RESUMEN
H2O2 and polarity are quite important in many physiological and pathological processes, and their relationship is complicated and obscure for researchers. Thus, it is vital and challenging to achieve simultaneous detection of H2O2 and polarity in vivo. Herein, the first naphthalimide-triphenylamine-based dual-site fluorescent probe NATPA is developed for simultaneously imaging intracellular H2O2 and polarity fluctuations. It exhibits excellent sensitivity (LOD = 44 nM), selectivity, and fast response (15 min) to H2O2 and a superior capacity for detecting polarity upon the intramolecular charge transfer (ICT) effect. Besides, the probe displays low cytotoxicity and lipid droplet targeting and is further applied in imaging H2O2 and polarity fluctuations in HepG2 and L-02 cells, so that NATPA is qualified to distinguish cancer cells from normal cells. This research contributes a new design principle for the construction of dual-site fluorescent probes for simultaneously detecting active molecules and polarity.
Asunto(s)
Colorantes Fluorescentes , Peróxido de Hidrógeno , Colorantes Fluorescentes/toxicidad , Células HeLa , Humanos , Gotas Lipídicas , Naftalimidas/toxicidadRESUMEN
There is a lack of molecular probes for imaging bacteria, in comparison to the array of such tools available for the imaging of mammalian cells. Here, organometallic molecular probes have been developed and assessed for bacterial imaging, designed to have the potential to support multiple imaging modalities. The chemical structure of the probes is designed around a metal-naphthalimide structure. The 4-amino-1,8-naphthalimide moiety, covalently appended through a pyridine ancillary ligand, acts as a luminescent probe for super-resolution microscopy. On the other hand, the metal centre, rhenium(i) or platinum(ii) in the current study, enables techniques such as nanoSIMS. While the rhenium(i) complex was not sufficiently stable to be used as a probe, the platinum(ii) analogue showed good chemical and biological stability. Structured illumination microscopy (SIM) imaging on live Bacillus cereus confirmed the suitability of the probe for super-resolution microscopy. NanoSIMS analysis was used to monitor the uptake of the platinum(ii) complex within the bacteria and demonstrate the potential of this chemical architecture to enable multimodal imaging. The successful combination of these two moieties introduces a platform that could lead to a versatile range of multi-functional probes for bacteria.
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Iluminación , Naftalimidas , Animales , Bacterias , Lípidos , Luminiscencia , Naftalimidas/toxicidadRESUMEN
We reported here a naphthalimide-based fluorescent probe LysOBr that localizes in the lysosome in live cells. LysOBr exhibits excellent HOBr selectivity and desirable optical properties. It can quantitatively detect lysosomal HOBr at 0-20 µM, with a detection limit of 243 nM. The short (4 s) response time allows real-time HOBr detection and imaging, as shown with studies in live HeLa cancer cells. It is thus the most rapidly responsive HOBr probe to date, among the most selective ones, and the first probe that is lysosome-specific with a "turn-on" signal. The probe structure is modular, and convenient structural modification should lead to other organelle-specific probes.
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Bromatos , Neoplasias , Colorantes Fluorescentes , Células HeLa , Humanos , Lisosomas , Naftalimidas/toxicidad , Imagen ÓpticaRESUMEN
Hydrogen sulfide (H2S) in mitochondria plays important roles in many mitochondria-related physiological and pathological processes. Herein, a cyanine/naphthalimide hybrid fluorescent probe, L1, was designed for the ratiometric detection and imaging of mitochondrial H2S, in which cyanine and naphthalimide were used as the mitochondria-targeting group and H2S response group, respectively. Besides its good mitochondria-targeting ability, L1 also showed high sensitivity and good selectivity for H2S. Moreover, on the basis of the fluorescence ratio of naphthalimide to cyanine fluorophore, it was successfully applied to monitor the endogenous and exogenous mitochondrial H2S in live cells. Additionally, the endogenous mitochondrial H2S in different cell lines was measured by probe L1.
