RESUMO
Aim: This study aimed to enhance the aqueous dissolution of SRPK inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340).Materials & Methods: A complex with p-sulfonic calix[6]arene (Host) and SRPIN340 (Guest) was prepared, studied via 1H nuclear magnetic resonance (NMR) and theoretical calculations and biologically evaluated on cancer cell lines.Results & conclusion: The 1:1 host (H)/guest (G) complex significantly enhanced the aqueous dissolution of SRPIN340, achieving 64.8% water solubility as determined by 1H NMR quantification analysis. The H/G complex reduced cell viability by 75% for HL60, â¼50% for Nalm6 and Jurkat, and â¼30% for B16F10 cells. It exhibited greater cytotoxicity than free SRPIN340 against Jurkat and B16F10 cells. Theoretical studies indicated hydrogen bond stabilization of the complex, suggesting broader applicability of SRPIN340 across diverse biological systems.
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Assuntos
Antineoplásicos , Calixarenos , Sobrevivência Celular , Calixarenos/química , Calixarenos/farmacologia , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Sobrevivência Celular/efeitos dos fármacos , Fenóis/química , Fenóis/farmacologia , Camundongos , Espectroscopia de Ressonância Magnética , Animais , Ácidos Sulfônicos/química , Ácidos Sulfônicos/antagonistas & inibidores , Ácidos Sulfônicos/farmacologia , Linhagem Celular Tumoral , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Proliferação de Células/efeitos dos fármacos , Piperidinas/química , Piperidinas/farmacologiaRESUMO
Introduction: Cocaine use disorder is a significant public health issue without a current specific approved treatment. Among different approaches to this disorder, it is possible to highlight a promising immunologic strategy in which an immunogenic agent may reduce the reinforcing effects of the drug if they are able to yield sufficient specific antibodies capable to bind cocaine and/or its psychoactive metabolites before entering into the brain. Several carriers have been investigated in the anti-cocaine vaccine development; however, they generally present a very complex chemical structure, which potentially hampers the proper assessment of the coupling efficiency between the hapten units and the protein structure. Objectives: The present study reports the design, synthesis and preclinical evaluation of two novel calix[n]arene-based anti-cocaine immunogens (herein named as V4N2 and V8N2) by the tethering of the hydrolysis-tolerant hapten GNE (15) on calix[4]arene and calix[8]arene moieties. Methods: The preclinical assessment corresponded to the immunogenicity and dose-response evaluation of V4N2 and V8N2. The potential of the produced antibodies to reduce the passage of cocaine analogue through the blood-brain-barrier (BBB), modifying its biodistribution was also investigated. Results: Both calix[n]arene-based immunogens elicited high titers of cocaine antibodies that modified the biodistribution of a cocaine radiolabeled analogue (99mTc-TRODAT-1) and decreased cocaine-induced behavior, according to an animal model. Conclusion: The present results demonstrate the potential of V4N2 and V8N2 as immunogens for the treatment of cocaine use disorder.
Assuntos
Calixarenos , Cocaína , Vacinas , Animais , Calixarenos/química , Calixarenos/farmacologia , Haptenos , Distribuição TecidualRESUMO
The first example of conjugation of open-resorcinarenes with chlorambucil, ibuprofen, naproxen and indomethacin are presented. The cytotoxic properties of the obtained conjugates were tested against the cancer cell lines U-251, PC-3, K-562, HCT-15, MCF-7 and SKLU-1. It was found that the conjugate with chlorambucil, naproxen or indomethacin (having 8 moieties) was toxic towards cancer cell lines U-251 and K-562, with no activity against non-cancerous COS-7 cells. The conjugates with naproxen and indomethacin showed high selectivity towards U-251 tumor cells.
Assuntos
Antineoplásicos/farmacologia , Calixarenos/farmacologia , Fenilalanina/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Células COS , Calixarenos/síntese química , Calixarenos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis of phenyl-resorcinarenes and pyrogallolarenes is known to produce a conformational mixture of cone and chair isomers. Depending on the synthesis conditions the composition of the conformational mixture is variable; however, the cone conformer is the greatest proportion of phenyl-resorcin[4]arenes and chair conformer of pyrogallol[4]arenes. The experimental evidence suggests that phenyl-substituted resorcinarene and pyrogallolarene exist as a dynamic boat in solution.
