RESUMEN
In a previous paper, we demonstrated the synergistic action of the anti-ischemic lubeluzole (Lube S) on the cytotoxic activity of doxorubicin (Dox) and paclitaxel in human ovarian cancer A2780 and lung cancer A549 cells. In the present paper, we extended in vitro the study to the multi-drug-resistant A2780/DX3 cell line to verify the hypothesis that the Dox and Lube S drug association may potentiate the antitumor activity of this anticancer compound also in the context of drug resistance. We also evaluated some possible mechanisms underlying this activity. We analyzed the antiproliferative activity in different cancer cell lines. Furthermore, apoptosis, Dox accumulation, MDR1 downregulation, ROS, and NO production in A2780/DX3 cells were also evaluated. Our results confirm that Lube S improves Dox antiproliferative and apoptotic activities through different mechanisms of action, all of which may contribute to the final antitumor effect. Moderate stereoselectivity was found, with Lube S significantly more effective than its enantiomer (Lube R) and the corresponding racemate (Lube S/R). Docking simulation studies on the ABCB1 Cryo-EM structure supported the hypothesis that Lube S forms a stable MDR1-Dox-Lube S complex, which hampers the protein transmembrane domain flipping and blocks the efflux of Dox from resistant A2780/DX3 cells. In conclusion, our in vitro studies reinforce our previous hypothesis for repositioning the anti-ischemic Lube S as a potentiating agent in anticancer chemotherapy.
Asunto(s)
Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Línea Celular Tumoral , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Piperidinas/uso terapéutico , Doxorrubicina/farmacología , Doxorrubicina/uso terapéuticoRESUMEN
Caelyx and Myocet are clinically used liposomal forms of doxorubicin (Dox). To explore ways to improve their therapeutic index, we have studied their activity in vitro and in vivo when locally delivered by fibrin gels (FBGs). In vivo local toxic and anti-tumour activities of loaded FBGs were assessed in two immunodeficient mouse orthotopic human neuroblastoma (NB) models after application in the visceral space above the adrenal gland, either still tumour-bearing or after tumour removal. In parallel, in vitro assays were used to mimic the in vivo overlaying of FBGs on the tumour surface. FBGs were prepared with different concentrations of fibrinogen (FG) and clotted in the presence of Ca2+ and thrombin. The in vitro assays showed that FBGs loaded with Myocet possess a cytotoxic activity against NB cell lines generally greater than those loaded with free Dox or Caelyx. In vivo FBGs loaded with Myocet showed lower general and local toxicities as compared to gels loaded with Caelyx or free Dox, and also to free Dox administered i.v. (all treatments with Dox at 2.5 mg/Kg). The anti-tumour activity, evaluated in the two mouse orthotopic NB models of adjuvant and neo-adjuvant therapy, resulted in a better performance of FBGs loaded with Myocet compared to the other local (FBGs loaded with Caelyx or free Dox) or systemic (free Dox) treatments (administered at 2.5 and 5 mg/Kg Dox). Specifically, the application of FBGs at 40 mg/mL in the adjuvant model caused 92 % tumour volume reduction, while by the neo-adjuvant application of FBGs at 22 mg/mL a re-growing tumour volume reduction of 89 % was obtained. Taken together, our in vitro and in vivo results indicate a significantly higher activity for the FBGs loaded with Myocet. In particular, the lower toicity coupled with the higher anti-tumour activity on both the local treatment modalities strongly suggest a better therapeutic index when Myocet is administered through FBGs. Therefore, FBGs loaded with Myocet may be considered as a possible new tool for the loco-regional treatment of NB or even other tumour histotypes treatable by loco-regional chemotherapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Doxorrubicina/análogos & derivados , Fibrina/administración & dosificación , Neuroblastoma/tratamiento farmacológico , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Femenino , Geles , Humanos , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Ratones Desnudos , Neuroblastoma/patología , Polietilenglicoles/administración & dosificaciónRESUMEN
Over the years, cyclodextrin uses have been widely reviewed and their proprieties provide a very attractive approach in different biomedical applications. Cyclodextrins, due to their characteristics, are used to transport drugs and have also been studied as molecular chaperones with potential application in protein misfolding diseases. In this study, we designed cyclodextrin polymers containing different contents of ß- or γ-cyclodextrin, and a different number of guanidinium positive charges. This allowed exploration of the influence of the charge in delivering a drug and the effect in the protein anti-aggregant ability. The polymers inhibit Amiloid ß peptide aggregation; such an ability is modulated by both the type of CyD cavity and the number of charges. We also explored the effect of the new polymers as drug carriers. We tested the Doxorubicin toxicity in different cell lines, A2780, A549, MDA-MB-231 in the presence of the polymers. Data show that the polymers based on γ-cyclodextrin modified the cytotoxicity of doxorubicin in the A2780 cell line.
