capture efficiency by increasing the state of protonation of complexed vs uncomplexed polyamines. Altogether, we report here that a templating approach can divert the outcome of two reversible covalent chemistries involving nucleophilic additions and acid-base reactions, challenging therefore the common knowledge that noncovalent and covalent bonds operate in separate energy frames.

2.
J Enzyme Inhib Med Chem ; 33(1): 370-375, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29336193

RESUMO

Phenazine is known to regroup planar nitrogen-containing heterocyclic compounds. It was used here to enhance the bioavailability of the biologically important compound iodinin, which is near insoluble in aqueous solutions. Its water solubility has led to the development of new formulations using diverse amphiphilic α-cyclodextrins (CDs). With the per-[6-desoxy-6-(3-perfluorohexylpropanethio)-2,3-di-O-methyl]-α-CD, we succeeded to get iodinin-loaded nanoformulations with good parameters such as a size of 97.9 nm, 62% encapsulation efficiency and efficient control release. The study presents an interesting alternative to optimizing the water solubility of iodinin by chemical modifications of iodinin.


Assuntos
Nanopartículas/química , Fenazinas/química , alfa-Ciclodextrinas/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Estrutura Molecular , Tamanho da Partícula , Fenazinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Propriedades de Superfície , alfa-Ciclodextrinas/farmacologia
3.
J Org Chem ; 81(2): 654-61, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26691558

RESUMO

A family of p-cyclophanes based on bis- or tetrafunctionalized 1,4-bisthiophenol units linked by disulfide bridges was obtained by self-assembly on a gram scale and without any chromatographic purification. The nature of the functionalities borne by these so-called dyn[4]arenes plays a crucial role on their structural features as well as their molecular recognition abilities. Tuning these functions on demand yields tailored receptors for cations, anions, or zwitterions in organic or aqueous media.

4.
Molecules ; 20(11): 20269-85, 2015 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-26569209

RESUMO

Cyclodextrins, even the 6-membered α-cyclodextrin, are approved in the various pharmacopoeias as pharmaceutical excipients for solubilizing and stabilizing drugs as well as for controlling drug release. Recently α-cyclodextrin has also been marketed as health food with beneficial effects on blood lipid profiles. However, the concentration of α-cyclodextrin used may be very high in these cases, and its toxic attributes have to be seriously considered. The objective of this study was to investigate the cytotoxicity of various, differently substituted α-cyclodextrin derivatives and determine relationship between the structures and cytotoxicity. Three different methods were used, viability tests (MTT assay and Real Time Cell Electronic Sensing on Caco-2 cells) as well as hemolysis test on human red blood cells. The effect of α-cyclodextrin derivatives resulted in concentration-dependent cytotoxicity, so the IC50 values have been determined. Based on our evaluation, the Real Time Cell Electronic Sensing method is the most accurate for describing the time and concentration dependency of the observed toxic effects. Regarding the cytotoxicity on Caco-2 cells, phosphatidylcholine extraction may play a main role in the mechanism. Our results should provide help in selecting those α-cyclodextrin derivatives which have the potential of being used safely in medical formulations.


Assuntos
Eritrócitos/efeitos dos fármacos , alfa-Ciclodextrinas/farmacologia , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hemólise/efeitos dos fármacos , Humanos , alfa-Ciclodextrinas/toxicidade
5.
Eur J Med Chem ; 264: 115994, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38070431

RESUMO

Because they hold together molecules by means of non-covalent interactions - relatively weak and thus, potentially reversible - the anionic calixarenes have become an interesting tool for efficiently binding a large range of ligands - from gases to large organic molecules. Being highly water soluble and conveniently biocompatible, they showed growing interest for many interdisciplinary fields, particularly in biology and medicine. Thanks to their intrinsic conical shape, they provide suitable platforms, from vesicles to bilayers. This is a valuable characteristic, as so they mimic the biologically functional architectures. The anionic calixarenes propose efficient alternatives for overcoming the limitations linked to drug delivery and bioavailability, as well as drug resistance along with limiting the undesirable side effects. Moreover, the dynamic non-covalent binding with the drugs enables predictable and on demand drug release, controlled by the stimuli present in the targeted environment. This particular feature instigated the use of these versatile, stimuli-responsive compounds for sensing biomarkers of diverse pathologies. The present review describes the recent achievements of the anionic calixarenes in the field of life science, from drug carriers to biomedical engineering, with a particular outlook on their applications for the diagnosis and treatment of different pathologies.


