RESUMEN

Purpose: Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against Mycobacterium marinum (M. marinum) which is genetically related to Mycobacterium tuberculosis (Mtb) and resistant to many antituberculosis drugs. Methods: Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against M. marinum were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of M. marinum infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model. Results: The results reveal that EbSe acts as an antibiotic adjuvant over SM on M. marinum. EbSe + SM disrupted the intracellular redox microenvironment of M. marinum by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity. Conclusion: The above studies suggest that EbSe significantly enhanced the anti-Mtb effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.

Asunto(s)

Homeostasis , Isoindoles , Pruebas de Sensibilidad Microbiana , Compuestos de Organoselenio , Oxidación-Reducción , Estreptomicina , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química , Isoindoles/farmacología , Animales , Ratones , Homeostasis/efectos de los fármacos , Estreptomicina/farmacología , Antituberculosos/farmacología , Antituberculosos/química , Mycobacterium marinum/efectos de los fármacos , Azoles/farmacología , Azoles/química , Relación Dosis-Respuesta a Droga , Antibacterianos/farmacología , Antibacterianos/química , Relación Estructura-Actividad , Estructura Molecular , Ratones Endogámicos BALB C

RESUMEN

Drug-loaded polymeric micelles have proven to be highly effective carrier systems for the efficient delivery of hydrophobic photosensitizers (PSs) in photodynamic therapy (PDT). This study introduces the micellization potential of poly(oligoethylene glycol methyl ether methacrylate) (pOEGMA) as a novel approach, utilizing the hydrophobic methacrylate segments of pOEGMA to interact with highly hydrophobic zinc phthalocyanine (ZnPc), thereby forming a potential micellar drug carrier system. The ZnPc molecule was synthesized from phthalonitrile derivatives and its fluorescence, photodegradation, and singlet oxygen quantum yields were determined in various solvents. In solvents such as tetrahydrofuran, dimethyl sulfoxide, and N,N-dimethylformamide, the ZnPc compound exhibited the requisite photophysical and photochemical properties for PDT applications. The pOEGMA homopolymer was synthesized via reversible addition-fragmentation chain-transfer polymerization, while ZnPc-loaded pOEGMA micelles were prepared using the nanoprecipitation method. Characterization of the pOEGMA, ZnPc, and micelles was conducted using FTIR,1H-NMR, dynamic light scattering, matrix-assisted laser desorption/ionization time-of-flight mass spectrometries, gel permeation chromatography, and transmission electron microscopy. The critical micelle concentration was determined to be 0.027 mg ml-1using fluorescence spectrometry. The drug loading and encapsulation efficiencies of the ZnPc-loaded micelles were calculated to be 0.67% and 0.47%, respectively. Additionally, the release performance of ZnPc from pOEGMA micelles was monitored over a period of nearly 10 d, while the lyophilized micelles exhibited stability for 3 months. Lastly, the ZnPc-loaded micelles were more biocompatible than ZnPc on L929 cell line. The results suggest that the pOEGMA homopolymer possesses the capability to micellize through its methacrylate segments when interacting with highly hydrophobic molecules, presenting a promising avenue for enhancing the delivery efficiency of hydrophobic PSs in PDT. Moreover, it was also deciphered that obtained formulations were highly biocompatible according to cytotoxicity results and could be safely employed as drug delivery systems in further applications.

Asunto(s)

Portadores de Fármacos , Indoles , Isoindoles , Micelas , Compuestos Organometálicos , Fotoquimioterapia , Fármacos Fotosensibilizantes , Polietilenglicoles , Compuestos de Zinc , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/administración & dosificación , Indoles/química , Compuestos de Zinc/química , Compuestos Organometálicos/química , Polietilenglicoles/química , Portadores de Fármacos/química , Supervivencia Celular/efectos de los fármacos , Oxígeno Singlete/química , Interacciones Hidrofóbicas e Hidrofílicas

