RESUMO
Beta-amyloid (Aß), the most pivotal pathological hallmark for Alzheimer's disease (AD) diagnosis and drug evaluation, was recognized by TZ095, a high-affinity fluorescent probe developed by rational molecular design. With a TICT mechanism, TZ095 exhibited remarkable affinity with Aß aggregates (Kd = 81.54 nM for oligomers; Kd = 66.70 nM for fibril) and substantial fluorescence enhancement (F/F0 = 44), enabling real-time monitoring of Aß in live cells and nematodes. Significantly, this work used TZ095 to construct a new protocol that can quickly and conveniently monitor Aß changes at the cellular and nematode levels to evaluate the anti-AD efficacy of candidate compounds, and four reported Aß-lowering drug candidates were administrated for validation. Imaging data demonstrated that TZ095 can visually and quantitatively track the effect of Aß elimination after drug treatment. Furthermore, TZ095 excelled in ex vivo histological staining of 12-month-old APP/PS1 mouse brains, accurately visualizing Aß plaques. Integrating CUBIC technology, TZ095 facilitated whole-brain, 3D imaging of Aß distribution in APP/PS1 mice, enabling high-resolution in situ analysis of Aß plaques. Collectively, these innovative applications of TZ095 offer a promising strategy for rapid, convenient, and real-time monitoring of Aß levels in preclinical therapeutic assessments.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Desenho de Fármacos , Corantes Fluorescentes , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Humanos , Camundongos , Estrutura Molecular , Camundongos Transgênicos , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Relação Estrutura-Atividade , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Relação Dose-Resposta a Droga , Imagem ÓpticaRESUMO
Near-infrared (NIR) fluorescent probes with aggregation-induced emission (AIE) properties are of great significance in cell imaging and cancer therapy. However, the complexity of its synthesis, poor photostabilities, and expensive raw materials still pose some obstacles to their practical application. This study reported an AIE luminescent material with red emission and its application in in vitro imaging and photodynamic therapy (PDT) study. This material has the characteristics of simple synthesis, large Stokes shift, good photostabilities, and excellent lipid droplets-specific testing ability. Interestingly, this red-emitting material can effectively produce reactive oxygen species (ROS) under white light irradiation, further achieving PDT-mediated killing of cancer cells. In conclusion, this study demonstrates a simple approach to synthesize NIR AIE probes with both imaging and therapeutic effects, providing an ideal architecture for constructing long-wavelength emission AIE materials.
Assuntos
Corantes Fluorescentes , Raios Infravermelhos , Gotículas Lipídicas , Fotoquimioterapia , Espécies Reativas de Oxigênio , Humanos , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Gotículas Lipídicas/química , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Sobrevivência Celular/efeitos dos fármacos , Imagem Óptica , Estrutura Molecular , Células HeLaRESUMO
Potent antioxidants, like 3-hydroxy flavones, attracted considerable attention due to their excited state intramolecular proton transfer (ESIPT)-based fluorescence behaviour. This article is an interesting demonstration of a series of synthetic 3-hydroxy flavone analogues having high antioxidant activity as molecular rotor-like viscosity probes. Among these flavone analogues, 4'-N,N-dimethylamino-3-hydroxy flavone (3) is the most potent one, showing the twisted intramolecular charge transfer (TICT)-dependent fluoroprobing activity toward the blood viscosity changes associated with diabetes and free fatty acids (FFA)-induced nuclear viscosity changes of MIN6 cells. The TICT dynamics of (3), which instigates its viscosity probing activity, was comprehended with the help of DFT-based computational studies. Abnormal cellular viscosity changes are the pathological traits for various diseases, and non-toxic flavone-based viscosity probes can be useful for diagnosing such pathological conditions.