Asunto(s)
Celulosa , Ciclodextrinas , Doxorrubicina , Portadores de Fármacos , Neoplasias/tratamiento farmacológico , Células A549 , Celulosa/química , Celulosa/farmacocinética , Celulosa/farmacología , Ciclodextrinas/química , Ciclodextrinas/farmacocinética , Ciclodextrinas/farmacología , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Humanos , Neoplasias/metabolismo , Neoplasias/patología , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacocinética , beta-Ciclodextrinas/farmacología , gamma-Ciclodextrinas/química , gamma-Ciclodextrinas/farmacocinética , gamma-Ciclodextrinas/farmacologíaRESUMEN
In the few last years, nanosystems have emerged as a potential therapeutic approach to improve the efficacy and selectivity of many drugs. Cyclodextrins (CyDs) and their nanoparticles have been widely investigated as drug delivery systems. The covalent functionalization of CyD polymer nanoparticles with targeting molecules can improve the therapeutic potential of this family of nanosystems. In this study, we investigated cross-linked γ- and ß-cyclodextrin polymers as carriers for doxorubicin (ox) and oxaliplatin (Oxa). We also functionalized γ-CyD polymer bearing COOH functionalities with arginine-glycine-aspartic or arginine moieties for targeting the integrin receptors of cancer cells. We tested the Dox and Oxa anti-proliferative activity in the presence of the precursor polymer with COOH functionalities and its derivatives in A549 (lung, carcinoma) and HepG2 (liver, carcinoma) cell lines. We found that CyD polymers can significantly improve the antiproliferative activity of Dox in HepG2 cell lines only, whereas the cytotoxic activity of Oxa resulted as enhanced in both cell lines. The peptide or amino acid functionalized CyD polymers, loaded with Dox, did not show any additional effect compared to the precursor polymer. Finally, studies of Dox uptake showed that the higher antiproliferative activity of complexes correlates with the higher accumulation of Dox inside the cells. The results show that CyD polymers could be used as carriers for repositioning classical anticancer drugs such as Dox or Oxa to increase their antitumor activity.