RESUMEN

Amyloid ß peptide (Aß) aggregation and deposition are considered the main causes of Alzheimer's disease. In a previous study, we demonstrated that anionic Zn-phthalocyanine (ZnPc) can interact with the Aß peptide and inhibit the fibril-formation process. However, due to the inability of anionic ZnPc to cross the intact blood-brain barrier, we decided to explore the interaction of cationic methylated Zn-phthalocyanine (cZnPc) with the peptide. Using a ThT fluorescence assay, we observed that cZnPc dose-dependently and time-dependently inhibited Aß1-42 fibril levels under in vitro fibril-formation conditions. Electron microscopy revealed that it caused Aß1-42 peptides to form small aggregates. Western blotting and dot immunoblot oligomer experiments demonstrated that cZnPc increased rather than decreased the levels of oligomers from the very early stages of incubation. A binding assay confirmed that cZnPc could bind with the peptide. Docking simulations indicated that the oligomer species of Aß1-42 had a higher ability to interact with cZnPc. ANS fluorescence assay results indicated that cZnPc did not affect the hydrophobicity of the peptide. However, cZnPc significantly increased intrinsic tyrosine fluorescence of the peptide after 8 h of incubation in fibril-formation conditions. Importantly, cell culture experiments demonstrated that cZnPc did not exhibit any toxicity up to a concentration of 10 µM. Instead, it protected a neuronal cell line from Aß1-42-induced toxicity. Thus, our results suggest that cZnPc can affect the aggregation process of Aß1-42, rendering it non-toxic, which could be crucial for the therapy of Alzheimer's disease.

Asunto(s)

Enfermedad de Alzheimer , Péptidos beta-Amiloides , Indoles , Isoindoles , Compuestos Organometálicos , Fragmentos de Péptidos , Compuestos de Zinc , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Indoles/química , Indoles/farmacología , Humanos , Compuestos de Zinc/química , Compuestos de Zinc/farmacología , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/química , Fragmentos de Péptidos/química , Fragmentos de Péptidos/toxicidad , Fragmentos de Péptidos/farmacología , Agregado de Proteínas/efectos de los fármacos , Animales , Simulación del Acoplamiento Molecular , Neuronas/efectos de los fármacos , Neuronas/metabolismo

RESUMEN

The use of TiO2 as a photosensitizer in photodynamic therapy is limited due to TiO2 generates reactive oxygen species only under UV irradiation. The TiO2 surface has been modified with different functional groups to achieve activation at longer wavelengths (visible light). This work reports the synthesis, characterization, and biological toxicity assay of TiO2 nanoparticles functionalized with folic acid and combined with a zinc phthalocyanine to obtain a nano-photosensitizer for its application in photodynamic therapy for glioblastoma cancer treatment. The nano-photosensitizer was prepared using the sol-gel method. Folic acid and zinc phthalocyanine were added during the hydrolysis and condensation of titanium butoxide, which was the TiO2 precursor. The samples obtained were characterized by several microscopy and spectroscopy techniques. An in vitro toxicity test was performed using the MTT assay and the C6 cellular line. The results of the characterization showed that the structure of the nanoparticles corresponds mainly to the anatase phase. Successful functionalization with folic acid and an excellent combination with phthalocyanine was also achieved. Both folic acid-functionalized TiO2 and phthalocyanine-functionalized TiO2 had no cytotoxic effect on C6 cells (even at high concentrations) in comparison to Cis-Pt, which was very toxic to C6 cells. The materials behaved similarly to the control (untreated cells). The cell viability and light microscopy images suggest that both materials could be considered biocompatible and mildly phototoxic in these cells when activated by light.

Asunto(s)

Supervivencia Celular , Ácido Fólico , Glioblastoma , Indoles , Isoindoles , Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Titanio , Compuestos de Zinc , Titanio/química , Ácido Fólico/química , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Indoles/química , Indoles/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Nanopartículas/química , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Humanos , Animales , Ratas

RESUMEN

Novel anticancer strategies reduce side effects on healthy tissues by elevating the lethal abilities of cancer cells. The development of effective particles with good bioavailability and selectivity remains problematic. For undesirable features, green chemistry is used to synthesize the best compounds, or natural-based particles are improved. Photodynamic therapy (PDT), modelled on phthalocyanines (Pcs), still delivers second-generation sensitizers which are complemented with metal ions, such as Zn2+, Al3+, or Ga3+. Gallium octacarboxyphthalocyanine hydroxide (Ga(OH)PcOC), was designed for skin cancer treatment, and was used as a pro-apoptotic and pro-oxidative agent on normal skin cell lines, fibroblasts (NHDF), and keratinocytes (HaCaT), with promising selectivity against melanoma cancer cells (Me45) in vitro. Compared to the previous reported findings, where the ZnPcOC acted on the skin cell lines at higher doses, the sensitivities to the Ga(OH)PcOC allows for an effective reduction of the sensitizer dose. The effective dose, for a novel Ga(OH)PcOC particle, was significantly reduced from 30 µM to 6 µM on Me45 cancer cells, tested using 24 h MTT viability, as well as cytometric pro-oxidative and pro-apoptotic assays. The promising photosensitizer did not reduce viability in normal fibroblasts and keratinocytes without reactive oxygen species (ROS) elevation or apoptosis induction. The improvement to the previous findings is better Ga-based photosensitizer selectivity against the cancer Me45 cells, then observed in Zn-based compounds.