Assuntos
Calixarenos , Calixarenos/química , Sistemas de Liberação de Medicamentos , Portadores de Fármacos , Disponibilidade Biológica , Liberação Controlada de Fármacos
6.
Int J Mol Sci ; 14(11): 21899-942, 2013 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-24196356

RESUMO

Solid lipid nanoparticles (SLNs) have attracted increasing attention during recent years. This paper presents an overview about the use of calix[n]arenes and calix-resorcinarenes in the formulation of SLNs. Because of their specific inclusion capability both in the intraparticle spaces and in the host cavities as well as their capacity for functionalization, these colloidal nanostructures represent excellent tools for the encapsulation of different active pharmaceutical ingredients (APIs) in the area of drug targeting, cosmetic additives, contrast agents, etc. Various synthetic routes to the supramolecular structures will be given. These various routes lead to the formulation of the corresponding SLNs. Characterization, properties, toxicological considerations as well as numerous corresponding experimental studies and analytical methods will be also exposed and discussed.


Assuntos
Calixarenos/química , Lipídeos/química , Nanopartículas/química , Coloides/química , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos , Humanos , Lipídeos/administração & dosagem
7.
Molecules ; 18(5): 5993-6007, 2013 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-23698051

RESUMO

The anionic calixarenes para-sulphonatocalix[4]arene and 1,3-di-O-phosphonatocalix[ 4]arene, have been used to cap silver nanoparticles. The binding of these functional particles with regard to various serum albumins (bovine serum albumin, human serum albumin, porcine serum albumin and sheep serum albumin) has been studied by variable temperature fluorescence spectroscopy. The quenching of the fluorescence of the proteins was shown to vary as a function of the anionic calixarene capping molecule and also as a function of the origin of the serum albumin. It is thus possible to discriminate between the different species.


Assuntos
Calixarenos/química , Nanopartículas Metálicas/química , Soroalbumina Bovina/química , Prata/química , Animais , Bovinos , Humanos , Ligação Proteica , Ovinos , Especificidade da Espécie , Suínos
8.
Chem Sci ; 14(26): 7126-7135, 2023 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-37416699

RESUMO

The diastereoselective assembly of achiral constituents through a single spontaneous process into complex covalent architectures bearing multiple stereogenic elements still remains a challenge for synthetic chemists. Here, we show that such an extreme level of control can be achieved by implementing stereo-electronic information on synthetic organic building blocks and templates and that non-directional interactions (i.e., electrostatic and steric interactions) can transfer this information to deliver, after self-assembly, high-molecular weight macrocyclic species carrying up to 16 stereogenic elements. Beyond the field of supramolecular chemistry, this proof of concept should stimulate the on-demand production of highly structured polyfunctional architectures.

9.
Pharmaceutics ; 15(12)2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38140042

RESUMO

The aim of this study was to formulate and characterize CK2 inhibitor-loaded alginate microbeads via the polymerization method. Different excipients were used in the formulation to improve the penetration of an active agent and to stabilize our preparations. Transcutol® HP was added to the drug-sodium alginate mixture and polyvinylpyrrolidone (PVP) was added to the hardening solution, alone and in combination. To characterize the formulations, mean particle size, scanning electron microscopy analysis, encapsulation efficiency, swelling behavior, an enzymatic stability test and an in vitro dissolution study were performed. The cell viability assay and permeability test were also carried out on the Caco-2 cell line. The anti-oxidant and anti-inflammatory effects of the formulations were finally evaluated. The combination of Transcutol® HP and PVP in the formulation of sodium alginate microbeads could improve the stability, in vitro permeability, anti-oxidant and anti-inflammatory effects of the CK2 inhibitor.

