RESUMEN
The development of sustainable biomaterials and surfaces to prevent the accumulation and proliferation of viruses and bacteria is highly demanded in healthcare areas. This study describes the assembly and full characterization of two new bioactive silver(I) coordination polymers (CPs) formulated as [Ag(aca)(µ-PTA)]n·5nH2O (1) and [Ag2(µ-ada)(µ3-PTA)2]n·4nH2O (2). These products were generated by exploiting a heteroleptic approach based on the use of two different adamantoid building blocks, namely 1,3,5-triaza-7-phosphaadamantane (PTA) and 1-adamantanecarboxylic (Haca) or 1,3-adamantanedicarboxylic (H2ada) acids, resulting in the assembly of 1D (1) and 3D (2). Antiviral, antibacterial, and antifungal properties of the obtained compounds were investigated in detail, followed by their incorporation as bioactive dopants (1 wt %) into hybrid biopolymers based on acid-hydrolyzed starch polymer (AHSP). The resulting materials, formulated as 1@AHSP and 2@AHSP, also featured (i) an exceptional antiviral activity against herpes simplex virus type 1 and human adenovirus (HAd-5) and (ii) a remarkable antibacterial activity against Gram-negative bacteria. Docking experiments, interaction with human serum albumin, mass spectrometry, and antioxidation studies provided insights into the mechanism of antimicrobial action. By reporting these new silver CPs driven by adamantoid building blocks and the derived starch-based materials, this study endows a facile approach to access biopolymers and interfaces capable of preventing and reducing the proliferation of a broad spectrum of different microorganisms, including bacteria, fungi, and viruses.
Asunto(s)
Plata , Virus , Humanos , Plata/farmacología , Plata/química , Polímeros/farmacología , Polímeros/química , Antibacterianos/farmacología , Antibacterianos/química , Bacterias , Antivirales/farmacología , Almidón , Proteínas Sanguíneas , Chaperonas MolecularesRESUMEN
This study presents a simple and energy-efficient self-assembly LAG synthetic method for novel water-soluble copper(I) complexes [Cu(terpy)(PTA)][PF6] (1) and [Cu(terpy)(PTA)2][PF6] (2). They were characterized by FT-IR, 1H, and 31P{1H} NMR spectroscopy, elemental analysis, and single-crystal/powder X-ray diffraction (for 2). The X-ray analysis of compound 2 indicates a bidentate coordination mode of terpyridine to the metal center. Variable-temperature NMR tests indicate dynamic properties for terpyridine in the case of both compounds, as well as for the PTA ligands in the case of 2. Additionally, compounds 1 and 2 exhibit interesting cytotoxic activity, which was tested on normal human dermal fibroblasts (NHDFs), human lung carcinoma (A549), human breast adenocarcinoma (MCF-7), and human cervix carcinoma (HeLa) established cell lines. In comparison to the other tested compounds, complexes 1 and 2 seem to have significantly lower IC50 values against cancer cells (A549, HeLa, MCF-7), indicating their potential as prospective anticancer agents. Moreover, both compounds show no significant toxicity towards normal skin cells (NHDFs), suggesting a certain selectivity in their action on cancer cells. Cisplatin as a reference compound also exhibited considerable cytotoxicity against cancer cells but with a low level of selectivity, which could lead to unwanted effects on normal cells. Remarkably, compounds 1 and 2 exhibit up to 30 times the cytotoxic activity of cisplatin, with a six-fold lower toxicity to normal cells. They also interact strongly with human serum albumin, suggesting potential therapeutic applications. Overall, these compounds hold significant promise as potential chemotherapeutic agents.
Asunto(s)
Adamantano/análogos & derivados , Antineoplásicos , Carcinoma , Complejos de Coordinación , Compuestos Organofosforados , Femenino , Humanos , Cisplatino/farmacología , Cobre/química , Línea Celular Tumoral , Agua , Estudios Prospectivos , Espectroscopía Infrarroja por Transformada de Fourier , Complejos de Coordinación/química , Antineoplásicos/farmacología , LigandosRESUMEN
The glycated human serum albumin (gHSA) interaction with antidiabetic agent - exenatide (exe) was investigated by spectroscopic techniques. The fluorescence spectroscopy showed an association between exe and protein as 4.57 × 104 M-1 (290 K), 3.33 × 104 M-1 (300K) and 2.54 × 104 M-1 (310K) and the number of binding sites were 1.15, 1.09, and 1.02, respectively. The binding process occurred spontaneously and the electrostatic bonds play a predominant role in the gHSA-exe interaction. The affinity drug to gHSA was studied in the presence of metal ions (Ca2+, Cr3+, Zn2+), which are often given as a supplement to the diet. Our study indicates that metal ions have an effect on the increase of the affinity of exenatide to glycated albumin and it is the result of the metal ion-exenatide-albumin interaction. Based on CD spectroscopy it is evident that exenatide has nonsignificant effect on the protein secondary structure, but the changes are visible in the presence of metal ions. Zeta potential measurements indicate instability of the system at lower concentration of the ligand - the effect is desired in point of view of pharmacology.
