RESUMEN
Cancer is a complex and multifactorial disease characterized by uncontrolled cell growth and is one of the main causes of death in the world. This work aimed to evaluate a small series of 10 different indole-thiosemicarbazone compounds as potential antitumor agents. This is a pioneering study. For this, the antioxidant and cytotoxic capacity against normal and tumor cells was evaluated. The results showed that the compounds were able to promote moderate to low antioxidant activity for the ABTS radical scavenging assay. ADMET in silico assays showed that the compounds exhibited good oral bioavailability. As for toxicity, they were able to promote low cytotoxicity against normal cells, in addition to not being hemolytic. The compounds showed promising in vitro antitumor activity against the T47D, MCF-7, Jurkat and DU-145 strains, not being able to inhibit the growth of the Hepg2 strain. Through this in vitro study, it can be concluded that the compounds are potential candidates for antitumor agents.
Asunto(s)
Antineoplásicos , Antioxidantes , Indoles , Tiosemicarbazonas , Humanos , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinética , Indoles/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antioxidantes/farmacología , Línea Celular Tumoral , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacosRESUMEN
α-N-Heterocyclic thiosemicarbazones such as triapine and COTI-2 are currently investigated as anticancer therapeutics in clinical trials. However, triapine was widely inactive against solid tumor types. A likely explanation is the short plasma half-life time and fast metabolism. One promising approach to overcome these drawbacks is the encapsulation of the drug into nanoparticles (passive drug-targeting). In a previous work we showed that it was not possible to stably encapsulate free triapine into liposomes. Hence, in this manuscript we present the successful preparation of liposomal formulations of the copper(II) complexes of triapine and COTI-2. To this end, various drug-loading strategies were examined and the resulting liposomes were physico-chemically characterized. Especially for liposomal Cu-triapine, a decent encapsulation efficacy and a slow drug release behavior could be observed. In contrast, for COTI-2 and its copper(II) complex no stable loading could be achieved. Subsequent in vitro studies in different cell lines with liposomal Cu-triapine showed the expected strongly reduced cytotoxicity and DNA damage induction. Also in vivo distinctly higher copper plasma levels and a continuous release could be observed for the liposomal formulation compared to free Cu-triapine. Taken together, the here presented nanoformulation of Cu-triapine is an important step further to increase the plasma half-life time and tumor targeting properties of anticancer thiosemicarbazones.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Cobre , Tiosemicarbazonas , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Cobre/administración & dosificación , Cobre/química , Cobre/farmacocinética , Liberación de Fármacos , Femenino , Humanos , Liposomas , Metahemoglobina/metabolismo , Ratones Endogámicos BALB C , Tiosemicarbazonas/administración & dosificación , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinéticaRESUMEN
PURPOSE: Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. METHODS: CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. RESULTS: When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. CONCLUSION: Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.
Asunto(s)
Complejos de Coordinación/farmacocinética , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Tiosemicarbazonas/farmacocinética , Administración Oral , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C3H , Tamaño de la PartículaRESUMEN
Considering the promising previous results on the remarkable activity exhibited by cobalt(III) and manganese(II) thiosemicarbazone compounds as antibacterial agents, the present study aimed to prepare and then evaluate the antibacterial activity of two different types of Cu(II) complexes based on a 2-acetylpyridine-N(4)-methyl-thiosemicarbazone ligand (Hatc-Me), a monomer complex [CuCl(atc-Me)] and a novel dinuclear complex [{Cu(µ-atc-Me)}2µ-SO4]. The compounds were characterized by infrared spectra, ultraviolet visible and CHN elemental analysis. In addition, the crystalline structures of the complexes were determined by single-crystal X-ray diffraction. In both cases, the Schiff base ligand coordinated in a tridentate mode via the pyridine nitrogen, imine nitrogen and sulfur atoms. The two Cu(II) atoms in the dimer are five coordinate, consisting of three NNS-donor atoms from the thiosemicarbazone ligand connected by a sulfate bridge. The Hirshfeld surface and energy framework of the complexes were additionally analyzed to verify the intermolecular interactions. The biological activity of the Cu(II) salts, the free ligand and its Cu(II) complexes was evaluated against six strains of mycobacteria including Mycobacterium tuberculosis. The complexes showed promising results as antibacterial agents for M. avium and M. tuberculosis, which ranged from 6.12 to 12.73 µM. Furthermore, molecular docking analysis was performed and the binding energy of the docked compound [{Cu(µ-atc-Me)}2µ-SO4] with M. tuberculosis and M. avium strains were extremely favorable (-11.11 and - 14.03 kcal/mol, respectively). The in silico results show that the complexes are potential candidates for the development of new antimycobacterial drugs.