10.
Int J Biol Macromol ; 166: 1131-1140, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33161081

RESUMO

Phospholipase D (PLD) is a ubiquitous enzyme that cleaves the distal phosphoester bond of phospholipids generating phosphatidic acid (PA). In plants, PA is involved in numerous cell responses triggered by stress. Similarly, in mammals, PA is also a second messenger involved in tumorigenesis. PLD is nowadays considered as a therapeutic target and blocking its activity with specific inhibitors constitutes a promising strategy to treat cancers. Starting from already described PLD inhibitors, this study aims to investigate the effect of their structural modifications on the enzyme's activity, as well as identifying new potent inhibitors of eukaryotic PLDs. Being able to purify the plant PLD from Vigna unguiculata (VuPLD), we obtained a SAXS model of its structure. We then used a fluorescence-based test suitable for high-throughput screening to review the effect of eukaryotic PLD inhibitors described in the literature. In this regard, we found that only few molecules were in fact able to inhibit VuPLD and we confirmed that vanadate is the most potent of all with an IC50 around 58 µM. Moreover, the small-scale screening of a chemical library of 3120 compounds allowed us to optimize the different screening's steps and paved the way towards the discovery of new potent inhibitors.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/farmacologia , Fosfolipase D/antagonistas & inibidores , Álcoois/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Hidrólise , Fosfolipase D/metabolismo , Sais/farmacologia , Espalhamento a Baixo Ângulo , Vanadatos/farmacologia , Vigna/enzimologia , Difração de Raios X
11.
Chem Sci ; 11(31): 8151-8156, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34094174

RESUMO

During the last two decades, disulfide-based dynamic combinatorial chemistry has been extensively used in the field of molecular recognition to deliver artificial receptors for molecules of biological interest. Commonly, the nature of library members and their relative amounts are provided from HPLC-MS analysis of the libraries, allowing the identification of potential binders for a target (bio)molecule. By re-investigating dynamic combinatorial libraries generated from a simple 2,5-dicarboxy-1,4-dithiophenol building block in water, we herein demonstrated that multiple analytical tools were actually necessary in order to comprehensively describe the libraries in terms of size, stereochemistry, affinity, selectivity, and finally to get a true grasp on the different phenomena at work within dynamic combinatorial systems.

12.
Sci Rep ; 9(1): 5816, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967623

RESUMO

By means of Silicon Nano Tweezers (SNTs) the effects on the mechanical properties of λ-phage DNA during interaction with calf thymus nucleosome to form an artificial chromatin analog were measured. At a concentration of 100 nM, a nucleosome solution induced a strong stiffening effect on DNA (1.1 N m-1). This can be compared to the effects of the histone proteins, H1, H2A, H3 where no changes in the mechanical properties of DNA were observed and the complex of the H3/H4 proteins where a smaller increase in the stiffness is observed (0.2 N m-1). Para-sulphonato-calix[4]arene, SC4, known for epigenetic activity by interacting specifically with the lysine groups of histone proteins, was studied for its effect on an artificial chromatin. Using a microfluidic SNT device, SC4 was titrated against the artificial chromatin, at a concentration of 1 mM in SC4 a considerable increase in stiffness, 15 N m-1, was observed. Simultaneously optical microscopy showed a physical change in the DNA structure between the tips of the SNT device. Electronic and Atomic Force microscopy confirmed this structural re-arrangement. Negative control experiments confirmed that these mechanical and physical effects were induced neither by the acidity of SC4 nor through nonspecific interactions of SC4 on DNA.


Assuntos
Bacteriófago lambda/genética , Cromatina/química , DNA Viral/química , Conformação de Ácido Nucleico , Nucleossomos/química , Animais , Bovinos , Cromatina/genética , Cromossomos Artificiais , DNA Viral/genética , Histonas/química , Microscopia de Força Atômica , Nucleossomos/genética , Pinças Ópticas , Estudo de Prova de Conceito
13.
Antibiotics (Basel) ; 8(2)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163674

RESUMO

Inhibition of H3N2 influenza PA endonuclease activity by a panel of anionic calix[n]arenes and ß-cyclodextrin sulfate has been studied. The joint experimental and theoretical results reveal that the larger, more flexible and highly water-soluble sulfonato-calix[n]arenes have high inhibitory activity, with para-sulfonato-calix[8]arene, SC8, having an IC50 value of 6.4 µM. Molecular docking calculations show the SC8 can interact at both the polyanion binding site and also the catalytic site of H3N2 influenza PA endonuclease.