Asunto(s)
Antineoplásicos/uso terapéutico , Celulosa/uso terapéutico , Ciclodextrinas/uso terapéutico , Doxorrubicina/uso terapéutico , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/uso terapéutico , Oxaliplatino/uso terapéutico , Células A549 , Secuencias de Aminoácidos , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Celulosa/química , Ciclodextrinas/química , Doxorrubicina/química , Portadores de Fármacos/química , Células Hep G2 , Humanos , Nanopartículas/química , Oxaliplatino/química , beta-Ciclodextrinas/química , beta-Ciclodextrinas/uso terapéutico , gamma-Ciclodextrinas/química , gamma-Ciclodextrinas/uso terapéuticoRESUMEN
To develop potent and selective anticancer agents, a series of novel polysubstituted indazoles was synthesized and evaluated for their in vitro antiproliferative and apoptotic activities against two selected human cancer cell lines (A2780 and A549). Several compounds showed an interesting antiproliferative activity, with IC50 values ranging from 0.64 to 17 µM against both cell lines. The most active indazoles were then tested in different pharmacological dilution conditions, adding five new cell lines (A2780, A549, IMR32, MDA-MB-231, and T47D) as targets, confirming their antiproliferative activity. Furthermore, selected compounds were able to trigger apoptosis to a significant extent and to cause, in part, a block of cells in the S phase of the cell cycle, with a concomitant decrease of cells in the G2/M and/or G0/G1 phases and the generation of hypodiploid peaks. However, molecule 7d caused a great increase of cells in G2/M and the appearance of polyploid cells. Altogether, our results suggest a good pharmacological activity for our selected polysubstituted indazoles, which are suggestive of a preferential mechanism of action as cell cycle-specific antimetabolites or as an inhibitor of enzyme activities involved in DNA synthesis, except for 7d, which, on the contrary, seems to have a mechanism involving the microtubule system.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Indazoles/farmacología , Neoplasias/tratamiento farmacológico , Células A549 , Antineoplásicos/síntesis química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Indazoles/síntesis química , Concentración 50 Inhibidora , Estructura Molecular , Neoplasias/patología , Relación Estructura-ActividadRESUMEN
Our research groups have been involved for many years in studies aimed at identifying new active organic compounds endowed with pharmacological properties. In this work, we focused our attention on the evaluation of cardiovascular and molecular drug resistance (MDR) reverting activities of some nitrosubstituted sulphur-containing heterocycles. Firstly, we have examined the effects of 4-nitro-3-(4-methylphenyl)-3,6-dihydro-2H-thiopyran S,S-dioxide 5, and have observed no activity. Then we have extended our investigation to the 3-aryl-4-nitrobenzothiochromans S,S-dioxide 6 and 7, and have observed an interesting biological profile. Cardiovascular activities were assessed for all compounds using ex vivo studies, while the MDR reverting effect was evaluated only for selected compounds using tumor cell lines. All compounds were shown to affect cardiovascular parameters. Compound 7i exerted the most effect on negative inotropic activity, while 6d and 6f could be interesting molecules for the development of more active ABCB1 inhibitors. Both 6 and 7 represent structures of large possible biological interest, providing a scaffold for the identification of new ABCB1 inhibitors.
Asunto(s)
Antineoplásicos/farmacología , Canales de Calcio/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromanos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Atrios Cardíacos/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Canales de Calcio/metabolismo , Línea Celular Tumoral , Cromanos/síntesis química , Cromanos/química , Doxorrubicina/farmacología , Sinergismo Farmacológico , Cobayas , Atrios Cardíacos/metabolismo , Humanos , Concentración 50 Inhibidora , Músculo Liso/fisiología , Piranos/síntesis química , Piranos/química , Compuestos de Sulfhidrilo/síntesis química , Compuestos de Sulfhidrilo/química , Tiamina/análogos & derivados , Tiamina/síntesis química , Tiamina/química , Tiamina/farmacologíaRESUMEN
Polymeric cyclodextrin-based nanoparticles are currently undergoing clinical trials as nanotherapeutics. Using a non-covalent approach, we decorated two cross-linked cyclodextrin polymers of different molecular weights with an RGD peptide derivative to construct a novel carrier for the targeted delivery of doxorubicin. RGD is the binding sequence for the integrin receptor family that is highly expressed in tumour tissues. The assembled host-guest systems were investigated using NMR and DLS techniques. We found that, in comparison with free doxorubicin or the binary complex doxorubicin/cyclodextrin polymer, the RGD units decorating the cyclodextrin-based nanosystems improved the selectivity and cytotoxicity of the complexed doxorubicin towards cultured human tumour cell lines. Our results suggest that the nanocarriers under study may contribute to the development of new platforms for cancer therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Celulosa/administración & dosificación , Ciclodextrinas/administración & dosificación , Doxorrubicina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Oligopéptidos/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , HumanosRESUMEN