Assuntos
Antioxidantes , Teoria da Densidade Funcional , Flavonas , Flavonas/química , Flavonas/farmacologia , Viscosidade , Antioxidantes/química , Antioxidantes/farmacologia , Diabetes Mellitus/tratamento farmacológico , Animais , Prótons , Camundongos , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Corantes Fluorescentes/síntese química , Ácidos Graxos não Esterificados/química , Ácidos Graxos não Esterificados/metabolismo , HumanosRESUMO
Myocardial infarction (MI), one of the leading causes of death worldwide, urgently needs further understanding of the pathological process and effective therapies. SO2 in endoplasmic reticulum in several cardiovascular diseases has been reported to be particularly important. However, the role of endogenous SO2 in endoplasmic reticulum in treating myocardial infarction is still ambiguous and needs to be elucidated. Herein, we developed TPA-HI-SO2 as the first endoplasmic reticulum-targeting fluorescent agent for specific imaging and detection of sulfur dioxide derivatives both in vitro and in vivo. TPA-HI-SO2 shows a highly sensitive and selective response to SO2 derivatives over other anions in aqueous solution with a satisfactory response time and detection limit. Furthermore, TPA-HI-SO2 decreased the SO2 concentration in H9C2 cells treated with H2O2 and in an MI mouse model. Most importantly, TPA-HI-SO2 protects H9C2 cells from H2O2-induced apoptosis and obviously protects against myocardial infarction in vivo through neutralization of endogenous SO2. Taken together, we developed the first ER-targeting ratiometric fluorescent probe for endogenous SO2 with excellent biocompatibility, high selectivity and sensitivity in this paper. More importantly, we demonstrated an obvious increase of the endogenous SO2 concentration in a myocardial infarction mouse model for the first time, which suggests that neutralization of endogenous SO2 in endoplasmic reticulum could be a promising therapeutic strategy for myocardial infarction.
Assuntos
Retículo Endoplasmático , Corantes Fluorescentes , Infarto do Miocárdio , Dióxido de Enxofre , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Animais , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Dióxido de Enxofre/farmacologia , Dióxido de Enxofre/metabolismo , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Estrutura Molecular , Apoptose/efeitos dos fármacos , Imagem Óptica , Masculino , Humanos , Nanomedicina Teranóstica , Linhagem Celular , Ratos , Relação Dose-Resposta a Droga , Relação Estrutura-AtividadeRESUMO
Hypoxia (low-oxygen) is one of the most common characteristics of solid tumours. Exploiting tumour hypoxia to reductively activate Pt(IV) prodrugs has the potential to deliver toxic Pt(II) selectively and thus overcome the systemic toxicity issues of traditional Pt(II) therapies. However, our current understanding of the behaviour of Pt(IV) prodrugs in hypoxia is limited. Here, we evaluated and compared the aryl carbamate fluorogenic Pt(IV) complexes, CisNap and CarboNap, as well as the previously reported OxaliNap, as potential hypoxia-activated Pt(IV) (HAPt) prodrugs. Low intracellular oxygen concentrations (<0.1%) induced the greatest changes in the respective fluorescence emission channels. However, no correlation between reduction under hypoxic conditions and toxicity was observed, except in the case for CarboNap, which displayed significant hypoxia-dependent toxicity. Other aryl carbamate Pt(IV) derivatives (including non-fluorescent analogues) mirrored these observations, where carboplatin(IV) derivative CarboPhen displayed a hypoxia-selective cytotoxicity similar to that of CarboNap. These findings underscore the need to perform extensive structure activity relationship studies on the cytotoxicity of Pt(IV) complexes under normoxic and hypoxic conditions.
Assuntos
Antineoplásicos , Corantes Fluorescentes , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/síntese química , Desenho de Fármacos , Linhagem Celular Tumoral , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Platina/química , Platina/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese químicaRESUMO
c-MYC is one of the most important oncogenes, which is overexpressed in many cancers, and is highly related to development, metastasis, and drug resistance of cancers. The G4 structure in the promoter of c-MYC oncogene contributes a lot to the gene transcriptional mechanism. Small-molecule ligands binding to the c-MYC G4 appear to be a new class of anticancer agents. However, selective ligands for the c-MYC G4 over other G4s have been rarely reported. In this study, we reported a novel fluorescent ligand by migrating the benzene group on a carbazole-benzothiazolium scaffold, which was demonstrated to exhibit considerable specificity to the c-MYC G4, which was distinguished from other small-molecule ligands. The further cellular experiments suggested that this ligand may indeed target the promoter G4 and cause apparent transcriptional inhibition of the c-MYC oncogene instead of other G4-mediated oncogenes, which thereby resulted in cancer cell growth inhibition. Collectively, this study provided a good example for developing specific c-MYC G4 ligands, which may further develop into an effective anticancer agent that inhibit the c-MYC expression.