Asunto(s)
Antituberculosos/farmacología , Complejos de Coordinación/farmacología , Tiosemicarbazonas/farmacología , Antituberculosos/síntesis química , Antituberculosos/metabolismo , Antituberculosos/farmacocinética , Proteínas Bacterianas/metabolismo , Complejos de Coordinación/síntesis química , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacocinética , Cobre/química , Ligandos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Mycobacterium avium/efectos de los fármacos , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Unión Proteica , Relación Estructura-Actividad , Termodinámica , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/metabolismo , Tiosemicarbazonas/farmacocinéticaRESUMEN
OBJECTIVES: Molecular imaging constitutes a promising technique for the early detection of rheumatoid arthritis (RA). Macrophages and hypoxia play significant roles in inflamed synovium. In the present study, we evaluated the efficacy of radiopharmaceuticals that target macrophage mannose receptors (99mTc-labeled mannosylated dextran or 99mTc(CO)3-DCM20) and hypoxia (copper(II) diacetyl-di(N4-methylthiosemicarbazone) or Cu-ATSM) for the early detection of RA in collagen-induced arthritis (CIA) mice models. METHODS: CIA model was developed in DBA/1 mice, and the clinical score for arthritis was visually assessed on a regular basis. Two biodistribution studies were performed in a paired-labeled format using 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG) as a reference: (1) 99mTc(CO)3-DCM20 with 18F-FDG and (2) 67Cu-ATSM with 18F-FDG. RESULTS: The accumulation levels of 99mTc(CO)3-DCM20 and 67Cu-ATSM in forepaws, hindpaws, and knee joints of CIA mice were significantly higher than that of control mice. In contrast, 18F-FDG uptake in hindpaws and knee joints showed no significant difference between CIA and control mice. The radioactivity levels of 99mTc(CO)3-DCM20 and 67Cu-ATSM were significantly correlated with the clinical scores for the paws. CONCLUSION: These results suggest the potential usefulness of 99mTc(CO)3-DCM20 and radiolabeled Cu-ATSM for the imaging and early detection of RA.
Asunto(s)
Artritis Experimental/diagnóstico por imagen , Compuestos Organometálicos/farmacocinética , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Compuestos de Tecnecio/farmacocinética , Tiosemicarbazonas/farmacocinética , Animales , Complejos de Coordinación , Diagnóstico Precoz , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos DBA , Distribución TisularRESUMEN
PURPOSE: To investigate the metabolic pathways of triapine in primary cultures of human hepatocytes and human hepatic subcellular fractions; to investigate interactions of triapine with tenofovir and emtricitabine; and to evaluate triapine as a perpetrator of drug interactions. The results will better inform future clinical studies of triapine, a radiation sensitizer currently being studied in a phase III study. METHODS: Triapine was incubated with human hepatocytes and subcellular fractions in the presence of a number of inhibitors of drug metabolizing enzymes. Triapine depletion was monitored by LC-MS/MS. Tenofovir and emtricitabine were co-incubated with triapine in primary cultures of human hepatocytes. Triapine was incubated with a CYP probe cocktail and human liver microsomes, followed by LC-MS/MS monitoring of CYP specific metabolite formation. RESULTS: Triapine was not metabolized by FMO, AO/XO, MAO-A/B, or NAT-1/2, but was metabolized by CYP450s. CYP1A2 accounted for most of the depletion of triapine. Tenofovir and emtricitabine did not alter triapine depletion. Triapine reduced CYP1A2 activity and increased CYP2C19 activity. CONCLUSION: CYP1A2 metabolism is the major metabolic pathway for triapine. Triapine may be evaluated in cancer patients in the setting of HIV with emtricitabine or tenofovir treatment. Confirmatory clinical trials may further define the in vivo triapine metabolic fate and quantify any drug-drug interactions.