In vivo local antitumor activity of fibrin gels (FBGs) loaded with the poly-cyclodextrin oCD-NH2/Dox, compared to free Dox, was evaluated in two mouse orthotopic neuroblastoma (NB) models, after positioning of the releasing devices in the visceral space. FBGs were prepared at the fibrinogen (FG) concentrations of 22 and 40â¯mg/ml clotted in the presence of 0.81â¯mM/mg FG Ca2+ and 1.32â¯U/mg FG thrombin. Our results indicate that FBGs loaded with oCD-NH2/Dox and applied as neoadjuvant loco-regional treatment, show an antitumor activity significantly greater than that displayed by the same FBGs loaded with identical dose of Dox or after free Dox administered intra venous (iv). In particular, FBGs prepared at 40â¯mg/ml showed a slightly lower antitumor activity, although after their positioning we observed a significant initial reduction of tumor burden lasting for several days after gel implantation. FBGs at 22â¯mg/ml loaded with oCD-NH2/Dox and applied after tumor removal (adjuvant treatment model) showed a significantly better antitumor activity than the iv administration of free Dox, with 90% tumor regrowth reduction compared to untreated controls. In all cases the weight loss post-treatment was limited after gel application, although in the adjuvant treatment the loss of body weight lasted longer than in the other treatment modality. In accordance with our recent published data on the low local toxic effects of FBGs, the present findings also underline an increase of the therapeutic index of Dox when locally administered through FBGs loaded with the oCD-NH2/Dox complex.
Asunto(s)
Celulosa/química , Ciclodextrinas/química , Doxorrubicina/administración & dosificación , Fibrina/administración & dosificación , Neuroblastoma/tratamiento farmacológico , Animales , Línea Celular Tumoral , Doxorrubicina/farmacología , Femenino , Fibrina/farmacología , Fibrina/toxicidad , Geles , Humanos , Ratones , Terapia Neoadyuvante , Neuroblastoma/patologíaRESUMEN
PURPOSE: Fibrin gels (FBGs) are potential delivery vehicles for many drugs, and can be easily prepared from purified components. We previously demonstrated their applicability for the release of different doxorubicin (Dox) nanoparticles used clinically or in an experimental stage, such as its inclusion complex with the amino ß-cyclodextrin polymer (oCD-NH2/Dox). Here we extend these studies by in vitro and in vivo evaluations. METHODS: An in vitro cytotoxicity model consisting of an overlay of a neuroblastoma (NB) cell-containing agar layer above a drug-loaded FBG layer was used. Local toxicity in vivo (histology and blood analysis) was studied in a mouse orthotopic NB model (SHSY5YLuc+ cells implanted into the left adrenal gland). RESULTS: In vitro data show that FBGs loaded with oCD-NH2/Dox have a slightly lower cytotoxicity against NB cell lines than those loaded with Dox. Fibrinogen (FG), and Ca2+ concentrations may modify this activity. In vivo data support a lower general and local toxicity for FBGs loaded with oCD-NH2/Dox than those loaded with Dox. CONCLUSION: Our results suggest a possible increase of the therapeutic index of Dox when locally administered through FBGs loaded with oCD-NH2/Dox, opening the possibility of using these releasing systems for the treatment of neuroblastoma.
Asunto(s)
Antineoplásicos/farmacología , Celulosa/química , Ciclodextrinas/química , Doxorrubicina/farmacología , Portadores de Fármacos/química , Fibrina/química , Nanopartículas/química , Neuroblastoma/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/sangre , Portadores de Fármacos/toxicidad , Femenino , Geles , Xenoinjertos , Humanos , Ratones Desnudos , Nanopartículas/toxicidadRESUMEN
Polymeric nanoparticles based on cyclodextrins are currently undergoing clinical trials as new promising nanotherapeutics. In light of this interest, we investigated cyclodextrin cross-linked polymers with different lengths as carriers for the poorly water-soluble drug sorafenib. Both polymers significantly enhanced sorafenib solubility, with shorter polymers showing the most effective solubilizing effect. Inclusion complexes between sorafenib and the investigated polymers exhibited an antiproliferative effect in tumor cells similar to that of free sorafenib. Polymer/Sorafenib complexes also showed lower in vivo tissue toxicity than with free sorafenib in all organs. Our results suggest that the inclusion of sorafenib in polymers represents a successful strategy for a new formulation of this drug.