Assuntos
Calixarenos/química , Fenilalanina/análogos & derivados , Pirogalol/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Fenilalanina/químicaRESUMO
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 , TermodinâmicaRESUMO
Here we describe the assembly and pH-driven operation of two nanocarriers based on non-functionalized (MCM-41) and carboxylate-functionalized (MCM-41-COOH) containers loaded with the anticancer drug doxorubicin (DOX) and capped by quaternary ammonium pillar[5]arene (P[5]A) nanogates. MCM-41 and MCM-41-COOH containers were synthesized and transmission and scanning electron microscopies showed nanoparticles with spherical morphology and dimensions of 85 ± 13 nm. The nanochannels of MCM-41 loaded with DOX were gated through the electrostatic interactions between P[5]A and the silanolate groups formed at the silica-water interface, yielding the MCM-41-DOX-P[5]A nanocarrier. The second nanocarrier was gated through the electrostatic interactions between the carboxylate groups mounted on the surface of MCM-41 and P[5]A, resulting in the MCM-41-COO-DOX-P[5]A nanocarrier. The DOX release profiles from both nanocarriers were investigated by UV-vis spectroscopy at different pH values (2.0, 5.5 and 7.4) and also in the presence of ions, such as citrate3- (19 mmol L-1) and Zn2+ (1.2 and 50 mmol L-1) at 37 °C. MCM-41-COO-DOX-P[5]A can be turned on and off eight times through the formation and breaking of electrostatic interactions. In vitro studies show that MCM-41-COO-DOX-P[5]A can penetrate and release DOX in the nucleus of human breast adenocarcinoma MCF-7 cancer cells leading to a pronounced cytotoxic effect. Therefore, the fabricated nanocarrier based on a water-soluble cationic pillar[5]arene nanogate, which is reversibly opened and closed by electrostatic interactions, can be considered as a promising drug transport and delivery technique for future cancer therapy.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Calixarenos/química , Doxorrubicina/farmacologia , Compostos de Amônio Quaternário/química , Dióxido de Silício/química , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Teste de Materiais , Nanopartículas/química , Tamanho da Partícula , Porosidade , Relação Estrutura-Atividade , Propriedades de Superfície , Células Tumorais CultivadasRESUMO
BACKGROUND: One of the possible ways of improving the activity and selectivity profile of anticancer agents is to design drug carrier systems employing nanomolecules. Calix[4]arene derivatives and chlorambucil and ibuprofen are important compounds that exhibit interesting anticancer properties. OBJECTIVE: The objective of this article is the synthesis of new calix[4]arene-derivative conjugates of chlorambucil or ibuprofen with potential anticancer activity. METHODS: Cytotoxicity assays were determined using the protein-binding dye sulforhodamine B (SRB) in microculture to measure cell growth as described [19, 20]. Conjugates of chlorambucil and resorcinarene-dendrimers were prepared in 2% DMSO and added into the culture medium immediately before use. Control cells were treated with 2% DMSO. RESULTS: Thus, calix[4]arene-derivative conjugates of chlorambucil or ibuprofen showed good stability of the chemical link between drug and spacer. Evaluation of the cytotoxicity of the calix[4]arene chlorambucil or ibuprofen conjugates employing a sulforhodamine B (SRB) assay in K-562 (human chronic myelogenous leukemia cells) and U-251 (human glioblastoma cells) demonstrated that the conjugate was more potent as an antiproliferative agent than free chlorambucil and ibuprofen. The conjugates did not show any activity against the COS-7 African green monkey kidney fibroblast cell line. CONCLUSION: In the paper, we report the synthesis and spectroscopic analyses of new calix[4]arene derivative conjugates of chlorambucil or ibuprofen. Cytotoxicity assays revealed that at 10 µM, the conjugates were very active against K-562 (human chronic myelogenous leukemia cells) and U- 251 (human glioblastoma cells) cancer cells' proliferation. In order to explain the molecular mechanisms involved in the anticancer activity of calix[4]arene chlorambucil or ibuprofen conjugates, our research will be continued.
Assuntos
Antineoplásicos/farmacologia , Calixarenos/farmacologia , Clorambucila/farmacologia , Ibuprofeno/farmacologia , Fenóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Calixarenos/química , Proliferação de Células/efeitos dos fármacos , Clorambucila/síntese química , Clorambucila/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ibuprofeno/síntese química , Ibuprofeno/química , Estrutura Molecular , Fenóis/química , Células Tumorais CultivadasRESUMO
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 , SolubilidadeRESUMO
Enthalpies of solution, Δsln H, of six C-alkylresorcin[4]arene ( C-ARA) solids, with alkyl substituents varying systematically from methyl (Me) to hexyl (Hx), have been measured in water, using solubility data, and in acetonitrile, by direct calorimetry. For all of the C-ARAs studied, the values of Δsln H were highly favorable (exothermic) for dissolution into water but were strongly unfavorable (endothermic) for dissolution into acetonitrile (ACN). The differences between the two solvents varied systematically with increasing carbon chain length, from about 100 kJ·mol-1 (for Me) to 140 kJ·mol-1 (for Hx). These extraordinary variances can be attributed to the loss of hydrophilic hydration of the eight -OH groups on the rim of the C-ARAs and also by the loss of (enthalpically favorable) hydrophobic hydration of the alkyl chains upon transfer from the highly structured, strongly H-bonding water to the aprotic, relatively weak donor/acceptor ACN. Although Δsln H values for the present C-ARAs in H2O are strongly favorable, they are more than counteracted by even larger negative changes in the entropy of dissolution, Δsln S. This enthalpy/entropy compensation effect is consistent with the low aqueous solubilities (<10-3 mol·kg-1) of the C-ARAs and their slight increase with increasing carbon chain length, which is opposite to typical behavior of the homologous series of organic molecules.
Assuntos
Acetonitrilas/química , Calixarenos/química , Fenilalanina/análogos & derivados , Água/química , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Fenilalanina/química , Soluções , TermodinâmicaRESUMO
The properties and characteristics of calix[n]arenes are described, as well as their capacity to form amphiphilic assemblies by means of the design of synthetic macrocycles with a hydrophilic head and a hydrophobic tail. Their interaction with various substances of interest in pharmacy, engineering, and medicine is also described. In particular, the role of the calix[n]arenes in the detection of dopamine, the design of vesicles and liposomes employed in the manufacture of systems of controlled release drugs used in the treatment of cancer, and their role in improving the solubility of testosterone and anthelmintic drugs and the biocompatibility of biomaterials useful for the manufacture of synthetic organs is emphasized. The versatility of these macrocycles, able to vary in size, shape, functional groups, and hydrophobicity and to recognize various biomolecules and molecules with biological activity without causing cytotoxicity is highlighted.