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Colorantes Fluorescentes , Sulfuro de Hidrógeno , Mitocondrias , Naftalimidas/toxicidad , Imagen ÓpticaRESUMEN
The current effort demonstrates that lutetium oxyorthosilicate doped with 1-10% cerium (Lu2SiO5:Ce, LSO:Ce) radioluminescent particles can be coated with a single dye or multiple dyes and generate an effective energy transfer between the core and dye(s) when excited via X-rays. LSO:Ce particles were surface modified with an alkyne modified naphthalimide (6-piperidin-1-yl-2-prop-2-yn-1-yl-1 H-benzo[ de]isoquinoline-1,3-(2 H)-dione, AlNap) and alkyne modified rhodamine B ( N-(6-diethylamino)-9-{2-[(prop-2-yn-1-yloxy)carbonyl]phenyl}-3 H-xanthen-3-ylidene)- N-ethylethanaminium, AlRhod) derivatives to tune the X-ray excited optical luminescence from blue to green to red using Förster Resonance Energy Transfer (FRET). As X-rays penetrate tissue much more effectively than UV/visible light, the fluorophore modified phosphors may have applications as bioimaging agents. To that end, the phosphors were incubated with rat cortical neurons and imaged after 24 h. The LSO:Ce surface modified with AlNap was able to be successfully imaged in vitro with a low-output X-ray tube. To use the LSO:Ce fluorophore modified particles as imaging agents, they must not induce cytotoxicity. Neither LSO:Ce nor LSO:Ce modified with AlNap showed any cytotoxicity toward normal human dermal fibroblast cells or mouse cortical neurons, respectively.
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Cerámica/química , Cerio/química , Colorantes Fluorescentes/química , Lutecio/química , Silicatos/química , Animales , Cerámica/efectos de la radiación , Cerámica/toxicidad , Cerio/efectos de la radiación , Cerio/toxicidad , Fibroblastos/efectos de los fármacos , Fluorescencia , Transferencia Resonante de Energía de Fluorescencia , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/efectos de la radiación , Colorantes Fluorescentes/toxicidad , Humanos , Lutecio/efectos de la radiación , Lutecio/toxicidad , Ratones , Naftalimidas/síntesis química , Naftalimidas/química , Naftalimidas/efectos de la radiación , Naftalimidas/toxicidad , Neuronas/efectos de los fármacos , Imagen Óptica/métodos , Ratas , Rodaminas/síntesis química , Rodaminas/química , Rodaminas/efectos de la radiación , Rodaminas/toxicidad , Silicatos/efectos de la radiación , Silicatos/toxicidad , Rayos XRESUMEN
Real-time monitoring of the cytochrome P450 1A1 (CYP1A1) activity in complex biological systems via a practical tool is highly sought after because of its significant role in the metabolism and bioactivation of various xenobiotics. Herein, according to slight differences in the 3D structure and substrate preference between CYP1A1 and its homologous CYP1A2, a series of novel ratiometric fluorescent probes were designed and synthesized using 1,8-naphthalimide because of its trait of naked-eye visualization and ratiometric fluorescence to achieve the detection of CYP1A1 in biological samples. Among these probes, NEiPN showed good water solubility, highly isoform selectivity and great sensitivity (LOD = 0.04874 nM) for CYP1A1 under simulated physiological conditions, which makes it favorable for monitoring CYP1A1 in vivo. Remarkably, NEiPN exhibited excellent reproducibility when it was used to detect the CYP1A1 content in human liver microsomes, which indicated that it has a great potential for quantifying the CYP1A1 content in real biological samples. Furthermore, NEiPN showed relatively low cytotoxicity and has been successfully applied in biological imaging in living cells and zebrafish. These findings indicate that NEiPN is capable of real-time monitoring of the activity of endogenous CYP1A1, which could provide support for CYP1A1-associated pathological processes.