Asunto(s)

Antineoplásicos , Apoptosis , Ensayos de Selección de Medicamentos Antitumorales , Galio , Indoles , Fármacos Fotosensibilizantes , Neoplasias Cutáneas , Humanos , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Galio/química , Galio/farmacología , Estructura Molecular , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Isoindoles/farmacología , Isoindoles/química , Isoindoles/síntesis química , Fotoquimioterapia , Relación Dosis-Respuesta a Droga , Supervivencia Celular/efectos de los fármacos , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Hidróxidos/química , Hidróxidos/farmacología

RESUMEN

Herein, a comparative study between novel water-soluble phthalocyanine-based biosensors was performed for the application of glucose sensing. For this purpose, two different copper (II) and manganese (III) phthalocyanines and their water-soluble derivatives were synthesized, and then their role as a supporting material for enzyme immobilization was evaluated by comparing their sensor performances. Two different phthalocyanine (AP-OH2-MnQ (MnPc) and AP-OH2-CuQ (CuPc)) were tested using electrochemical biosensor with immobilized glucose oxidase (GOx). To the best of our knowledge, the related water-soluble phthalocyanine-based glucose biosensors were attempted for the first time, and the developed approach resulted in improved biosensor characteristics. The constructed biosensors GE/MnPc/GOx and GE/CuPc/GOx showed good linearity between 0.003-1.0 mM and 0.05-0.4 mM, respectively. The limit of detection was estimated at 0.0026 mM for the GE/MnPc/GOx and 0.019 mM for the GE/CuPc/GOx. KMapp and sensitivity values were also calculated as 0.026 mM and 175.043 µAmM-1 cm-2 for the GE/MnPc/GOx biosensor and 0.178 mM and 117.478 µAmM-1 cm-2 for the GE/CuPc/GOx biosensor. Moreover, the fabricated biosensors were successfully tested to detect glucose levels in beverages with high recovery results. The present study shows that the proposed water-soluble phthalocyanines could be a good alternative for quick and cheap glucose sensing with improved analytical characteristics.

Asunto(s)

Técnicas Biosensibles , Enzimas Inmovilizadas , Glucosa Oxidasa , Glucosa , Indoles , Isoindoles , Solubilidad , Agua , Técnicas Biosensibles/métodos , Indoles/química , Enzimas Inmovilizadas/química , Glucosa Oxidasa/química , Glucosa Oxidasa/metabolismo , Agua/química , Glucosa/análisis , Técnicas Electroquímicas/métodos , Límite de Detección

RESUMEN

We designed 6-dimethylamino 3-methyleneisoindolin-1-one as an environment-sensitive fluorophore, examining its applications for protein labeling. Synthesized 3-methyleneisoindolin-1-one exhibits solvatochromic fluorescence (λemmax; 472 nm in 2-PrOH, 512 nm in H2O). A positive linear dependence between λemmax and solvent dielectric constant (DC), as well as between Stokes shift and DC, and a negative correlation between fluorescence quantum yield and DC are observed in protic solvents. These properties are similar to those of the oxygen isosteric fluorophore, 4-dimethylaminophthalimide, a slovatochromic fluorophore utilized for labeling oligodeoxynucleotides (ODNs) and peptides. Notably, fluorescence intensity of 3-methyleneisoindolin-1-one is higher than the phthalimide in protic solvents used in this study. The 3-methyleneisoindolin-1-one demonstrated the higher stability in pH 8 solution than in pH 6 solution in contrast to the stability profile of the phthalimide, which was stable at pH 6 but was hydrolyzed at pH 8. We also synthesized an o-keto benzaldehyde derivative that converts a primary amine to 6-dimethylamino 3-methyleneisoindolin-1-one under biocompatible conditions and introduced it into ODNs for turn-on fluorescent protein labeling. The synthesized ODN with a protein-binding sequence of Escherichia coli DnaA was employed to modify the DNA-binding domain of DnaA, and the fluorescent properties of the modified protein were investigated.