Assuntos
Antineoplásicos , Benzotiazóis , Carbazóis , Proliferação de Células , Corantes Fluorescentes , Quadruplex G , Proteínas Proto-Oncogênicas c-myc , Carbazóis/química , Carbazóis/farmacologia , Quadruplex G/efeitos dos fármacos , Humanos , Ligantes , Benzotiazóis/química , Benzotiazóis/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/genética , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Estrutura Molecular , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Relação Dose-Resposta a Droga , Benzeno/química , Benzeno/farmacologia , Linhagem Celular TumoralRESUMO
Aim: Lysosomal pH changes are associated with drug resistance, cell growth and invasion of tumors, but effective and specific real-time monitoring of lysosomal pH compounds for cancer therapy is lacking. Materials & methods: Here, based on the covalent linkage of the anticancer drug palbociclib and fluorescent dye fluorescein isothiocyanate (FITC), we designed and developed a novel palbociclib-derived multifunctional molecule (Pal-FITC) for lysosomal targeting and diagnostic therapeutic integration. Results & discussion: Pal-FITC fluoresces is 20-fold stronger than that of FITC and shows a linear response in the pH range of 4.0-8.2 (R2 = 0.9901). Pal-FITC blocks cells in G1 phase via Cyclin D-CDK4/6-Rb. Conclusion: Our study provides new strategies for tumor-targeted imaging and personalized therapy.
Based on the covalent linkage of the anticancer drug and the fluorescent dye, we designed and developed a novel palbociclib-derived multifunctional molecule (Pal-FITC) for lysosomal targeting and diagnostic therapeutic integration. Pal-FITC responded linearly in the pH range of 4.08.2. In addition, Pal-FITC was able to effectively treat lung cancer without toxic side effects on normal cells. It has a significant cell cycle blocking phenomenon and blocks G1 phase cells via Cyclin D-CDK4/6-Rb. Our study provides a new strategy for tumor-targeted imaging and personalized therapy.
Assuntos
Antineoplásicos , Lisossomos , Piperazinas , Piridinas , Humanos , Piridinas/química , Piridinas/farmacologia , Lisossomos/metabolismo , Piperazinas/química , Piperazinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Corantes Fluorescentes/síntese química , Fluoresceína-5-Isotiocianato/química , Proliferação de Células/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Estrutura MolecularRESUMO
Triple negative breast cancer (TNBC) is a notoriously difficult disease to treat, and many of the existing TNBC chemotherapeutics lack tumor selectivity and the capability for simultaneously visualizing and monitoring their own activity in the biological context. However, TNBC cells have been known to generate high levels of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2). To this end, three novel small molecule theranostics 1a, 1c, and 2 consisting of both H2O2-responsive nitrogen mustard prodrug and profluorophore character have been designed, synthesized, and evaluated as targeted cancer therapeutics and bioimaging agents. The three theranostics comprise of boronate esters that deactivate nitrogen mustard functional groups and fluorophores but allow their selective activation through H2O2-specific oxidative deboronation for the release of the active drug and fluorophore. The three theranostics demonstrated H2O2-inducible DNA-alkylating capability and fluorescence turn-on properties in addition to selective anticancer activity. They are particularly effective in killing TNBC MDA-MB-468 cells with high H2O2 level while safe to normal epithelial MCF-10A cell. The conjugated boron-masked fluorophores in 1c and 2 are highly responsive towards H2O2, which enabled tracking of the theranostics in living cellular mitochondria and nucleus organelles. The three theranostics 1a, 1c, and 2 are capable of both selective release of the active drug to take effect in H2O2-rich cancer sites and simultaneously monitoring its activity. This single molecule system is of utmost importance to understand the function, efficacy, and mechanism of the H2O2-activated prodrugs and theranostics within the living recipient.
Assuntos
Antineoplásicos , Corantes Fluorescentes , Peróxido de Hidrogênio , Nanomedicina Teranóstica , Humanos , Alquilação , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fluorescência , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Peróxido de Hidrogênio/farmacologia , Estrutura Molecular , Imagem Óptica , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/síntese química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologiaRESUMO
Nitrobenzoxadiazole (NBD)-incorporated naphthalene diimide derivatives were designed and synthesized as candidates of antitumor agents with cytotoxicity against human pancreatic cancer cell MIA PaCa-2. Among these, compounds 1NND and 3NND exhibited fluorescent "turn-off" property toward human telomeric G-quadruplex (G4), which allows the direct measurement of dissociation constant (Kd) of ligands against G4 by fluorescence titration method. Notably, the compound 1NND not only exhibited great cytotoxic activity against MIA PaCa-2 with a half maximal inhibitory concentration (IC50) of 77.9 nM, but also exhibited high affinity against G4 with Kd of 1.72 µM. Furthermore, the target binding properties were investigated by circular dichroism (CD) spectra and further studied by molecular docking methods.