Asunto(s)
Reacción de Maillard , Albúmina Sérica Humana , Humanos , Albúmina Sérica Humana/química , Exenatida/farmacología , Exenatida/metabolismo , Albúmina Sérica/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Sitios de Unión , Espectrometría de Fluorescencia , Unión ProteicaRESUMEN
Coordination polymers have emerged as a new class of potent biologically active agents due to a variety of important characteristics such as the presence of bioactive metal centers and linkers, low toxicity, stability, tailorable structures, and bioavailability. The research on intermediate metabolites has also been explored with implications toward the development of selective anticancer, antimicrobial, and antiviral therapeutic strategies. In particular, quinolinic acid (H2quin) is a recognized metabolite in kynurenine pathway and potent neurotoxic molecule, which has been selected in this study as a bioactive building block for assembling a new silver(I) coordination polymer, [Ag(Hquin)(µ-PTA)]n·H2O (1). This product has been prepared from silver oxide, H2quin, and 1,3,5-triaza-7-phosphaadamantane (PTA), and fully characterized by standard methods including single-crystal X-ray diffraction. Compound 1 has revealed distinctive bioactive features, namely (i) a remarkable antiviral activity against herpes simplex virus type 1 (HSV-1) and adenovirus 36 (Ad-36), (ii) a significant antibacterial activity against clinically important bacteria (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa), and (iii) a selective cytotoxicity against HeLa (human cervix carcinoma) cell line. The present work widens a growing family of bioactive coordination polymers with potent antiviral, antibacterial, and antiproliferative activity.
Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Polímeros/farmacología , Ácido Quinolínico/farmacología , Plata/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Ensayos de Selección de Medicamentos Antitumorales , Escherichia coli/efectos de los fármacos , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Polímeros/síntesis química , Polímeros/química , Pseudomonas aeruginosa/efectos de los fármacos , Ácido Quinolínico/química , Plata/química , Staphylococcus aureus/efectos de los fármacosRESUMEN
The interactions of proteins with drugs are very important from a pharmacological point of view. Holo-transferrin is a blood-plasma glycoprotein whose main function is iron-binding and the transport of other ligands. Additionally, the protein is only transferrin-form recognized by TfR1 and TfR2 receptors at the surface of rapidly proliferating malignant cells. Imatinib mesylate is a tyrosine-kinase inhibitor mainly used in the treatment of blood cancers, frequently in multidrug therapy with cyclophosphamide. In this study the effect of cyclophosphamide on the interaction of imatinib mesylate with human holo-transferrin has been investigated. Using spectroscopic techniques such as fluorescence, circular dichroism, ultraviolet-visible and electrophoretic light scattering additive parameters, system stability and the effect of the ligands on the protein conformation at varying pH values have been defined. Calculated quenching constants are in the order of 2 × 104 M-1 and the type of interaction depends on the reaction medium. Under physiological conditions binding constant is 1.329 × 106 M-1 whereas in an environment similar to that of cancer cells the constant is significantly lower, Ka = 6.060 × 104 M-1. N values are approximate to 1 in all cases. Moreover, some changes are observed in the α-helical structure of the protein after interaction with the drugs and the presence of cyclophosphamide slightly stabilizes the protein secondary structure. All collected data proves the effect of cyclophosphamide on the interaction between imatinib mesylate and human holo-transferrin. It is of great clinical interest due to anticancer, multidrug therapies including both imatinib mesylate and cyclophosphamide.