Asunto(s)

Colorantes Fluorescentes , Isoindoles , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Isoindoles/química , Isoindoles/síntesis química , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , ADN/química , Diseño de Fármacos , Estructura Molecular , Concentración de Iones de Hidrógeno

RESUMEN

Recombinant high-density lipoprotein (rHDL) as anti-atherosclerosis (AS) vehicle has unique advantages including multiple anti-atherogenic functions and homing features to plaques. However, rHDL may be converted into dysfunctional forms due to complex treatment during preparation. Herein, oxidation-induced dysfunction of non-split HDL and rHDL was initially investigated. It was found that although both non-split HDL and rHDL showed oxidative dysfunction behavior, non-split HDL demonstrated superior oxidation defense compared to rHDL due to its intact composition and avoidance of overprocessing such as split and recombination. Unfortunately, in vivo oxidative stress could compromise the functionality of HDL. Therefore, surface engineering of non-split HDL and rHDL with cascade antioxidant enzyme analogues Ebselen and mitochondrial-targeted TPGS-Tempo was conducted to construct a dual-line defense HDL nano system (i.e., T@E-HDLs/rHDL), aiming to restore plaque redox balance and preserving the physiological function of HDL. Results indicated that both T@E-HDLs and rHDLs performed without distinction and exhibited greater resistance to oxidative stress damage as well as better functions than unmodified HDLs in macrophage foam cells. Overall, the modification of dual antioxidants strategy bridges the gap between non-split HDL and rHDL, and provides a promising resolution for the dilemmas of oxidative stress in plaques and HDL self dysfunction.

Asunto(s)

Antioxidantes , Lipoproteínas HDL , Estrés Oxidativo , Proteínas Recombinantes , Estrés Oxidativo/efectos de los fármacos , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/farmacología , Antioxidantes/farmacología , Proteínas Recombinantes/farmacología , Animales , Humanos , Ratones , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Oxidación-Reducción/efectos de los fármacos , Isoindoles/farmacología , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química

RESUMEN

The derivatives of isoindoline-1,3-dione are interesting due to their biological activities, such as anti-inflammatory and antibacterial effects. Several series have been designed and evaluated for Alzheimer's therapy candidates. They showed promising activity. In this work, six new derivatives were first tested in in silico studies for their inhibitory ability against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Molecular docking and molecular dynamic simulation were applied. Next, these compounds were synthesized and characterized by 1H NMR, 13C NMR, FT-IR, and ESI-MS techniques. For all imides, the inhibitory activity against AChE and BuChE was tested using Ellaman's method. IC50 values were determined. The best results were obtained for the derivative I, with a phenyl substituent at position 4 of piperazine, IC50 = 1.12 µM (AChE) and for the derivative III, with a diphenylmethyl moiety, with IC50 = 21.24 µM (BuChE). The compounds tested in this work provide a solid basis for further structural modifications, leading to the effective design of potential inhibitors of both cholinesterases.

Asunto(s)

Acetilcolinesterasa , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Simulación del Acoplamiento Molecular , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Butirilcolinesterasa/metabolismo , Butirilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Relación Estructura-Actividad , Simulación de Dinámica Molecular , Humanos , Isoindoles/química , Isoindoles/farmacología , Isoindoles/síntesis química , Estructura Molecular

RESUMEN

Renal ischemia/reperfusion injury (RIRI) is an inevitable complication following kidney transplantation surgery, accompanied by the generation of a large amount of free radicals. A cascade of events including oxidative stress, extreme inflammation, cellular apoptosis, and thrombosis disrupts the microenvironment of renal cells and the hematological system, ultimately leading to the development of acute kidney injury (AKI). The current research primarily focuses on reducing inflammation and mitigating damage to renal cells through antioxidative approaches. However, studies on simultaneously modulating the renal hematologic system remain unreported. Herein, potent and novel drug-loaded nanomicelles can be efficiently self-assembled with magnolol (MG) and ebselen (EBS) by π-π conjugation, hydrophobic action and the surfactant properties of Tween-80. The ultrasmall MG/EBS nanomicelles (average particle size: 10-25 nm) not only fully preserve the activity of both drugs, but also greatly enhance drug utilization (encapsulation rates: MG: 90.1%; EBS: 49.3%) and reduce drug toxicity. Furthermore, EBS, as a glutathione peroxidase mimic and NO catalyst, combines with the multifunctional MG to scavenge free radicals and hydroperoxides, significantly inhibiting inflammation and thrombosis while effectively preventing apoptosis of vascular endothelial cells and renal tubular epithelial cells. This study provides a new strategy and theoretical foundation for the simultaneous regulation of kidney cells and blood microenvironment stability.