14.
Chem Commun (Camb) ; 55(61): 8935-8938, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31286126

RESUMO

The Eubacterium saburreum serine protease inhibitor from the human gut microbiota inhibits the eukaryotic pancreatic elastase associated with acute pancreatitis. Interestingly, the inhibition efficiency and stability are markedly increased by the para-sulphonato-calix[8]arene capped silver nanoparticles. Moreover, this enzyme is distinguishable by its high inhibitory effect at broad pH range between 2-10 and temperatures from 10 to 40 °C, in the presence of para-sulphonato-calix[8]arene capped silver nanoparticles the enzyme remains active even at 70 °C.


Assuntos
Calixarenos/química , Nanopartículas Metálicas/química , Elastase Pancreática/antagonistas & inibidores , Serpinas/química , Prata/química , Sequência de Aminoácidos , Animais , Ensaios Enzimáticos , Eubacterium/química , Concentração de Íons de Hidrogênio , Estabilidade Proteica , Alinhamento de Sequência , Serpinas/isolamento & purificação , Ácidos Sulfônicos/química , Suínos , Temperatura
15.
Chem Sci ; 10(1): 277-283, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30746081

RESUMO

By using a combination of readily accessible experimental and computational experiments in water, we explored the factors governing the association between polyanionic dyn[4]arene and a series of α,ω-alkyldiammonium ions of increasing chain length. We found that the lock-and-key concept based on the best match between the apolar and polar regions of the molecular partners failed to explain the observed selectivities. Instead, the dissection of the energetic and structural contributions demonstrated that the binding events were actually guided by two crucial solvent-related phenomena as the chain length of the guest increases: the expected decrease of the enthalpic cost of guest desolvation and the unexpected increase of the favourable enthalpy of complex solvation. By bringing to light the decisive enthalpic impact of complex solvation during the binding of polyelectrolytes by inclusion, this study may provide a missing piece to a puzzle that one day could display the global picture of molecular recognition in water.

16.
Pharmaceutics ; 11(6)2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31200501

RESUMO

3D printing is attracting considerable interest for its capacity to produce prototypes and small production runs rapidly. Fused deposit modeling (FDM) was used to produce polyvalent test plates for investigation of the physical, chemical, and in-vitro biological properties of printed materials. The polyvalent test plates (PVTPs) are poly-lactic acid cylinders, 14 mm in diameter and 3 mm in height. The polymer ester backbone was surface modified by a series of ramified and linear oligoamines to increase its hydrophilicity and introduce a positive charge. The chemical modification was verified by FT-IR spectroscopy, showing the introduction of amide and amine functions, and contact angle measurements confirmed increased hydrophilicity. Morphology studies (SEM, optical microscopy) indicated that the modification of PVTP possessed a planar morphology with small pits. Positron annihilation lifetime spectroscopy demonstrated that the polymeric free volume decreased on modification. An MTT-based prolonged cytotoxicity test using Caco-2 cells showed that the PVTPs are non-toxic at the cellular level. The presence of surface oligoamines on the PVTPs reduced biofilm formation by Candida albicans SC5314 significantly. The results demonstrate that 3D printed objects may be modified at their surface by a simple amidation reaction, resulting in a reduced propensity for biofilm colonization and cellular toxicity.

17.
J Org Chem ; 73(18): 7317-26, 2008 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-18722405

RESUMO

Twelve new di- and tetraderivatized alpha-cyclodextrin molecules having either alkylthio and perfluoroalkylpropanethio functions at the primary face have been synthesized by using the procedure of Sinay for di-O-debenzylation of perbenzylated alpha-cyclodextrins. A new strategy of protection/deprotection has been developed for introducing the lipophilic chains. The coupling reaction involves the reaction between the appropriate alpha-cyclodextin derivative, regioselectively modified at C-6 positions by a good leaving group (O-mesityl for disubstituted or iodine for tetrasubstituted derivatives), with the thioalkyl or the thioperfluoroakylpropane chains. These nucleophilic reagents are obtained from the in situ basic hydrolysis of the alkylisothiouronium bromides or perfluoalkylropropane and the isothiouronium iodides. These multistep reactions give the desired amphiphilic alpha-cyclodextrins in good overall yields of 33% to 58%.