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Citocromo P-450 CYP1A1/análisis , Colorantes Fluorescentes/química , Naftalimidas/química , Proteínas de Pez Cebra/análisis , Animales , Línea Celular Tumoral , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/toxicidad , Humanos , Límite de Detección , Microscopía Confocal/métodos , Microscopía Fluorescente/métodos , Microsomas Hepáticos/metabolismo , Naftalimidas/síntesis química , Naftalimidas/toxicidad , Isoformas de Proteínas/análisis , Reproducibilidad de los Resultados , Solubilidad , Agua/química , Pez CebraRESUMEN
In recent years, targeting drugs made by physical loading or chemical bonding of drugs on small molecular carriers have shown a very wide application prospect in the field of tumor and cancer treatment. How to achieve the release of drugs in cancer cells has become the core of this research. One of the most important bases for drug localization is to use the difference of small molecular biothiol concentration between cancer cells and normal cells. Details of the changes of biothiol levels in the growth and reproduction of cancer cells are still poorly understood, and the main reason is the lack of sensitive real-time imaging tools for biothiols in cancer cells. In this work, we reasonably designed and synthesized the combination of 4-hydroxy-1,8-naphthalimide and NBD-Cl as a concise fluorescent probe HN-NBD for imaging biothiols in live cells and zebrafish. In addition, due to the advantages of HN-NBD design, it is sufficiently sensitive to biothiols, and further imaging can distinguish cancer cells from normal cells. Probe HN-NBD would be of great significance to biomedical researchers for the study of biothiol-related diseases, the screening of new anticancer drugs, and the early diagnosis and treatment of cancers.
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Cisteína/análisis , Colorantes Fluorescentes/química , Glutatión/análisis , Homocisteína/análisis , Neoplasias/diagnóstico por imagen , 4-Cloro-7-nitrobenzofurazano/análogos & derivados , 4-Cloro-7-nitrobenzofurazano/síntesis química , 4-Cloro-7-nitrobenzofurazano/toxicidad , Animales , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/toxicidad , Células HeLa , Células Endoteliales de la Vena Umbilical Humana , Humanos , Límite de Detección , Ratones , Microscopía Confocal/métodos , Microscopía Fluorescente/métodos , Naftalimidas/síntesis química , Naftalimidas/química , Naftalimidas/toxicidad , Imagen Óptica/métodos , Células RAW 264.7 , Pez CebraRESUMEN
Piperazine appended naphthalimide-BODIPYs (NPB1-NPB4) exhibiting solvatochromism and aggregation-induced emission with a large Stokes shift (up to 146 nm) have been described. Separation of naphthalimide and BODIPY fluorophores by piperazine in these conjugates creates a donor-acceptor system and induces twisted intramolecular charge transfer, in addition to photoinduced electron transfer. The crucial role of naphthalimide, the alkyl chain length, the piperazine ring, and the solid-state packing on AIE has been extensively investigated by various studies. Superior cell permeability coupled with bio-compatibility of these conjugates offers a unique opportunity for their potential applications in live cell lysosomal tracking.
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Compuestos de Boro/química , Colorantes Fluorescentes/química , Lisosomas/metabolismo , Naftalimidas/química , Piperazinas/química , Compuestos de Boro/síntesis química , Compuestos de Boro/efectos de la radiación , Compuestos de Boro/toxicidad , Fluorescencia , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/efectos de la radiación , Colorantes Fluorescentes/toxicidad , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Luz , Estructura Molecular , Naftalimidas/síntesis química , Naftalimidas/efectos de la radiación , Naftalimidas/toxicidad , Piperazinas/síntesis química , Piperazinas/efectos de la radiación , Piperazinas/toxicidad , Espectrometría de FluorescenciaRESUMEN
Sensing hypoxia in tissues and cell models can provide insights into its role in disease states and cell development. Fluorescence imaging is a minimally-invasive method of visualising hypoxia in many biological systems. Here we present a series of improved bioreductive fluorescent sensors based on a nitro-naphthalimide structure, in which selectivity, photophysical properties, toxicity and cellular uptake are tuned through structural modifications. This new range of compounds provides improved probes for imaging and monitoring hypoxia, customised for a range of different applications. Studies in monolayers show the different reducing capabilities of hypoxia-resistant and non-resistant cell lines, and studies in tumour models show successful staining of the hypoxic region.