Asunto(s)

Compuestos de Bifenilo , Lignanos , Micelas , Compuestos de Organoselenio , Daño por Reperfusión , Daño por Reperfusión/prevención & control , Daño por Reperfusión/tratamiento farmacológico , Compuestos de Bifenilo/química , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/farmacología , Lignanos/farmacología , Lignanos/química , Lignanos/administración & dosificación , Humanos , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/administración & dosificación , Isoindoles/farmacología , Isoindoles/administración & dosificación , Isoindoles/química , Apoptosis/efectos de los fármacos , Nanopartículas/química , Nanopartículas/administración & dosificación , Azoles/química , Azoles/farmacología , Azoles/administración & dosificación , Animales , Riñón/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/administración & dosificación , Tamaño de la Partícula , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Portadores de Fármacos/química , Estrés Oxidativo/efectos de los fármacos

RESUMEN

Background: How to ingeniously design multi-effect photosensitizers (PSs), including multimodal imaging and multi-channel therapy, is of great significance for highly spatiotemporal controllable precise phototherapy of malignant tumors. Methods: Herein, a novel multifunctional zinc(II) phthalocyanine-based planar micromolecule amphiphile (ZnPc 1) was successfully designed and synthesized, in which N atom with photoinduced electron transfer effect was introduced to enhance the near-infrared absorbance and nonradiative heat generation. After simple self-assembling into nanoparticles (NPs), ZnPc 1 NPs would exhibit enhanced multimodal imaging properties including fluorescence (FL) imaging (FLI) /photoacoustic (PA) imaging (PAI) /infrared (IR) thermal imaging, which was further used to guide the combined photodynamic therapy (PDT) and photothermal therapy (PTT). Results: It was that under the self-guidance of the multimodal imaging, ZnPc 1 NPs could precisely pinpoint the tumor from the vertical and horizontal boundaries achieving highly efficient and accurate treatment of cancer. Conclusion: Accordingly, the integration of FL/PA/IR multimodal imaging and PDT/PTT synergistic therapy pathway into one ZnPc 1 could provide a blueprint for the next generation of phototherapy, which offered a new paradigm for the integration of diagnosis and treatment in tumor and a promising prospect for precise cancer therapy.

Asunto(s)

Indoles , Isoindoles , Imagen Multimodal , Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Imagen Multimodal/métodos , Animales , Humanos , Indoles/química , Indoles/farmacología , Fotoquimioterapia/métodos , Nanopartículas/química , Ratones , Compuestos de Zinc/química , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Línea Celular Tumoral , Técnicas Fotoacústicas/métodos , Terapia Fototérmica/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Ratones Endogámicos BALB C , Fototerapia/métodos , Femenino

RESUMEN

Gas sensors based on ambipolar materials offer significant advantages in reducing the size of the analytical system and enhancing its efficiency. Here, bilayer heterojunction devices are constructed using different octafluorinated phthalocyanine complexes, with Zn and Co as metal centers, combined with a lutetium bisphthalocyanine complex (LuPc2). Stable p-type behavior is observed for the ZnF8Pc/LuPc2 device under both electron-donating (NH3) and -oxidizing (NO2 and O3) gaseous species, while the CoF8Pc/LuPc2 device exhibits n-type behavior under reducing gases and p-type behavior under oxidizing gases. The nature of majority of the charge carriers of Co-based devices varies depending on the nature of target gases, displaying an ambipolar behavior. Both heterojunction devices demonstrate stable and observable response toward all three toxic gases in the sub-ppm range. Remarkably, the Co-based device is highly sensitive toward ammonia with a limit of detection (LOD) of 200 ppb, whereas the Zn-based device demonstrates exceptional sensitivity toward oxidizing gases, with excellent LOD values of 4.9 and 0.75 ppb toward NO2 and O3, respectively, which makes it one of the most effective organic heterojunction sensors reported so far for oxidizing gases.