Asunto(s)
Celulosa/química , Ciclodextrinas/química , Portadores de Fármacos/química , Nanopartículas/química , Sorafenib/farmacología , Animales , Apoptosis/efectos de los fármacos , Peso Corporal , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Dicroismo Circular , Femenino , Humanos , Concentración 50 Inhibidora , Cinética , Ratones Desnudos , Especificidad de Órganos , SolubilidadRESUMEN
Polymeric nanoparticles and fibrin gels (FBGs) are attractive biomaterials for local delivery of a variety of biotherapeutic agents, from drugs to proteins. We combined these different drug delivery approaches by preparing nanoparticle-loaded FBGs characterized by their intrinsic features of drug delivery rate and antiproliferative/apoptotic activities. Inclusion complexes of doxorubicin (DOXO) with oligomeric ß-cyclodextrins (oCyD) functionalized with different functional groups were studied. These nanocarriers were able to interact with FBGs as shown by a decreased release rate of DOXO. One of these complexes, oCyDNH2/DOXO, demonstrated good antiproliferative and apoptotic activity in vitro, reflecting a higher drug uptake by cells. As hypothesized, the nanocarrier/FBG complexes showed a lower drug release rate than similar FBGs loaded with the corresponding non-functionalized oCyD/DOXO. Taken together, our results provide experimental evidence that oCyDNH2/DOXO complexes may be useful components in enhanced FBGs and further build support for the great promise these complex molecules hold for clinical use in localized anticancer therapy of inoperable or surgically removable tumors of different histological origin.
Asunto(s)
Ciclodextrinas/farmacología , Doxorrubicina/farmacología , Portadores de Fármacos/química , Nanopartículas/química , Línea Celular Tumoral , Ciclodextrinas/sangre , Doxorrubicina/química , Sistemas de Liberación de Medicamentos/métodos , Geles/química , Geles/farmacología , Humanos , Polímeros/químicaRESUMEN
We have previously reported the enhancement of the antiproliferative and apoptotic activities of cis-diamminedichloroplatinum(II) (DDP) when it is coadministered with a class I antiarrhythmic drug procainamide hydrochloride (PA). Here, we determined the antiproliferative activity of DDP, either in solution or loaded in liposomes, in the presence of PA, in the bulk solution, or directly embedded in liposomes together with DDP. Our results show that PA potentiates the activity of DDP-liposomes and that this effect is maintained at least in some of the investigated cell types when both drugs were mixed and loaded together into liposomes.
Asunto(s)
Cisplatino/farmacología , Liposomas/química , Procainamida/farmacología , Células A549 , Animales , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Concentración 50 Inhibidora , Liposomas/síntesis químicaRESUMEN
Fibrin gels are attractive biomaterials for local delivery of a variety of agents, from drugs to proteins. Similarly, polymer-anticancer-drug conjugates and nanoparticles are emerging as potential candidates for cancer treatment. Combining these different approaches, we have studied the efficacy of fibrin gels loaded with cisplatin (DDP) and a complex of DDP with hyaluronate (DDP-HA) for tumor growth inhibition in a melanoma model. Loaded gels prepared at relatively high fibrinogen concentration (22 mg/ml) showed good in vitro antiproliferative activities, prolonged release of the anticancer drug, and a long persistence (10-15 days) in vivo when implanted subcutaneously (sc) in immunodeficient mice. Gels loaded with DDP or DDP-HA containing 1/3 or even 1/6 of their systemic dose (6 mg/kg) and positioned under the tumor mass in mice bearing a sc human SK-Mel-28 tumor showed an antitumor activity better than that of the original parent compound given intraperitoneally (ip). Moreover, in an additional experiment in vivo, fibrin gels loaded with N-trimethyl chitosan-based nanoparticles containing a DDP-HA complex were assayed, resulting in a further 8 % improvement of anticancer activity, with lesser adverse systemic toxic effects. Taken together, these results suggest that the combination of fibrin gels and drugs complexed with suitable macromolecules holds great promise for loco-regional anticancer therapy of melanoma and other surgically removable cancer types.