Asunto(s)
Colorantes Fluorescentes/química , Hipoxia/diagnóstico por imagen , Naftalimidas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/toxicidad , Humanos , Células Madre Mesenquimatosas/metabolismo , Microscopía Confocal , Microscopía Fluorescente , Naftalimidas/síntesis química , Naftalimidas/toxicidad , Esferoides Celulares/metabolismoRESUMEN
Platinum-based anticancer drugs act therapeutically by forming DNA adducts, but suffer from severe toxicity and resistance problems, which have not been overcome in spite of decades of research. And yet defined chromatin targets have generally not been considered in the drug development process. Here we designed novel platinum-intercalator species to target a highly deformed DNA site near the nucleosome center. Between two seemingly similar structural isomers, we find a striking difference in DNA site selectivity in vitro, which comes about from stereochemical constraints that limit the reactivity of the trans isomer to special DNA sequence elements while still allowing the cis isomer to efficiently form adducts at internal sites in the nucleosome core. This gives the potential for controlling nucleosome site targeting in vivo, which would engender sensitivity to epigenetic distinctions and in particular cell type/status-dependent differences in nucleosome positioning. Moreover, while both compounds yield very similar DNA-adduct structures and display antitumor cell activity rivalling that of cisplatin, the cis isomer, relative to the trans, has a much more rapid cytotoxic effect and distinct impact on cell function. The novel stereochemical principles for controlling DNA site selectivity we discovered could aid in the design of improved site discriminating agents.
Asunto(s)
Antineoplásicos/química , Sustancias Intercalantes/química , Naftalimidas/química , Nucleosomas/química , Compuestos Organoplatinos/química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Aductos de ADN/análisis , Humanos , Sustancias Intercalantes/toxicidad , Naftalimidas/toxicidad , Compuestos Organoplatinos/toxicidad , EstereoisomerismoRESUMEN
As one of the simplest reactive carbonyl species, formaldehyde is implicated in nervous system diseases and cancer. Organelles play crucial roles in various physiological processes in living cells. Accordingly, the detection of endogenous formaldehyde at the subcellular level is of high interest. We herein describe the development of the first organelle-targeted fluorescent formaldehyde probe (Na-FA-Lyso). The new probe exhibits favorable features including a large fluorescence enhancement (about 350-fold) and a fast response to formaldehyde. Significantly, the novel probe Na-FA-Lyso was employed to visualize the endogenous formaldehyde in the lysosomes in living cells for the first time.
Asunto(s)
Colorantes Fluorescentes/farmacología , Formaldehído/análisis , Hidrazinas/farmacología , Lisosomas/metabolismo , Naftalimidas/farmacología , Fluorescencia , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/efectos de la radiación , Colorantes Fluorescentes/toxicidad , Células HeLa , Humanos , Hidrazinas/síntesis química , Hidrazinas/efectos de la radiación , Hidrazinas/toxicidad , Luz , Naftalimidas/síntesis química , Naftalimidas/efectos de la radiación , Naftalimidas/toxicidadRESUMEN
In this study, we developed a turn-on mitochondria-targeting hydrogen sulfide, "probe 1", based on the selective thiolysis of 7-nitro-1,2,3-benzoxadiazole amine moiety attached to the piperazine-based naphthalimide scaffold. Probe 1 exhibited excellent properties with 68-fold fluorescence enhancement, a low detection limit (2.46 µM), a low cytotoxicity, and a good selectivity toward hydrogen sulfide. The success of intracellular imaging indicated that probe 1 could be used in further applications for the investigation of biological functions and pathological roles of H2S in living systems.
Asunto(s)
Colorantes Fluorescentes/química , Sulfuro de Hidrógeno/análisis , Mitocondrias/química , Supervivencia Celular/efectos de los fármacos , Colorantes Fluorescentes/toxicidad , Células HeLa , Humanos , Sulfuro de Hidrógeno/química , Sulfuro de Hidrógeno/metabolismo , Microscopía Confocal , Mitocondrias/metabolismo , Naftalimidas/química , Naftalimidas/toxicidad , Espectrometría de FluorescenciaRESUMEN
CONTEXT: The widely used antineoplastic drug cyclophosphamide causes pulmonary toxicity by inducing oxidative stress. Selenium, a dietary micronutrient, has been found to protect various organs from oxidative injuries. OBJECTIVE: This study was designed to investigate the protective efficacy of an organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione against cyclophosphamide-induced pulmonary toxicity in Swiss albino mice. MATERIALS AND METHODS: Cyclophosphamide (25 mg/kg b.w.) was administered intraperitoneally for 10 d and the organoselenium compound (3 mg/kg b.w.) was given by oral gavage in concomitant and pretreatment schedules. Various biochemical parameters related to oxidative stress and antioxidant enzymes along with histology of lungs were evaluated to assess the effect of the test compound. RESULTS: The oral LD50 of the test compound was more than 1000 mg/kg b.w. in Swiss albino mice. The test compound substantially ameliorated cyclophosphamide-induced pulmonary injury by reducing the levels of reactive oxygen species, reactive nitrogen species, and lipid peroxidation, respectively, by 14.88, 18.54, and 21.10% in concomitant treatment schedule and by 23.89, 35.73, and 30.76% in the pretreatment schedule as well as by restoring the level of reduced glutathione and activities of glutathione-S-transferase, superoxide dismutase, catalase, and glutathione peroxidase, respectively, by 36.88, 42.43, 38.0, 35.0, and 34.06% in the concomitant treatment schedule and by 66.02, 59.29, 57.23, 71.59, and 57.22% in the pretreatment schedule. The test compound also attenuated cyclophosphamide-induced histological alterations of lung tissue. DISCUSSION AND CONCLUSION: The test compound emerged as an efficient antioxidant protecting lungs tissue from cyclophosphamide-induced injury.