Asunto(s)

Gases , Indoles , Zinc , Indoles/química , Gases/análisis , Gases/química , Zinc/química , Zinc/análisis , Isoindoles , Límite de Detección , Cobalto/química , Lutecio/química , Amoníaco/análisis , Dióxido de Nitrógeno/análisis , Dióxido de Nitrógeno/química , Compuestos Organometálicos/química , Contaminantes Atmosféricos/análisis

RESUMEN

O-GlcNAcase (OGA) is implicated in several important biological and disease-relevant processes. Here, we synthesized fluorogenic probes for OGA by grafting GlcNAc directly or using a self-immolative linker to the hydroxyl position of 4-hydroxylisoindoline (BHID), a typical excited-state intramolecular proton transfer (ESIPT) probe. The probe was used for a fluorogenic assay to determine the half maximal inhibitory concentration of a known OGA inhibitor and differentiate between OGA and hexosaminidase when GlcNAc is replaced by GlcNPr, where a propionyl group is used instead of an acetyl group.

Asunto(s)

Colorantes Fluorescentes , Isoindoles , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Isoindoles/química , Isoindoles/síntesis química , Humanos , beta-N-Acetilhexosaminidasas/metabolismo , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Estructura Molecular , Espectrometría de Fluorescencia

RESUMEN

Despite the potential of photodynamic therapy (PDT) in cancer treatment, the development of efficient and photostable photosensitizing molecules that operate at long wavelengths of light has become a major hurdle. Here, we report for the first time an Ir(III)-phthalocyanine conjugate (Ir-ZnPc) as a novel photosensitizer for high-efficiency synergistic PDT treatment that takes advantage of the long-wavelength excitation and near infrared (NIR) emission of the phthalocyanine scaffold and the known photostability and high phototoxicity of cyclometalated Ir(III) complexes. In order to increase water solubility and cell membrane permeability, the conjugate and parent zinc phthalocyanine (ZnPc) were encapsulated in amphoteric redox-responsive polyurethane-polyurea hybrid nanocapsules (Ir-ZnPc-NCs and ZnPc-NCs, respectively). Photobiological evaluations revealed that the encapsulated Ir-ZnPc conjugate achieved high photocytotoxicity in both normoxic and hypoxic conditions under 630 nm light irradiation, which can be attributed to dual Type I and Type II reactive oxygen species (ROS) photogeneration. Interestingly, PDT treatments with Ir-ZnPc-NCs and ZnPc-NCs significantly inhibited the growth of three-dimensional (3D) multicellular tumor spheroids. Overall, the nanoencapsulation of Zn phthalocyanines conjugated to cyclometalated Ir(III) complexes provides a new strategy for obtaining photostable and biocompatible red-light-activated nano-PDT agents with efficient performance under challenging hypoxic environments, thus offering new therapeutic opportunities for cancer treatment.

Asunto(s)

Antineoplásicos , Indoles , Isoindoles , Fotoquimioterapia , Fármacos Fotosensibilizantes , Humanos , Indoles/química , Indoles/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Iridio/química , Iridio/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Compuestos de Zinc/química , Especies Reactivas de Oxígeno/metabolismo , Nanocápsulas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos

RESUMEN

In this study, (E)-4-{4-[(1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl]phenoxy}phthalonitrile (4) and its phthalocyanine derivatives (5-8) were synthesized for the first time. Aggregation behaviors of the novel soluble phthalocyanines in organic solvents were investigated. In addition, the efficiency of 1O2 production of (5) and ZnPc (6) was investigated. The singlet oxygen quantum yields (ΦΔ) for 2HPc (5) and ZnPc (6) were found to be 0.58 and 0.83, respectively. Additionally, novel phthalocyanines (5-8) were investigated for their ability to inhibit enzymes. They exhibited a highly potent inhibition effect on human carbonic anhydrase I and II (hCA I and II) and α-glycosidase (α-Gly) enzymes. Ki values are in the range of 2.60 ± 9.87 to 11.53 ± 6.92 µM, 3.35 ± 0.53 to 15.47 ± 1.20 µM, and 28.60 ± 4.82 to 40.58 ± 7.37 nM, respectively. The calculations of the studied molecule at the B3LYP, HF, and M062X levels in the 6-31G basis sets were made using the Gaussian package program. Afterward, the interactions occurring in the docking calculation against a protein that is the crystal structure of hCA I (PDB ID: 2CAB), the crystal structure of hCA II (PDB ID: 5AML), and the crystal structure of α-Gly (PDB ID: 1R47), were examined. Following that, Protein-Ligand Interaction Profiler (PLIP) analysis was used to look at the interactions that occurred during the docking calculation in further detail.