Assuntos
Antineoplásicos , Desenho de Fármacos , Quadruplex G , Imidas , Naftalenos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Quadruplex G/efeitos dos fármacos , Imidas/química , Imidas/farmacologia , Imidas/síntese química , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftalenos/química , Naftalenos/farmacologia , Naftalenos/síntese química , Relação Estrutura-AtividadeRESUMO
The potential of using image-guided photodynamic therapy (ig-PDT) for cancer, especially with highly biocompatible fluorescent agents free of heavy atoms, is well recognized. This is due to key advantages related to minimizing adverse side effects associated with standard cancer chemotherapy. However, this theragnostic approach is strongly limited by the lack of synthetically-accessible and easily-modulable chemical scaffolds, enabling the rapid design and construction of advanced agents for clinical ig-PDT. In fact, there are still very few ig-PDT agents clinically approved. Herein we report a readily accessible, easy-tunable and highly fluorescent all-organic small photosensitizer, as a model design for accelerating the development and translation of advanced ig-PDT agents for cancer. This scaffold is based on BODIPY, which assures high fluorescence, accessibility, and ease of performance adaptation by workable chemistry. The optimal PDT performance of this BODIPY dye, tested in highly resistant pancreatic cancer cells, despite its high fluorescent behavior, maintained even after fixation and cancer cell death, is based on its selective accumulation in mitochondria. This induces apoptosis upon illumination, as evidenced by proteomic studies and flow cytometry. All these characteristics make the reported BODIPY-based fluorescent photosensitizer a valuable model for the rapid development of ig-PDT agents for clinical use.
Assuntos
Compostos de Boro , Corantes Fluorescentes , Fotoquimioterapia , Fármacos Fotossensibilizantes , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Humanos , Compostos de Boro/química , Compostos de Boro/farmacologia , Compostos de Boro/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Estrutura Molecular , Linhagem Celular Tumoral , Imagem Óptica , Sobrevivência Celular/efeitos dos fármacosRESUMO
There is an urgent need to develop phototherapeutic agents with imaging capabilities to assess the treatment process and efficacy in real-time during cancer phototherapy for precision cancer therapy. The safe near-infrared (NIR) fluorescent dyes have garnered significant attention and are desirable for theranostics agents. However, until now, achieving excellent photostability and fluorescence (FL) imaging capability in aggregation-caused quenching (ACQ) dyes remains a big challenge. Here, for the only FDA-approved NIR dye, indocyanine green (ICG), we developed a dual-ferrocene (Fc) chimeric nanonetwork ICG@HFFC based on the rigid-flexible strategy through one-step self-assembly, which uses rigid Fc-modified hyaluronic acid (HA) copolymer (HA-Fc) and flexible octadecylamine (ODA) bonded Fc (Fc-C18) as the delivery system. HA-Fc reserved the ability of HA to target the CD44 receptor of the tumor cell surface, and the dual-Fc region provided a rigid space for securely binding ICG through metal-ligand interaction and π-π conjugation, ensuring excellent photostability. Additionally, the alkyl chain provided flexible confinement for the remaining ICG through hydrophobic forces, preserving its FL. Thereby, a balance is achieved between outstanding photostability and FL imaging capability. In vitro studies showed improved photobleaching resistance, enhanced FL stability, and increased singlet oxygen (1O2) production efficiency in ICG@HFFC. Further in vivo results display that ICG@HFFC had good tumor tracing ability and significant tumor inhibition which also exhibited good biocompatibility.. Therefore, ICG@HFFC provides an encouraging strategy to realize simultaneous enhanced tumor tracing and photothermal/photodynamic therapy (PTT/PDT) and offers a novel approach to address the limitations of ACQ dyes.