Asunto(s)
Inhibidores del Citocromo P-450 CYP1A2/farmacocinética , Inductores del Citocromo P-450 CYP2C19/farmacocinética , Neoplasias/terapia , Piridinas/farmacocinética , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Tiosemicarbazonas/farmacocinética , Células Cultivadas , Quimioradioterapia/métodos , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP1A2/metabolismo , Inhibidores del Citocromo P-450 CYP1A2/uso terapéutico , Citocromo P-450 CYP2C19/metabolismo , Inductores del Citocromo P-450 CYP2C19/uso terapéutico , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Emtricitabina/farmacocinética , Hepatocitos , Humanos , Inactivación Metabólica , Microsomas Hepáticos , Cultivo Primario de Células , Piridinas/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Espectrometría de Masas en Tándem , Tenofovir/farmacocinética , Tiosemicarbazonas/uso terapéuticoRESUMEN
PURPOSE: Most solid tumors contain areas of chronic hypoxia. Gold nanoparticles (GNP) have been extensively explored as enhancers of external beam radiation; however, GNP have lower cellular uptake in hypoxic conditions than under normoxic conditions. Conversely, the chelator diacetyl-bis (N(4)-methylthiosemicarbazonato) copper II (CuATSM) deposits copper in hypoxic regions, allowing for dose enhancement in previously inaccessible regions. METHODS: External beam sources with different spectra were modeled using a Monte Carlo code (EGSnrc) to evaluate radioenhancement in a layered model with metal solutions. Also considered was a simple concentric layered tumor model containing a hypoxic core with each layer varying in concentrations of either copper or gold according to hypoxic conditions. Low energy external photon beams were then projected onto the tumor to determine the regional dose enhancement dependent on hypoxic conditions. RESULTS: Dose enhancement was more pronounced for beam spectra with low energy photons (225 kVp) and was highly dependent on metal concentrations from 0.1 g/kg to 100 g/kg. Increasing the depth of the metallic solution layer from 1 cm to 6 cm decreased dose enhancement. A small increase in the dose enhancement factor (DEF) of 1.01 was predicted in the hypoxic regions of the tumor model with commonly used diagnostic concentrations of CuATSM. At threshold concentrations of toxic subcutaneous injection levels, the DEF increases to 1.02, and in simulation of a high concentration of CuATSM, the DEF increased to 1.07. High concentration treatments are also considered, as well as synergistic combinations of GNP/CuATSM treatments. CONCLUSION: The research presented is novel utilization of CuATSM to target hypoxic regions and act as a radiosensitizer by the nature of its ability to deposit copper metal in reduced tissue. We demonstrate CuATSM at high concentrations with low energy photons can increase dose deposition in hypoxic tumor regions.