Asunto(s)

Inhibidores de Anhidrasa Carbónica , Indoles , Isoindoles , Humanos , Isoindoles/síntesis química , Isoindoles/farmacología , Isoindoles/química , Indoles/farmacología , Indoles/química , Indoles/síntesis química , Relación Estructura-Actividad , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Estructura Molecular , Simulación del Acoplamiento Molecular , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/metabolismo , Anhidrasa Carbónica I/antagonistas & inhibidores , Anhidrasa Carbónica I/metabolismo , Oxígeno Singlete/metabolismo , Relación Dosis-Respuesta a Droga

RESUMEN

Photodynamic therapy (PDT) utilizes reactive oxygen species (ROS) for eradication of cancer cells. Its effectiveness is governed by the oxygen content, which is scarce in the hypoxic tumor microenvironment. We report herein two zinc(II) phthalocyanines substituted with two or four nitric oxide (NO)-releasing moieties, namely ZnPc-2NO and ZnPc-4NO, which can suppress the mitochondrial respiration, thereby sparing more intracellular oxygen for PDT. Using HT29 human colorectal adenocarcinoma cells and A549 human lung carcinoma cells, we have demonstrated that both conjugates release NO upon interaction with the intracellular glutathione, which can reduce the cellular oxygen consumption rate and adenosine triphosphate generation and alter the mitochondrial membrane potential. They can also relieve the hypoxic status of cancer cells and decrease the expression of hypoxia-inducible factor protein HIF-1α. Upon light irradiation, both conjugates can generate ROS and induce cytotoxicity even under a hypoxic condition, overcoming the oxygen-dependent nature of PDT. Interestingly, the photodynamic action of ZnPc-2NO elicits the release of damage-associated molecular patterns, inducing the maturation of dendritic cells and triggering an antitumor immune response. The immunogenic cell death caused by this oxygen-economized PDT has been demonstrated through a series of in vitro and in vivo experiments.

Asunto(s)

Óxido Nítrico , Oxígeno , Fotoquimioterapia , Fármacos Fotosensibilizantes , Humanos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Óxido Nítrico/metabolismo , Oxígeno/química , Oxígeno/metabolismo , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Muerte Celular Inmunogénica/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Indoles/química , Indoles/farmacología , Animales , Isoindoles/química , Compuestos de Zinc/química

RESUMEN

A variety of 3-hydroxy-isoindolin-1-one derivatives were synthesized using the photodecarboxylative addition of carboxylates to phthalimide derivatives in aqueous media. Subsequent acid-catalyzed dehydration furnished 3-(alkyl and aryl)methyleneisoindolin-1-ones with variable E-diastereoselectivity in good to excellent overall yields. Noteworthy, the parent 3-phenylmethyleneisoindolin-1-one underwent isomerization and oxidative decomposition when exposed to light and air. Selected 3-hydroxy-isoindolin-1-one and 3-(alkyl and aryl)methyleneisoindolin-1-one derivatives showed moderate antibacterial activity that justifies future elaboration and study of these important bioactive scaffolds.

Asunto(s)

Antibacterianos , Ácidos Carboxílicos , Isoindoles , Pruebas de Sensibilidad Microbiana , Ftalimidas , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Ftalimidas/química , Ftalimidas/síntesis química , Ftalimidas/farmacología , Isoindoles/química , Isoindoles/síntesis química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Procesos Fotoquímicos , Luz , Estructura Molecular , Relación Estructura-Actividad , Catálisis

RESUMEN

While research has identified several inhibitors of the main protease (Mpro) of SARS-CoV-2, a significant portion of these compounds exhibit reduced activity in the presence of reducing agents, raising concerns about their effectiveness in vivo. Furthermore, the conventional biosafety level 3 (BSL-3) for cellular assays using viral particles poses a limitation for the widespread evaluation of Mpro inhibitor efficacy in a cell-based assay. Here, we established a BSL-1 compatible cellular assay to evaluate the in vivo potential of Mpro inhibitors. This assay utilizes mammalian cells expressing a tagged Mpro construct containing N-terminal glutathione S-transferase (GST) and C-terminal hemagglutinin (HA) tags and monitors Mpro autodigestion. Using this method, GC376 and boceprevir effectively inhibited Mpro autodigestion, suggesting their potential in vivo activity. Conversely, carmofur and ebselen did not exhibit significant inhibitory effects in this assay. We further investigated the inhibitory potential of selenoneine on Mpro using this approach. Computational analyses of binding energies suggest that noncovalent interactions play a critical role in facilitating the covalent modification of the C145 residue, leading to Mpro inhibition. Our method is straightforward, cost-effective, and readily applicable in standard laboratories, making it accessible to researchers with varying levels of expertise in infectious diseases.