Assuntos
Compostos Ferrosos , Ácido Hialurônico , Verde de Indocianina , Metalocenos , Fotoquimioterapia , Compostos Ferrosos/química , Humanos , Metalocenos/química , Animais , Camundongos , Verde de Indocianina/química , Verde de Indocianina/uso terapêutico , Verde de Indocianina/farmacologia , Ácido Hialurônico/química , Terapia Fototérmica , Feminino , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Camundongos Endogâmicos BALB C , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Camundongos Nus , Linhagem Celular Tumoral , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Neoplasias/patologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Nanopartículas/química , Nanopartículas/uso terapêuticoRESUMO
Advanced photosensitizers for high-performance fluorescence imaging-guided photothermal therapy demand excellent near-infrared (NIR) brightness [molar absorption coefficient (ε) × quantum yield (QY)] and exceptional photothermal performance [ε × photothermal conversion efficiency (PCE)]. However, integrating high brightness and potent photothermal performance within a single molecule faces a formidable challenge. This article proposes a method to address this issue by preparing J-aggregate nanoparticles (NPs) using molecules with high ε. J-aggregates effectively improve QY and induce molecular emission redshift, while high ε molecules play a crucial role in improving the brightness and photothermal performance. By optimizing the molecular structure based on the pyrrolopyrrole cyanine (PPCy), precise control over the QY and PCE of PPCy J-aggregates is achieved. Ultimately, PDDO NPs exhibiting superior brightness (ε × QY = 3.32 × 104 M-1 cm-1) and photothermal performance (ε × PCE = 1.21 × 105 M-1 cm-1) are identified as high-performance photosensitizers. Notably, each parameter represents one of the highest levels among the reported fluorescence or photothermal probes to date. The in vivo studies demonstrate that PDDO NPs possess exceptional NIR imaging capabilities and remarkable photothermal tumor inhibition rates. This study provides innovative insights into the development of high-performance multifunctional photosensitizers.
Assuntos
Nanopartículas , Fármacos Fotossensibilizantes , Pirróis , Nanomedicina Teranóstica , Animais , Nanopartículas/química , Nanopartículas/uso terapêutico , Camundongos , Pirróis/química , Pirróis/farmacologia , Humanos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Raios Infravermelhos , Terapia Fototérmica , Carbocianinas/química , Feminino , Camundongos Endogâmicos BALB C , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Imagem Óptica , Linhagem Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologia , FototerapiaRESUMO
Therapy-induced modulation of the tumor microenvironment (TME) to overcome the immunosuppressive TME is considered to be an opportunity for cancer treatment. However, monitoring of TME modulation during the therapeutic process to accurately determine immune responses and adjust treatment plans in a timely manner remains to be challenging. Herein, we report a carrier-free nanotheranostic system (CANPs) assembled by two boron dipyrromethene (BODIPY) dyes, a sonophotosensitizer C-BDP, and a nitric oxide (NO) probe amino-BODIPY (A-BDP). CANPs can exert combined sonophototherapeutic effects of C-BDP under ultrasound and light irradiation and simultaneously induce inflammatory TME, as well as emit bright fluorescence via A-BDP by monitoring tumor-associated macrophages (TAMs) repolarization through the released NO in vitro and in vivo. Of note, transforming growth factor-ß (TGF-ß) could be the key cytokine involved in the sonophototherapy-induced TME reprogramming. By virtue of high physiological stability, good biocompatibility, and effective tumor targetability, CANPs could be a potential nanotheranostic system for the simultaneous induction and detection of TME reprogramming triggered by sonophototherapy.
Assuntos
Nanomedicina Teranóstica , Microambiente Tumoral , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Camundongos , Porfobilinogênio/análogos & derivados , Porfobilinogênio/química , Porfobilinogênio/farmacologia , Humanos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Compostos de Boro/química , Compostos de Boro/farmacologia , Óxido Nítrico/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Feminino , Nanopartículas/química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Células RAW 264.7RESUMO
A versatile and efficient chemo selective synthesis of 4-aryl-3-formyl-2H-chromenes (AFC) was undertaken using Pd-catalyzed cross-coupling conditions. The key oxidative transmetalation was successfully applied to a significant range of substitutions on the chromene moiety and aryl ring in Ar(BOH)3, accommodating both electron-rich and electron-deficient groups. These π-extended scaffolds exhibited green-yellow fluorescence with a large Stokes shift and high quantum yield. Measurement of photophysical properties revealed that the compound with methoxy substitution in the chromene ring, 3t, caused a significant bathochromic shift. The AFCs obtained from this method can be transformed into biologically active 4-aryl-3-iminoantipyrine-2H-chromenes (AAC) through functionalization of the formyl chromenes. The AFCs and AACs with methoxy substitutions (3t and 4e) were docked against AChE inhibition, and compound 4e had the lowest binding energy of -11.20â kcal/mol. DFT calculations performed on representative compounds revealed that compound 4e is more reactive than 3t, which is in accordance with the docking studies.