Asunto(s)
Oro/química , Nanopartículas del Metal/química , Método de Montecarlo , Compuestos Organometálicos/farmacocinética , Fotones , Tiosemicarbazonas/farmacocinética , Hipoxia Tumoral , Complejos de Coordinación , Relación Dosis-Respuesta en la Radiación , Modelos Biológicos , Fantasmas de Imagen , Fármacos Sensibilizantes a Radiaciones/farmacología , Hipoxia Tumoral/efectos de los fármacos , Hipoxia Tumoral/efectos de la radiaciónRESUMEN
Two new Schiff base ligands (TE and TF) were prepared from conjugation of testosterone with 4-(4-ethylphenyl)-3-thiosemicarbazide and 4-(4-fluorophenyl)-3-thiosemicarbazide, respectively. Their nickel (NE and NF) and zinc (ZE and ZF) complexes were reported. X-ray crystallography revealed a distorted square planar geometry was adopted by NE. The compounds demonstrated excellent selectivity towards the colorectal carcinoma cell line HCT 116 despite their weak preferences towards the prostate cancer cell lines (PC-3 and LNCaP). Against HCT 116, all these compounds were able to arrest cell cycle at G0/G1 phase and induce apoptosis via mitochondria-dependent (TE, NE, and TF) and extrinsic apoptotic pathway (ZE, NF, and ZF). Moreover, only ZE was able to act as topoisomease I poison and halt its enzymatic reactions although all compounds presented excellent affinity towards DNA.
Asunto(s)
Neoplasias Colorrectales , Complejos de Coordinación , Níquel , Testosterona , Tiosemicarbazonas , Zinc , Muerte Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Complejos de Coordinación/farmacología , Células HCT116 , Humanos , Níquel/química , Níquel/farmacocinética , Níquel/farmacología , Testosterona/química , Testosterona/farmacocinética , Testosterona/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinética , Tiosemicarbazonas/farmacología , Zinc/química , Zinc/farmacocinética , Zinc/farmacologíaRESUMEN
Iron(III) and nickel(II) complexes bearing a thiosemicarbazone framework were synthesized by a one-pot synthesis method. The structures were characterized by elemental analysis, IR, 1 H NMR, APCI Mass, conductivity, magnetic moment measurements. Molecular and crystal structures of the iron(III) complex were obtained from single-crystal X-ray diffraction. The findings showed that the metal atom adopts a slightly distorted square-pyramidal coordination, with the four donor atoms of the thiosemicarbazone ligand defining the basal plane and a chloride atom occupying the apical position. In the crystal lattice, the structure is stabilized by intermolecular OâH···O and CâH···O interactions. The cytotoxic activity was studied by MTT assay, the expression levels of cytochrome P450 (CYP) enzymes by Western blot, and the lipophilicity (LogP) by using the shake-flask method, another pharmacokinetic parameter. The findings showed that the IC50 values decreased with the decrease of the LogP values of the substances. Cytochrome P450 expression levels were found specific for each compound and each cell line. As a result, the pharmacokinetic properties of the newly synthesized thiosemicarbazone compounds are crucial for oral administration and provide us with clues for prospective in vivo studies.
Asunto(s)
Antineoplásicos , Citotoxinas , Tiosemicarbazonas , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Células CACO-2 , Citotoxinas/síntesis química , Citotoxinas/química , Citotoxinas/farmacocinética , Citotoxinas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células HT29 , Células Hep G2 , Humanos , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinética , Tiosemicarbazonas/farmacologíaRESUMEN
A series of novel 8-nitro quinoline-based thiosemicarbazone analogues were synthesized and characterized by various spectroscopic and single crystal X-ray analyses. The potent antitumor effects of synthesized compounds towards the cancer cells were evaluated by MTT assay. Amongst, the compound 3a exhibited the highest inhibitory activity and the compounds 3f and 3b were also showed significant activity. The molecular mechanistic studies of cell death have demonstrated that the treated potent compound 3a induced G1/S & G2/M phase cell cycle arrest and induced apoptosis via mitochondrial dysfunction and increased the production of cytotoxic ROS levels. The RT-PCR gene expression analysis revealed that the cell death induced by activation of caspase-3 dependent intrinsic apoptotic signaling pathway. Further, the molecular binding affinity of compounds with estrogen receptor alpha was calculated by molecular docking studies. Thus, novel 8-nitro quinoline-thiosemicarbazone analogues provide a unique tool for breast cancer therapeutic tactics.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Quinolinas/química , Quinolinas/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Cristalografía por Rayos X , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Modelos Moleculares , Simulación del Acoplamiento Molecular , Quinolinas/síntesis química , Quinolinas/farmacocinética , Especies Reactivas de Oxígeno/metabolismo , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/farmacocinética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/metabolismoRESUMEN