Asunto(s)

Antivirales , Azoles , Proteasas 3C de Coronavirus , Isoindoles , Compuestos de Organoselenio , Prolina , SARS-CoV-2 , Antivirales/farmacología , Antivirales/química , Humanos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química , Isoindoles/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Azoles/farmacología , Azoles/química , Prolina/análogos & derivados , Prolina/farmacología , Prolina/química , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Tratamiento Farmacológico de COVID-19 , COVID-19/virología , Células HEK293 , Lactamas , Leucina/análogos & derivados , Ácidos Sulfónicos

RESUMEN

Indoleamine 2,3-dioxygenase (IDO), highly expressed in hepatocellular carcinoma (HCC), plays a pivotal role in creating an immune-suppressive tumor microenvironment. Inhibiting IDO activity has emerged as a promising immunotherapeutic strategy; however, the delivery of IDO inhibitors to the tumor site is constrained, limiting their therapeutic efficacy. In this study, we developed a magnetic vortex nanodelivery system for the targeted delivery of the IDO inhibitor NLG919, integrated with magnetic hyperthermia therapy to reverse the immune-suppressive microenvironment of liver cancer and inhibit tumor growth. This system comprises thermoresponsive polyethylenimine-coated ferrimagnetic vortex-domain iron oxide nanorings (PI-FVIOs) loaded with NLG919 (NLG919/PI-FVIOs). Under thermal effects, NLG919 can be precisely released from the delivery system, counteracting IDO-mediated immune suppression and synergizing with NLG919/PI-FVIOs-mediated magnetothermodynamic (MTD) therapy-induced immunogenic cell death (ICD), resulting in effective HCC suppression. In vivo studies demonstrate that this combination therapy significantly inhibits tumor growth and metastasis by enhancing the accumulation of cytotoxic T lymphocytes and suppressing regulatory T cells within the tumor. Overall, our findings reveal that NLG919/PI-FVIOs can induce a potent antitumor immune response by disrupting the IDO pathway and activating the ICD, offering a promising therapeutic avenue for HCC treatment.

Asunto(s)

Indolamina-Pirrol 2,3,-Dioxigenasa , Neoplasias Hepáticas , Microambiente Tumoral , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Animales , Microambiente Tumoral/efectos de los fármacos , Ratones , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Hipertermia Inducida , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Ratones Endogámicos BALB C , Antineoplásicos/química , Antineoplásicos/farmacología , Imidazoles , Isoindoles

RESUMEN

A novel photoelectrochemical sensor, employing an S-scheme heterojunction of phthalocyanine and TiO2 nanoparticles, has been developed to enable highly sensitive determination of glutathione. By integrating the favorable stability, environmental benignity, and electronic properties of the TiO2 matrix with the unique photoactivity of phthalocyanine species, the designed sensor presents a substantial linear dynamic range and a low detection limit for the quantification of glutathione. The sensitivity is attributed to efficient charge transfer and separation across the staggered heterojunction energy levels, which generates measurable photocurrent signals. Systematic variation of phthalocyanine content reveals an optimal composition that balances light harvesting capacity and electron-hole recombination rates. The incorporation of phosphotungstic acid (PTA) in sample preparation effectively minimizes interference from compounds like L-cysteine and others. Consequently, this leads to an improvement in accuracy through the reduction of impurity levels. Appreciable photocurrent enhancements are observed upon introduction of both oxidized and reduced glutathione at the optimized composite photoanode. Coupled with advantageous features of photoelectrochemical transduction such as simplicity, cost-effectiveness, and resistance to fouling, this sensor holds great promise for practical applications in complex biological media.

Asunto(s)

Técnicas Electroquímicas , Glutatión , Indoles , Isoindoles , Titanio , Titanio/química , Glutatión/química , Glutatión/análisis , Indoles/química , Técnicas Electroquímicas/métodos , Técnicas Electroquímicas/instrumentación , Límite de Detección , Procesos Fotoquímicos , Electrodos