Asunto(s)
Leprostáticos , Transferrina , Ciclofosfamida , Quimioterapia Combinada , Humanos , Mesilato de Imatinib , Unión Proteica , Transferrina/metabolismoRESUMEN
A series of water-soluble copper(II) complexes based on 2,9-dimethyl-1,10-phenanthroline (dmphen) and mixed-ligands, containing PTA=O (1,3,5-triaza-7-phosphaadamantane-7-oxide) have been synthesized and fully characterized. Two types of complexes have been obtained, monocationic [Cu(NO3)(O-PTA=O)(dmphen)][PF6] (1), [Cu(Cl)(dmphen)2][PF6] (2), and neutral [Cu(NO3)2(dmphen)] (3). The solid-state structures of all complexes have been determined by single-crystal X-ray diffraction. Magnetic studies for the complex 1-3 indicated a very weak antiferromagnetic interaction between copper(II) ions in crystal lattice. Complexes were successfully evaluated for their cytotoxic activities on the normal human dermal fibroblast (NHDF) cell line and the antitumor activity using the human lung carcinoma (A549), epithelioid cervix carcinoma (HeLa), colon (LoVo), and breast adenocarcinoma (MCF-7) cell lines. Complexes 1 and 3 revealed lower toxicity to NHDF than A549 and HeLa cells, meanwhile compound 2 appeared to be more toxic to NHDF cell line in comparison to all cancer lines. Additionally, interactions between the complexes and human apo-transferrin (apo-Tf) using fluorescence and circular dichroism (CD) spectroscopy were also investigated. All compounds interacted with apo-transferrin, causing same changes of the protein conformation. Electrostatic interactions dominate in the 1/2 - apo- Tf systems and hydrophobic and ionic interactions in the case of 3.
Asunto(s)
Adamantano/química , Antineoplásicos/síntesis química , Apoproteínas/química , Complejos de Coordinación/síntesis química , Cobre/química , Fenantrolinas/química , Transferrina/química , Células A549 , Adamantano/análogos & derivados , Antineoplásicos/farmacología , Apoproteínas/metabolismo , Cationes Bivalentes , Cationes Monovalentes , Línea Celular , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Concentración 50 Inhibidora , Cinética , Células MCF-7 , Óxidos/química , Unión Proteica , Termodinámica , Transferrina/metabolismoRESUMEN
The interactions between transport proteins and drugs are very important from the pharmacological point of view. In this study, using fluorescence and circular dichroism (CD) techniques, we investigated the interaction between human serum albumin (HSA) and incretin antidiabetic drug - exenatide. Moreover, the effect of common metal ions (Ca2+, Zn2+, Cr3+) on the exenatide-HSA binding - was also described. Based on the experimental data under pseudophysiological conditions, the calculated binding constant values are on the order of 104 M-1, and the constants are lower in the presence of metal ions. We observed the increase of the hydrophobicity near the tryptophan-214 residue in subdomain IIA, but almost no change in the hydrophobicity surrounding tyrosine residues. A similar effect on the tryptophan microenvironment is influenced by metal ions. The calculated thermodynamic parameters indicated that the characteristic electrostatic and hydrophobic interactions play an important role in the albumin-exenatide complexes. The CD studies showed that exenatide does not change the secondary structure of the protein but used metal ions have some impact on albumin α-helical content.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Hipoglucemiantes , Albúmina Sérica Humana , Sitios de Unión , Dicroismo Circular , Exenatida , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Conformación Proteica , Albúmina Sérica Humana/metabolismo , Espectrometría de Fluorescencia , TermodinámicaRESUMEN
From the well-known 1,3,5-triaza-phosphaadamantane (PTA, 1a), the novel N-allyl and N-benzyl tetrafuoroborate salts 1-allyl-1-azonia-3,5-diaza-7-phosphaadamantane (APTA(BF4), 1b) and 1-benzyl-1-azonia-3,5-diaza-7-phosphaadamantane (BzPTA(BF4), 1c) were obtained. These phosphines were then allowed to react with (Pt(µ-Cl)(C6F5)(tht))2 (tht = tetrahydrothiophene) affording the water soluble Pt(II) complexes trans-(PtCl(C6F5)(PTA)2) (2a) and its bis-cationic congeners trans-(PtCl(C6F5)(APTA)2)(BF4)2 (2b) and trans-(PtCl(C6F5)(BzPTA)2)(BF4)2 (2c). The compounds were fully characterized by multinuclear NMR, ESI-MS, elemental analysis and (for 2a) also by single crystal X-ray diffraction, which proved the trans configuration of the phosphine ligands. Furthermore, in order to evaluate the cytotoxic activities of all complexes the normal human dermal fibroblast (NHDF) cell culture were used. The antineoplastic activity of the investigated compounds was checked against the human lung carcinoma (A549), epithelioid cervix carcinoma (HeLa) and breast adenocarcinoma (MCF-7) cell cultures. Interactions between the complexes and human serum albumin (HSA) using fluorescence spectroscopy and circular dichroism spectroscopy (CD) were also investigated.