BACKGROUND: Glioblastoma multiform (GBM), a malignant brain tumour, has a very often poor prognosis. The therapeutic approach is represented by surgery followed by radiotherapy and chemotherapy. Hypoxia is a factor that causes a reduction of both radiotherapy and chemotherapy effectiveness in GBM and other cancers. Through the use of [64Cu][Cu(ATSM)], a hypoxia-targeting positron emission tomography (PET) radiotracer, is possible to identify the presence of hypoxic areas within a lesion and therefore modulate the therapeutic approach according to the findings. CASE PRESENTATION: In this case report, we observed an increase of radiotracer uptake from early acquisition to late acquisition in hypoxia sites and high correlation between [64Cu][Cu(ATSM) PET/CT results and expression of the hypoxia marker HIF-1α. CONCLUSIONS: [64Cu][Cu(ATSM) PET/CT represents a valid opportunity to reveal in vivo hypoxic areas in GBM lesion which can guide clinicians on selecting GMB patient's therapeutic scheme.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Glioblastoma/diagnóstico por imagen , Compuestos Organometálicos/farmacocinética , Tiosemicarbazonas/farmacocinética , Anciano , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Hipoxia de la Célula , Complejos de Coordinación , Relación Dosis-Respuesta en la Radiación , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/radioterapia , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Tomografía Computarizada por Tomografía de Emisión de Positrones , Trazadores Radiactivos , Radioterapia de Intensidad Modulada , Resultado del TratamientoRESUMEN
This study aims to develop a new anti-cancer formulation based on the chelator Dp44mT (Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone). Dp44mT has outstanding anti-tumor activity and the unique ability to overcome multidrug-resistance in cancer cells. This highly toxic compound has thus far only been applied in free form, limiting its therapeutic effectiveness. To reach its full therapeutic potential, however, Dp44mT should be encapsulated in a nano-carrier that would enable its selective and controlled delivery to malignant cells. As the first step towards this goal, here we encapsulate Dp44mT in nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA), characterize this nano-formulation, and evaluate its therapeutic potential against cancer cells in vitro. Our results showed that the Dp44mT-loaded NPs were homogenous in shape and size, and had good colloidal stability. These PLGA NPs also showed high encapsulation efficiency and loading capacity for Dp44mT and enabled the sustained and tunable release of this chelator. Dp44mT-NPs were uptaken by cancer cells, showed a strong and dose-dependent cytotoxicity towards these cells, and significantly increased apoptotic cell death, in both monolayer and spheroid tumor models. This formulation had a low-level of toxicity towards healthy control cells, indicating an inherent selectivity towards malignant cells. These results demonstrate the great potential of this novel Dp44mT-based nano-formulation for the use in cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Tiosemicarbazonas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacocinética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Quelantes/química , Quelantes/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Tamaño de la Partícula , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinéticaRESUMEN
OBJECTIVES: Drug resistance exists to all current and investigational antimalarial drug classes. Consequently, we have set out to develop chemically and mechanistically discrete antimalarials. Here we report on the development of thiosemicarbazone (TSC) antimalarials, with TSC3 as the most advanced lead. METHODS: Thiosemicarbazones were generated through simple condensation reactions of thiosemicarbazides and ketones. TSC3 was selected and tested for in vitro antimalarial activities against MDR Plasmodium falciparum lines using the [3H]hypoxanthine growth assay, in vitro cytotoxicity against mammalian cell lines using the alamarBlue fluorescence cell viability assay, in vivo potency in the mouse-Plasmodium berghei model and blood exposure in mice measured by LC-MS for pharmacokinetic analysis. RESULTS: TSC3 showed potent in vitro activity against atovaquone-, dihydroartemisinin-, chloroquine- and mefloquine-resistant P. falciparum lines (EC50 <15 nM). The selectivity index (EC50 cells/EC50Pf W2 line) of TSC3 was >500 in two of three mammalian cell lines. In P. berghei-infected mice, TSC3 showed potent activity in the Peters 4 day suppression test (ED50 1.2 mg/kg/day) and was as potent as artesunate and chloroquine in the curative modified Thompson test. A single oral dose of TSC3 at 16 mg/kg in healthy mice achieved a mean maximum blood concentration of 1883 ng/mL at 1 h after dosing and an elimination half-life of 48.7 h in groups of five mice. CONCLUSIONS: TSC3 shows promise as a persistent, potent and orally effective antimalarial. This, coupled with the extremely low cost of synthesis, suggests that the further development of antimalarial thiosemicarbazones is clearly warranted.