Assuntos
Benzopiranos , Inibidores da Colinesterase , Teoria da Densidade Funcional , Paládio , Paládio/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Benzopiranos/química , Benzopiranos/síntese química , Benzopiranos/farmacologia , Catálise , Acetilcolinesterase/metabolismo , Estrutura Molecular , Simulação de Acoplamento Molecular , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The formation of amyloid-ß (Aß) plaques is one of the key neuropathological hallmarks of Alzheimer's disease (AD). Near-infrared (NIR) probes show great potential for imaging of Aß plaques in vivo and in vitro. Dicyanoisophorone (DCIP) based Aß probes have attracted considerable attention due to their exceptional properties. However, DCIP probes still has some drawbacks, such as short emission wavelength (<650 nm) and low fluorescence intensity after binding to Aß. It is clear that further modification is needed to improve their luminescence efficiency and sensitivity. RESULTS: We designed and synthesize four novel pyrrolidine-alkylamino-substituted DCIP derivatives (6a-d) as imaging agents for ß-amyloid (Aß) aggregates. Compound 6c responds better to Aß aggregates than the other three compounds (6a, 6b and 6d) and its precursor DCIP. The calculated detection limit is to be as low as 0.23 µM. Compound 6c shows no cytotoxicity in the tested concentration for SH-SY5Y and HL-7702 cells. Additionally, compound 6c is successfully applied to monitor Aß aggregates in live SH-SY5Y cells and APP/PS1 transgenic mice. The retention time in the transgenic mice brain is much longer than that of age-matched wild-type mice. SIGNIFICANCE: The results indicates that compound 6c had an excellent ability to penetrate the blood-brain barrier and it could effectively distinguish APP/PS1 transgenic mice and wide-type mice. This represents its promising applications for Aß detection in basic and biomedical research.
Assuntos
Cicloexanonas , Humanos , Linhagem Celular , Precursor de Proteína beta-Amiloide/análise , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Pirrolidinas/química , Cicloexanonas/síntese química , Cicloexanonas/química , Cicloexanonas/farmacologia , Espectroscopia de Luz Próxima ao Infravermelho , Estrutura Molecular , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Espectrometria de Fluorescência , Modelos Moleculares , Estrutura Terciária de Proteína , Simulação de Acoplamento Molecular , Sobrevivência Celular/efeitos dos fármacos , Animais , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Encéfalo/metabolismo , Aminação , AlquilaçãoRESUMO
In this study, super-resolution structured illumination microscope (SIM) was used to analyze molecular mechanism of endocytic acidification inhibitors in the SARS-CoV-2 pandemic, such as Chloroquine (CQ), Hydroxychloroquine (HCQ) and Bafilomycin A1 (BafA1). We fluorescently labeled the SARS-CoV-2 RBD and its receptor ACE2 protein with small molecule dyes. Utilizing SIM imaging, the real-time impact of inhibitors (BafA1, CQ, HCQ, Dynasore) on the RBD-ACE2 endocytotic process was dynamically tracked in living cells. Initially, the protein activity of RBD and ACE2 was ensured after being labeled. And then our findings revealed that these inhibitors could inhibit the internalization and degradation of RBD-ACE2 to varying degrees. Among them, 100â nM BafA1 exhibited the most satisfactory endocytotic inhibition (~63.9 %) and protein degradation inhibition (~97.7 %). And it could inhibit the fusion between endocytic vesicles in the living cells. Additionally, Dynasore, a widely recognized dynein inhibitor, also demonstrated cell acidification inhibition effects. Together, these inhibitors collectively hinder SARS-CoV-2 infection by inhibiting both the viral internalization and RNA release. The comprehensive evaluation of pharmacological mechanisms through super-resolution fluorescence imaging has laid a crucial theoretical foundation for the development of potential drugs to treat COVID-19.