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Antineoplásicos Alquilantes/toxicidad , Antioxidantes/uso terapéutico , Ciclofosfamida/toxicidad , Lesión Pulmonar/prevención & control , Pulmón/efectos de los fármacos , Naftalimidas/uso terapéutico , Compuestos de Organoselenio/uso terapéutico , Animales , Antioxidantes/toxicidad , Femenino , Dosificación Letal Mediana , Pulmón/enzimología , Pulmón/patología , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Ratones , Estructura Molecular , Naftalimidas/toxicidad , Compuestos de Organoselenio/toxicidad , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The synthesis and characterisation of five bis-1,8-naphthalimide containing Tröger's bases 15 formed from their corresponding 3-amino-1,8-naphthalimide precursors 610 is described. The photophysical investigations of 15 and 610 were carried out in several organic solvents as well as in water and as a function of pH using UV-Vis absorption and fluorescence spectroscopies. The DNA binding affinities of 15 in aqueous solution at pH 7.4 were also investigated using several UV-Vis absorption and fluorescence experiments by using calf thymus DNA (ct-DNA). These molecules exhibited significant DNA binding affinities; where large binding values (Kb) in the range of 10(6) M(−1) were determined, even in competitive media (50 mM and 160 mM NaCl at pH 7.4). Thermal denaturation measurements also showed that 15 significantly stabilised the DNA helix. Using linear and circular dichroism we further demonstrated that the DNA binding interaction occurs both by intercalation and by groove binding. The Tröger's bases were further shown to be rapidly taken up into cells using confocal fluorescence spectroscopy; and cytotoxic studies in HeLa and MCF-7 cells showed that most of the Tröger's bases were effective cytotoxic agents with EC50 values of between 1.112 µM and that all the active compounds induced programmed cell death by apoptosis, where up to 70% cellular death was observed after 24 h of incubation for 4.
Asunto(s)
Citotoxinas/toxicidad , ADN/química , Sustancias Intercalantes/toxicidad , Naftalimidas/toxicidad , Animales , Apoptosis/efectos de los fármacos , Bovinos , Citotoxinas/síntesis química , Citotoxinas/química , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Sustancias Intercalantes/síntesis química , Sustancias Intercalantes/química , Células MCF-7 , Naftalimidas/síntesis química , Naftalimidas/química , Conformación de Ácido Nucleico/efectos de los fármacos , Procesos Fotoquímicos , Estereoisomerismo , Agua/químicaRESUMEN
Nucleic acid binding molecules have been extensively explored for nucleic acid assay, nuclear imaging, and antitumor and antivirus therapies. Most of these molecules usually bear positive charges to enhance their binding affinity. However, their in vivo applications are limited by poor membrane permeability and the lack of selectivity to nucleic acids. Here we describe the effects of positive charged side chains (including aminoethyl, dimethylaminopropyl and guanidinoethyl) on the DNA binding ability, cell permeability, cellular localization and cytotoxicity of 4-aminonaphthalimides, a class of DNA-intercalating agents and fluorophores. The synthesized 4-aminonaphthalimides have a strong binding ability to duplex DNA, and can be used as pre-staining dyes for gel electrophoresis of DNA and RNA. When entering into cells, they rapidly concentrate in cell nuclei, especially in nucleoli. The guanidinoethyl side chains increase the binding ability to nucleic acids, but do not favour the cell permeability and cytotoxicity; dimethylaminopropyl groups enhance the cell permeability and cytotoxicity of 4-aminonaphthalimides. These results suggest the potential applications of 4-aminonaphthalimides in nucleic acid assay and nuclear imaging, and provide useful information for the molecular design of DNA-binding drugs and fluorescent probes.