Asunto(s)
Antimaláricos/administración & dosificación , Malaria/tratamiento farmacológico , Tiosemicarbazonas/administración & dosificación , Administración Oral , Animales , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Análisis Químico de la Sangre , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cromatografía Liquida , Modelos Animales de Enfermedad , Femenino , Humanos , Espectrometría de Masas , Ratones , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/farmacocinética , Tiosemicarbazonas/farmacología , Resultado del TratamientoRESUMEN
The present work aimed to carry out in vitro biological assays of indol-3-yl derivatives thiosemicarbazones (2a-e) and 4-thiazolidinones (3a-d) against juvenile and adult worms of S. mansoni, as well as the in silico determination of pharmacokinetic parameters for the prediction of the oral bioavailability of these derivatives. All compounds were initially screened at a concentration of 200⯵M against S. mansoni adult worms and the results evidenced the good activity of compounds 2b, 2d and 3b, which caused 100% mortality after 24, 48 and 72â¯h, respectively. Subsequent studies with these same compounds revealed that compound 2b was able to reduce the viability of the parasites by 85% and 83% at concentrations of 200 and 100⯵M, respectively. In relation to the juvenile worms, all compounds (2b, 2d and 3b) were able to cause mortality, but compound 2b demonstrated better activity causing 100% mortality in 48â¯h. Additionally, it was possible to observe reduction in the viability of juvenile worms of 85%, 81% and 64% at concentrations of 200, 100 and 50⯵M, respectively. Several ultrastructural damages were observed when adult and juvenile S. mansoni worms were exposed to compound 2b (200⯵M) that was characterized by extensive destruction by the integument, which may justify the mortality rate of cultured parasites. In the DNA interaction assay, fragmentation of the genetic material of adult worms when treated with compound 2b (200⯵M) was evidenced, indicating the apoptosis process as mechanism of parasite death. Regarding pharmacokinetic properties, all derivatives are according to the required parameters, predicting good oral bioavailability for the studied compounds. The results presented in this study reveal the good activity of compound 2b in both adult and juvenile worms of S. mansoni, pointing this compound as promising in the development of further studies on schistosomicidal activity.
Asunto(s)
Schistosoma mansoni/efectos de los fármacos , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/farmacocinética , Animales , Helmintos/efectos de los fármacos , Esquistosomicidas/farmacocinética , Esquistosomicidas/farmacologíaRESUMEN
18 F-radiolabeled diphenyl gallium thiosemicarbazone was prepared by [18 F] fluoride exchange of a nitrato anion under mild conditions. The diphenyl gallium thiosemicarbazone chloride is easily prepared in gram quantities and can be used at room temperature in the presence of oxygen. The corresponding nitrate complex is prepared using silver nitrate in methanol solvent and can be stored under nitrogen for weeks before radiolabeling. The biodistribution of this new tracer was studied in mice using positron emission tomography (PET).