Assuntos
Enzima de Conversão de Angiotensina 2 , Tratamento Farmacológico da COVID-19 , Cloroquina , Endossomos , Hidrazonas , Hidroxicloroquina , Macrolídeos , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , Endossomos/metabolismo , Endossomos/efeitos dos fármacos , Humanos , Cloroquina/farmacologia , Cloroquina/química , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Macrolídeos/farmacologia , Macrolídeos/química , Hidroxicloroquina/farmacologia , Hidroxicloroquina/química , Hidrazonas/farmacologia , Hidrazonas/química , Endocitose/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , COVID-19/virologia , COVID-19/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Concentração de Íons de Hidrogênio , Internalização do Vírus/efeitos dos fármacos , Chlorocebus aethiopsRESUMO
The isatin group is widespread in nature and is considered to be a privileged building block for drug discovery. In order to develop novel SHP1 inhibitors with fluorescent properties as tools for SHP1 biology research, this work designed and synthesized a series of isatin derivatives. The presentive compound 5a showed good inhibitory activity against SHP1PTP with IC50 of 11 ± 3 µM, displayed about 92% inhibitory rate against MV-4-11 cell proliferation at the concentration of 20 µM, exhibited suitable fluorescent properties with a long emission wavelength and a large Stokes shift, and presented blue fluorescent imaging in HeLa cells with low cytotoxicity. This study could offer chemical tool to further understand SHP1 biology and develop novel SHP1 inhibitors in therapy.
Assuntos
Proliferação de Células , Isatina , Isatina/química , Isatina/farmacologia , Isatina/síntese química , Humanos , Células HeLa , Proliferação de Células/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Linhagem Celular Tumoral , FluorescênciaAssuntos
Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Desenho Assistido por Computador , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Mutações Sintéticas Letais , Metionina Adenosiltransferase/antagonistas & inibidores , Metionina Adenosiltransferase/química , Metionina Adenosiltransferase/metabolismoRESUMO
The chemical reaction of 2-(methylsulfinyl)naphtho[2,3-d]thiazole-4,9-dione (3) using different amines, including benzylamine (4a), morpholine (4b), thiomorpholine (4c), piperidine (4d), and 4-methylpiperazine (4e), produced corresponding new tricyclic naphtho[2,3-d]thiazole-4,9-dione compounds (5a-e) in moderate-to-good yields. The photophysical properties and antimicrobial activities of these compounds (5a-e) were then characterized. Owing to the extended π-conjugated system of naphtho[2,3-d]thiazole-4,9-dione skeleton and substituent effect, 5a-e showed fluorescence both in solution and in the solid state. The introduction of nitrogen-containing heterocycles at position 2 of the thiazole ring on naphtho[2,3-d]thiazole-4,9-dione led to large bathochromic shifts in solution, and 5b-e exhibited orange-red fluorescence with emission maxima of over 600 nm in highly polar solvents. Staphylococcus aureus (S. aureus) is a highly pathogenic bacterium, and infection with its antimicrobial-resistant pathogen methicillin-resistant S. aureus (MRSA) results in serious clinical problems. In this study, we also investigated the antimicrobial activities of 5a-e against S. aureus, MRSA, and S. epidermidis. Compounds 5c with thiomorpholine group and 5e with 4-methylpiperazine group showed potent antimicrobial activity against these bacteria. These results will lead to the development of new fluorescent dyes with antimicrobial activity in the future.
Assuntos
Testes de Sensibilidade Microbiana , Tiazóis , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/síntese química , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Staphylococcus/efeitos dos fármacos , Staphylococcus/crescimento & desenvolvimento , Estrutura Molecular , Relação Estrutura-Atividade , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologiaRESUMO
As one of the most widely distributed reactive oxygen species in vivo, hydrogen peroxide plays divergent and important roles in cell growth, differentiation and aging. When the level of hydrogen peroxide in the body is abnormal, it will lead to genome mutation and induce irreversible oxidative modification of proteins, lipids and polysaccharides, resulting in cell death or even disease. Therefore, it is significant to develop a sensitive and specific probe for real-time detection of hydrogen peroxide in vivo. In this study, the response mechanism between hydrogen peroxide and probe QH was investigated by means of HRMS and the probe showed good optical properties and high selectivity to hydrogen peroxide. Note that the evaluating of probe biocompatibility resulted from cytotoxicity test, behavioral test, hepatotoxicity test, cardiotoxicity test, blood vessel toxicity test, immunotoxicity test and neurotoxicity test using cell and transgenic zebrafish models with more than 20 toxic indices. Furthermore, the detection performance of the probe for hydrogen peroxide was evaluated by multiple biological models and the probe was proved to be much essential for the monitoring of hydrogen peroxide in vivo.