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Antineoplásicos/síntesis química , ADN/química , Naftalimidas/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Supervivencia Celular/efectos de los fármacos , Electroforesis en Gel de Agar , Humanos , Sustancias Intercalantes/síntesis química , Sustancias Intercalantes/química , Sustancias Intercalantes/farmacología , Células MCF-7 , Naftalimidas/química , Naftalimidas/farmacocinética , Naftalimidas/toxicidad , Permeabilidad/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacosRESUMEN
Polyamines as a vector to ferry toxic agents have attracted attention, and naphthalimide-polyamine conjugates show potent activity and tumor cell selectivity. The present study was carried out to evaluate the antitumor effects and preliminary systemic toxicity of ANISpm, a novel 3-amino-naphthalimide-spermine conjugate. The polyamine transport system recognition of ANISpm, supported by α-difluoromethylornithine (DFMO)/spermidine (Spd) experiments, is in accordance with its potent cell selectivity between human hepatoma HepG2 cells and normal QSG7701 hepatocyte. The antiproliferative effect is because of ANISpm-induced cell apoptosis, a common characteristic of both naphthalimide and polyamine analogs. Various apoptotic assessment assays have shown that ANISpm can induce apoptosis through the PI3K/Akt signal pathway. The apoptotic signaling cascade involves Akt inactivation, which results in a series of cellular events. The downstream pathway includes Bad dephosphorylation, dissociation of 14-3-3 and Bad, and binding to Bcl-xL, which triggers the disruption of the mitochondrial membrane, release of cytochrome c, and caspases' cascade activation. Furthermore, the Akt/mTOR signal pathway is also involved in ANISpm-mediated cell-cycle arrest. Additive DFMO or Spd, which only enhances or attenuates ANISpm-mediated cell apoptosis, respectively, does not alter the signal pathway. In addition, preliminary toxicology evaluation showed that ANISpm had no obvious system toxicity at a dose of 2.5 mg/kg, which exerted potent antitumor activity in vivo, especially hematotoxicity. Thus, ANISpm merits further investigation as a potential chemotherapeutic agent against hepatocellular carcinoma.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Naftalimidas/farmacología , Espermina/análogos & derivados , Animales , Apoptosis/efectos de los fármacos , Células CHO , Carcinoma Hepatocelular/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Naftalimidas/síntesis química , Naftalimidas/toxicidad , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Espermina/síntesis química , Espermina/farmacología , Espermina/toxicidad , Serina-Treonina Quinasas TOR/metabolismo , Pruebas de Toxicidad , Proteína Letal Asociada a bcl/metabolismoRESUMEN
A series of arylnaphthalimides were designed and synthesized to overcome the dose-limiting cytotoxicity of N-acetylated metabolites arising from amonafide, the prototypical antitumour naphthalimide whose biomedical properties have been related to its ability to intercalate the DNA and poison the enzyme Topoisomerase II. Thus, these arylnaphthalimides were first evaluated for their antiproliferative activity against two tumour cell lines and for their antitopoisomerase II in vitro activities, together with their ability to intercalate the DNA in vitro and also through docking modelization. Then, the well-known DNA damage response in Saccharomyces cerevisiae was employed to critically evaluate whether these novel compounds can damage the DNA in vivo. By performing all these assays we conclude that the 5-arylsubstituted naphthalimides not only keep but also improve amonafide's biological activities.