Asunto(s)
Radioisótopos de Flúor/química , Galio/química , Halógenos/química , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinética , Animales , Técnicas de Química Sintética , Femenino , Marcaje Isotópico , Mesilatos/química , Ratones , Ratones Endogámicos C57BL , Nitratos/química , Tomografía de Emisión de Positrones , Tiosemicarbazonas/síntesis química , Distribución TisularRESUMEN
BACKGROUND: In this study, the antioxidant property of new synthesized azomethins has been investigated as theoretical and experimental. METHODS AND RESULTS: Density functional theory (DFT) was employed to investigate the Bond Dissociation Enthalpy (BDE), Mulliken Charges, NBO analysis, Ionization Potential (IP), Electron Affinities (EA), HOMO and LUMO energies, Hardness (η), Softness (S), Electronegativity (µ), Electrophilic Index (ω), Electron Donating Power (ω-), Electron Accepting Power (ω+) and Energy Gap (Eg) in order to deduce scavenging action of the two new synthesized azomethines (FD-1 and FD-2). Spin density calculations and NBO analysis were also carried out to understand the antioxidant activity mechanism. Comparison of BDE of FD-1 and FD-2 indicate the weal antioxidant potential of these structures. CONCLUSION: FD-1 and FD-2 have very high antioxidant potential due to the planarity and formation of intramolecular hydrogen bonds.
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Antioxidantes/química , Antioxidantes/farmacología , Compuestos Azo/química , Compuestos Azo/farmacocinética , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinética , Algoritmos , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antioxidantes/síntesis química , Compuestos Azo/síntesis química , Fenómenos Químicos , Técnicas de Química Sintética , Modelos Moleculares , Modelos Teóricos , Tiosemicarbazonas/síntesis químicaRESUMEN
The synthesis of new bis(thiosemicarbazonato)copper(II) complexes featuring polyamine substituents via selective transamination reactions is presented. Polyamines of different lengths, with different ionizable substituent groups, were used to modify and adjust the hydrophilic/lipophilic balance of the copper complexes. The new analogues were radiolabeled with copper-64 and their lipophilicities estimated using distribution coefficients. The cell uptake of the new polyamine complexes was investigated with preliminary in vitro biological studies using a neuroblastoma cancer cell line. The in vivo biodistribution of three of the new analogues was investigated in vivo in mice using positron-emission tomography imaging, and one of the new complexes was compared to [64Cu]Cu(atsm) in an A431 squamous cell carcinoma xenograft model. Modification of the copper complexes with various amine-containing functional groups alters the biodistribution of the complexes in mice. One complex, with a pendent ( N, N-dimethylamino)ethane functional group, displayed tumor uptake similar to that of [64Cu]Cu(atsm) but higher brain uptake, suggesting that this compound has the potential to be of use in the diagnostic brain imaging of tumors and neurodegenerative diseases.
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Encéfalo/metabolismo , Complejos de Coordinación/farmacocinética , Radioisótopos de Cobre/química , Poliaminas/farmacocinética , Radiofármacos/farmacocinética , Tiosemicarbazonas/farmacocinética , Animales , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Femenino , Humanos , Ligandos , Ratones Endogámicos BALB C , Poliaminas/síntesis química , Poliaminas/química , Tomografía de Emisión de Positrones , Radiofármacos/síntesis química , Radiofármacos/química , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/química , Distribución TisularRESUMEN
Triapine, an iron chelator that inhibits ribonucleotide reductase, has been evaluated in clinical trials for cancer treatment. Triapine in combination with other chemotherapeutic agents shows promising efficacy in certain hematologic malignancies; however, it is less effective against many advanced solid tumors, probably due to the unsatisfactory potency and pharmacokinetic properties. In this report, we developed a triapine derivative IC25 (10) with potent antitumor activity. 10 Preferentially inhibited the proliferation of hematopoietic cancers by inducing mitochondria reactive oxygen species production and mitochondrial dysfunction. Unlike triapine, 10 executed cytotoxic action in a copper-dependent manner. 10-Induced up-expression of thioredoxin-interacting protein resulted in decreased thioredoxin activity to permit c-Jun N-terminal kinase and p38 activation and ultimately led to the execution of the cell death program. Remarkedly, 10 showed good bioavailability and inhibited tumor growth in mouse xenograft models. Taken together, our study identifies compound 10 as a copper-dependent antitumor agent, which may be applied to the treatment of hematopoietic cancers.