Assuntos
Ciclodextrinas/síntese química , Configuração de Carboidratos , Sequência de Carboidratos , Isótopos de Carbono , Ciclodextrinas/química , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/normas , Dados de Sequência Molecular , Padrões de Referência , Estereoisomerismo
18.
Pharmaceuticals (Basel) ; 11(1)2018 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-29373552

RESUMO

Since the approval of imatinib in 2001, kinase inhibitors have revolutionized cancer therapies. Inside this family of phosphotransferases, casein kinase 2 (CK2) is of great interest and numerous scaffolds have been investigated to design CK2 inhibitors. Recently, functionalized indeno[1,2-b]indoles have been revealed to have high potency against human cancer cell lines such as MCF-7 breast carcinoma and A-427 lung carcinoma. 4-Methoxy-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (THN7), identified as a potent inhibitor of CK2 (IC50 = 71 nM), was selected for an encapsulation study in order to evaluate its antiproliferative activity as THN7-loaded cyclodextrin nanoparticles. Four α-cyclodextrins (α-CDs) were selected to encapsulate THN7 and all experiments indicated that the nanoencapsulation of this CK2 inhibitor in α-CDs was successful. No additional surface-active agent was used during the nanoformulation process. Nanoparticles formed between THN7 and α-C6H13 amphiphilic derivative gave the best results in terms of encapsulation rate (% of associated drug = 35%), with a stability constant (K11) of 298 mol·L-1 and a size of 132 nm. Hemolytic activity of the four α-CDs was determined before the in cellulo evaluation and the α-C6H13 derivative gave the lowest value of hemolytic potency (HC50 = 1.93 mol·L-1). Only the THN7-loaded cyclodextrin nanoparticles showing less toxicity on human erythrocytes (α-C6H13, α-C8H17 and α-C4H9) were tested against A-427 cells. All drug-loaded nanoparticles caused more cytotoxicity against A-427 cells than THN7 alone. Based on these results, the use of amphiphilic CD nanoparticles could be considered as a drug delivery system for indeno[1,2-b]indoles, allowing an optimized bioavailability and offering perspectives for the in vivo development of CK2 inhibitors.

19.
Org Lett ; 20(8): 2420-2423, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29624063

RESUMO

The extension of the family of dyn[ n]arenes toward a three-membered macrocycle is reported. Through a templated approach, a single diastereoisomer of a dyn[3]arene that bears six carboxyl groups could be isolated by precipitation in 59-63% yield and excellent purity (≥95%). A combination of experimental and computational experiments in water at physiological pH revealed that the macrocycle could bind parent biogenic polyamines with a unique diversity of surface-binding modes. Whereas no binding event could be accurately measured with 1,3-diaminopropane, spermidine formed a classical stoichiometric complex with the dyn[3]arene in the millimolar concentration range. On the other hand, the data obtained for spermine could only be attributed to a more complex binding event with the formation of a 2:1 complex at high [host]/[guest] ratios and redistribution toward a 1:1 complex upon further addition of guest.


Assuntos
Poliaminas Biogênicas/química , Estrutura Molecular , Estereoisomerismo , Água
20.
Sci Rep ; 8(1): 1226, 2018 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-29352239

RESUMO

The couple Calix[4]arene-1,3-O-diphosphorous acid (C4diP) and zinc ions (Zn2+) acts as a synergistic DNA binder. Silicon NanoTweezer (SNT) measurements show an increase in the mechanical stiffness of DNA bundles by a factor of >150, at Zn2+ to C4diP ratios above 8, as compared to Zinc alone whereas C4diP alone decreases the stiffness of DNA. Electroanalytical measurements using 3D printed devices demonstrate a progression of events in the assembly of C4diP on DNA promoted by zinc ions. A mechanism at the molecular level can be deduced in which C4diP initially coordinates to DNA by phosphate-phosphate hydrogen bonds or in the presence of Zn2+ by Zn2+ bridging coordination of the phosphate groups. Then, at high ratios of Zn2+ to C4diP, interdigitated dimerization of C4diP is followed by cross coordination of DNA strands through Zn2+/C4diP inter-strand interaction. The sum of these interactions leads to strong stiffening of the DNA bundles and increased inter-strand binding.


Assuntos
Calixarenos/química , DNA/química , Compostos de Zinco/química , Ligação de Hidrogênio , Ácidos Fosforosos/química , Polimerização
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