Asunto(s)
Antineoplásicos/síntesis química , ADN-Topoisomerasas de Tipo II/química , ADN/metabolismo , Sustancias Intercalantes/síntesis química , Naftalimidas/química , Antineoplásicos/química , Antineoplásicos/toxicidad , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN/química , Daño del ADN/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Sustancias Intercalantes/química , Sustancias Intercalantes/toxicidad , Células MCF-7 , Simulación del Acoplamiento Molecular , Naftalimidas/síntesis química , Naftalimidas/toxicidad , Estructura Terciaria de Proteína , Saccharomyces cerevisiae/genéticaRESUMEN
Hepatocellular carcinoma (HCC) is one of the main causes of death in cancer. Some naphthalimide derivatives exert high anti-proliferative effects on HCC. In this study, it is confirmed that 3-nitro-naphthalimide and nitrogen mustard conjugate (NNM-25), a novel compound conjugated by NNM-25, displayed more potent therapeutic action on HCC, both in vivo and in vitro, than amonafide, a naphthalimide drug in clinical trials. More importantly, preliminary toxicological evaluation also supported that NNM-25 exhibited less systemic toxicity than amonafide at the therapeutic dose. The antitumor mechanism of conjugates of naphthalimides with nitrogen mustard remains poorly understood up to now. Here, we first reported that apoptosis might be the terminal fate of cancer cells treated with NNM-25. Inhibition of p53 by siRNA resulted in a significant decrease of NNM-25-induced apoptosis, which corroborated that p53 played a vital role in the cell apoptosis triggered by NNM-25. NNM-25 inhibited the PARP-1 activity, AKT phosphorylation, up-regulated the protein expression of p53, Bad, and mTOR as well as down-regulating the protein expression of Bcl-2 and decreasing mitochondrial membrane potential. It also facilitated cytochrome c release from mitochondria to cytoplasm, activated caspase 8, caspase 9, and caspase 3 in HepG2 cells in vitro, as also authenticated in H22 tumor-bearing mice in vivo. Collectively, the conjugation of naphthalimides with nitrogen mustard provides favorable biological activity and thus is a valuable strategy for future drug design in HCC therapy.
Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Naftalimidas/farmacología , Compuestos de Mostaza Nitrogenada/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Western Blotting , Carcinoma Hepatocelular/enzimología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN de Neoplasias/metabolismo , Fluorescencia , Humanos , Sustancias Intercalantes/farmacología , Neoplasias Hepáticas/enzimología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Naftalimidas/síntesis química , Naftalimidas/química , Naftalimidas/toxicidad , Proteínas de Neoplasias/metabolismo , Compuestos de Mostaza Nitrogenada/síntesis química , Compuestos de Mostaza Nitrogenada/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Acrolein is a highly toxic agent that can be generated exogenously and endogenously. Therefore, a highly specific and sensitive probe for acrolein with potential applications in acrolein detection must be developed. In this research, a novel fluorescent probe named "probe for acrolein detection" (Pr-ACR) was designed and synthesized based on a naphthalimide fluorophore skeleton, and a thiol group (-SH) was introduced into its structure for acrolein recognition. The -SH traps acrolein via Michael addition and the resultant interaction product of the probe inhibits the photoinduced electron transfer process and produce a strong fluorescence at 510 nm. The probe showed high sensitivity and specificity for acrolein. HPLC-MS/MS analysis verified that it can be used to quantify acrolein in foods, such as soda crackers, red wine, and baijiu, with a fluorescence spectrophotometer. After methyl esterification, the methyl esterified probe (mPr-ACR) successfully visualised acrolein in Hela cells under a laser scanning confocal microscope. This finding proved that Pr-ACR and mPr-ACR are potential tools for the detection and visualisation of acrolein from different sources.
Asunto(s)
Acroleína , Naftalimidas , Acroleína/toxicidad , Colorantes Fluorescentes , Células HeLa , Humanos , Naftalimidas/toxicidad , Espectrometría de Masas en TándemRESUMEN
Naphthalimide-based fluorescent probes (NAN0-N3 and NAN6-N3) were developed with dual locked fluorescence. Here, ≥1.9 × 10-2 mM of H2S and ≥2.2 × 10-2 µg mL-1 of DNA could unlock a highly sensitive off-on fluorescence response through synergistic changes of the molecular structure and conformation. As such, the probes could monitor DNA damage induced by the overexpression of H2S, and were able to evaluate the degree of apoptosis of living cells mediated by H2S-induced mtDNA or nDNA damage.