Asunto(s)
Cisplatino/administración & dosificación , Fibrina/administración & dosificación , Ácido Hialurónico/administración & dosificación , Melanoma/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Cisplatino/farmacocinética , Femenino , Fibrina/farmacocinética , Geles , Humanos , Ácido Hialurónico/farmacocinética , Melanoma/metabolismo , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Oxidative stress and protein aggregation have been demonstrated to be the major factors involved in neurodegenerative diseases. Metal ions play a pivotal role, acting as mediators of neurotoxicity either by favoring or redox cycling. Thus, they represent a promising and suitable therapeutic target for the treatment of neurodegenerative disorders. In particular, the development of bifunctional or multifunctional molecules, which have antiaggregant and metal-chelating/antioxidant properties, may be considered as a valuable strategy for the treatment of neurodegeneration considering its multifactorial nature. Herein, we report the design and the characterization of four new multifunctional sugar-appended 8-hydroxyquinolines focusing on the effects of the conjugation with trehalose, a nonreducing disaccharide involved in the protection of proteins and cells against environmental stresses. These glycoconjugates do not exhibit any antiproliferative activity against three human cell lines of different histological origin, unlike 8-hydroxyquinolines. The multiple properties of the new derivatives are highlighted, reporting their Cu(2+) and Zn(2+) binding ability, and antioxidant and antiaggregant capacities. In particular, these latter were determined by different assays, including the evaluation of their ability to modulate or even suppress the aggregation of Aß1-40 and Aß1-42 peptides induced by copper or zinc ions.
Asunto(s)
Péptidos beta-Amiloides/química , Glucosa/química , Metales/farmacología , Fragmentos de Péptidos/química , Multimerización de Proteína/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cobre/farmacología , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Humanos , Modelos Moleculares , Estructura Secundaria de Proteína , Solubilidad , Zinc/farmacologíaRESUMEN
Some new N-[6-indazolyl]arylsulfonamides and N-[alkoxy-6-indazolyl]arylsulfonamides were prepared by the reduction of 2-alkyl-6-nitroindazoles with SnCl2 in different alcohols, followed by coupling the corresponding amine with arylsulfonyl chlorides in pyridine. The newly synthesized compounds were evaluated for their antiproliferative and apoptotic activities against two human tumor cell lines: A2780 (ovarian carcinoma) and A549 (lung adenocarcinoma). Preliminary in vitro pharmacological studies revealed that N-(2-allyl-2H-indazol-6-yl)-4-methoxybenzenesulfonamide 4 and N-[7-ethoxy-2-(4-methyl-benzyl)-2H-indazol-6-yl]-4-methyl-benzenesulfonamide 9 exhibited significant antiproliferative activity against the A2780 and A549 cell lines with IC50 values in the range from 4.21 to 18.6 µM, and also that they trigger apoptosis in a dose-dependent manner. Furthermore, both active compounds were able to cause an arrest of cells in the G2/M phase of the cell cycle, typical but not exclusive of tubulin interacting agents, although only infrequent interactions with the microtubule network were observed by immunofluorescence microscopy, while docking analysis showed a possible different behavior between the two active compounds.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Indazoles/síntesis química , Indazoles/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Microscopía Fluorescente , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