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Antineoplásicos/farmacocinética , Muerte Celular/efectos de los fármacos , Cobre/metabolismo , Neoplasias Hematológicas/patología , Piridinas/farmacología , Tiosemicarbazonas/farmacología , Animales , Disponibilidad Biológica , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Activación Enzimática , Neoplasias Hematológicas/metabolismo , Humanos , MAP Quinasa Quinasa 4/metabolismo , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Piridinas/química , Piridinas/farmacocinética , Especies Reactivas de Oxígeno/metabolismo , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinética , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Niemann-Pick C disease (NPC) is an autosomal recessive lysosomal storage disorder resulting from mutations in the NPC1 (95% of cases) or NPC2 genes. Disturbance of copper homeostasis has been reported in NPC1 disease. In this study we have used whole-body positron emission tomography (PET) and brain electronic autoradiography with copper-64 (64Cu), in the form of the copper(II) bis(thiosemicarbazonato) complex 64Cu-GTSM, to image short-term changes in copper trafficking after intravenous injection in a transgenic mouse model of NPC1 disease. 64Cu-GTSM is taken up in all tissues and dissociates rapidly inside cells, allowing monitoring of the subsequent efflux and redistribution of 64Cu from all tissues. Significantly enhanced retention of 64Cu radioactivity was observed in brain, lungs and blood at 15 h post-injection in symptomatic Npc1-/- transgenic mice compared to wildtype controls. The enhanced retention of 64Cu in brain was confirmed by electronic autoradiography, particularly in the midbrain, thalamus, medulla and pons regions. Positron emission tomography imaging with 64Cu in selected chemical forms could be a useful diagnostic and research tool for the management and understanding of NPC1 disease.
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Radioisótopos de Cobre/metabolismo , Radioisótopos de Cobre/farmacocinética , Modelos Animales de Enfermedad , Enfermedad de Niemann-Pick Tipo C/metabolismo , Tomografía de Emisión de Positrones , Animales , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacocinética , Radioisótopos de Cobre/administración & dosificación , Inyecciones Intravenosas , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Tiosemicarbazonas/administración & dosificación , Tiosemicarbazonas/química , Tiosemicarbazonas/metabolismo , Tiosemicarbazonas/farmacocinéticaRESUMEN
To be used as a carrier of 68Ga radioisotope for possible blood pool imaging studies, dialdehyde dextran thiosemicarbazone (DADTSC) Schiff base polymer with different thiosemicarbazone contents (TSCC)â¯=â¯0.93, 2.43, and 3.4â¯mmol/g were synthesized and characterized by FT-IR, GPC, and CHNS. Although they were successfully radiolabeled at room temperature, stable radio-complexes were prepared at 60⯰C. Effect of thiosemicarbazone content on the dissolution rate, cytotoxicity, coagulation and hemolysis activities, and radiolabeling efficiency of Schiff bases as well as on the in-vitro radio-complexes stability was investigated. DADTSC1 (TSCCâ¯=â¯0.93â¯mmol/g) showed a less cytotoxicity (cell viability, CV50â¯=â¯490⯵g/ml), a better solubility, suitable coagulation and hemolytic activities, and a sufficient radiolabeling efficiency (Radiochemical purity (RCP)â¯>â¯95%) and formed a stable (RCPâ¯>â¯90%) radio-complex, which be chosen for in-vivo biodistribution study in healthy rats through tissue sampling and counting for radioactivity. Like blood pool imaging agents, 68Ga-DADTSC1 presented a retention profile in blood circulation, though more studies, including imaging in larger mammals, are required.