RESUMEN
A series of novel silver(i) 2,2':6',2''-terpyridine (tpy), 4'-(4-methylphenyl)-2,2':6':2''-terpyridine (tpy-Ph-Me) and 1,10-phenanthroline-5,6-dione (dione) derivatives containing PTA (1,3,5-triaza-7-phosphaadamantane) or 1,3,5-triaza-7-phosphaadamantane-7-sulfide (PTA[double bond, length as m-dash]S) have been synthesized and fully characterized. Two types of complexes have been obtained, monocationic [Ag(tpy)(PTA)](NO3) (1), [Ag(tpy-Ph-Me)(PTA)](NO3) (2), [Ag(dione)(PTA[double bond, length as m-dash]S)](BF4) (4) and [Ag(dione)2](PF6) (5) and neutral [Ag(dione)(PTA[double bond, length as m-dash]S)(NO3)] (3). The solid-state structures of four complexes have been determined by single-crystal X-ray diffraction. Complexes 1 and 2 are luminescent at room temperature and 77 K while 5 shows emission only at 77 K. Compounds 3 and 4 are not emissive. Furthermore, representative light-stable and water-soluble 1 and 3 were evaluated for their cytotoxic activities on the normal human dermal fibroblast (NHDF) cell line and their antitumor activity using the human lung carcinoma (A549), epithelioid cervix carcinoma (HeLa) and human breast adenocarcinoma (MCF-7) cell lines. Interactions between the complexes and human serum albumin (HSA) using UV-Vis, fluorescence and circular dichroism spectroscopy (CD) were also investigated.
RESUMEN
The interaction between glycated human serum albumin (gHSA) and folic acid (FA) was investigated by various spectroscopic techniques, such as fluorescence, circular dichroism, UV-vis absorption spectroscopy and electrophoretic light scattering technique. These methods characterize the binding properties of an albumin-folic acid system. The binding constants values (Ka) at 300 and 310 K are about 104 M-1. The standard enthalpy change (ΔH) and the standard entropy change (ΔS) were calculated to be â¼-20 kJ mol-1 and â¼16 J mol-1 K-1, respectively, which indicate characteristic electrostatic interactions between gHSA and folic acid. The CD studies showed that there are no significant conformational changes in the secondary structure of the protein. Moreover, the zeta potential measurements proved that under physiological conditions the gHSA-folic acid complex shows instability. No significant changes in the secondary structure of the protein and reversible drug binding are the desirable effect from pharmacological point of view. Communicated by Ramaswamy H. Sarma.
Asunto(s)
Ácido Fólico/metabolismo , Albúmina Sérica Humana/metabolismo , Análisis Espectral , Sitios de Unión , Unión Competitiva , Dicroismo Circular , Transferencia de Energía , Glicosilación , Hemina/metabolismo , Humanos , Cinética , Ligandos , Espectrometría de Fluorescencia , Electricidad Estática , TemperaturaRESUMEN
Imatinib mesylate (Imt) is a tyrosine kinase inhibitor mainly used in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+CML). Human serum transferrin is the most abundant serum protein responsible for the transport of iron ions and many endogenous and exogenous ligands. In this study the mechanism of interactions between the imatinib mesylate and all states of transferrin (apo-Tf, Htf and holo-Tf) has been investigated by fluorescence, ultraviolet-visible (UV-vis), circular dichroism (CD) and zeta potential spectroscopic methods. Based on the experimental results it was proved that under physiological conditions the imatinib mesylate binds to the each form of transferrin with a binding constant c.a. 105M-1. The thermodynamic parameters indicate that hydrogen bonds and van der Waals were involved in the interaction of apo-Tf with the drug and hydrophobic and ionic strength participate in the reaction of Htf and holo-Tf with imatinib mesylate. Moreover, it was shown that common metal ions, Zn2+ and Ca2+ strongly influenced apo-Tf-Imt binding constant. The CD studies showed that there are no conformational changes in the secondary structure of the proteins. No significant changes in secondary structure of the proteins upon binding with the drug and instability of apo-Tf-Imt system are the desirable effects from pharmacological point of view.