As a result of the ring-into-ring conversion of nitrosoimidazole derivatives, we obtained a molecular scaffold that, when properly decorated, is able to decrease inotropy by blocking L-type calcium channels. Previously, we used this scaffold to develop a quantitative structure-activity relationship (QSAR) model, and we used the most potent oxadiazolothiazinone as a template for ligand-based virtual screening. Here, we enlarge the diversity of chemical decorations, present the synthesis and in vitro data for 11 new derivatives, and develop a new 3D-QSAR model with recent in silico techniques. We observed a key role played by the oxadiazolone moiety: given the presence of positively charged calcium ions in the transmembrane channel protein, we hypothesize the formation of a ternary complex between the oxadiazolothiazinone, the Ca2+ ion and the protein. We have supported this hypothesis by means of pharmacophore generation and through the docking of the pharmacophore into a homology model of the protein. We also studied with docking experiments the interaction with a homology model of P-glycoprotein, which is inhibited by this series of molecules, and provided further evidence toward the relevance of this scaffold in biological interactions.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/química , Compuestos Heterocíclicos/química , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , Cobayas , Atrios Cardíacos/efectos de los fármacos , Simulación del Acoplamiento Molecular , Músculo Liso/efectos de los fármacos , Relación Estructura-Actividad Cuantitativa , Homología Estructural de ProteínaRESUMEN
The indazole ring system of the title compound, C19H21N3O3S, is almost planar (r.m.s. deviation = 0.0192â Å) and forms dihedral angles of 77.99â (15) and 83.9â (3)° with the benzene ring and allyl group, respectively. In the crystal, centrosymmetrically related mol-ecules are connected by pairs of N-Hâ¯O hydrogen bonds into dimers, which are further linked by C-Hâ¯O hydrogen bonds, forming columns parallel to the b axis.
RESUMEN
In recent years, nanoparticles based on cyclodextrins have been widely investigated, mainly for drug delivery. In this work, we synthesized nanoparticles with a hyaluronic acid backbone (11â kDa and 45â kDa) functionalized with γ-cyclodextrins. We tested sorafenib in the presence of the new hyaluronan-cyclodextrin conjugates in A2780 (ovarian cancer), SK-HeP-1 (adenocarcinoma) and MDA-MB-453 (breast cancer) cell lines. We found that hyaluronan-cyclodextrin conjugates improve the antiproliferative activity of sorafenib. Remarkably, the system based on the 11â kDa hyaluronan conjugate was the most effective and, in the MDA-MB-453â cell line, significantly reduced the IC50 value of sorafenib cells by about 75 %.
RESUMEN
Ovarian cancer (OC) is one of the most prevalent malignancies in female reproductive organs, and its 5-year survival is below 45%. Despite the advances in surgical and chemotherapeutic options, OC treatment is still a challenge, and new anticancer agents are urgently needed. Drug repositioning has gained significant attention in drug discovery, representing a smart way to identify new clinical applications for drugs whose human safety and pharmacokinetics have already been established, with great time and cost savings in pharmaceutical development endeavors. This review offers an update on the most promising drugs repurposable for OC treatment and/or prevention.
Asunto(s)
Antineoplásicos , Reposicionamiento de Medicamentos , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéuticoRESUMEN
Recent investigations have rekindled interest in 8-hydroxyquinolines as therapeutic agents for cancer, Alzheimer's disease, and other neurodegenerative disorders. Three new ß-cyclodextrin conjugates of 8-hydroxyquinolines and their copper(II) and zinc(II) complexes have been synthesized and characterized spectroscopically. In addition to improving aqueous solubility, due to the presence of the cyclodextrin moiety, the hybrid systems have interesting characteristics including antioxidant activity, and their copper(II) complexes are efficient superoxide dismutase (SOD) mimics. The ligands and their copper(II) complexes show low cytotoxicity, attributed to the presence of the cyclodextrin moiety. These compounds have potential as therapeutic agents in diseases related both to metal dyshomeostasis and oxidative stress.