RESUMEN
Green-synthesized silver and copper nanoparticles (NPs), along with their composites, exhibit various biological activities. Ocimum sanctum (Holy basil), traditionally used as medicine in South Asia, treats respiratory disorders, digestive issues, skin diseases and inflammatory conditions. Modern scientific studies support these bioactivities; however, no studies have investigated their bioactivity in combination with NPs. In this study, silver and copper NPs were synthesized using AgNO3 and CuSO4·5H2O solutions, respectively, with Ocimum sanctum leaf extract, and their antibacterial, antioxidant and anticancer properties were examined. Spectroscopic analyses, including Fourier transform infra-red (FTIR), transmission electron microscopy (TEM) and X-ray diffraction (XRD), elucidated the physicochemical characteristics of the green-synthesized nanoparticles (Os-AgNPs and Os-CuNPs), revealing sizes of 11.7 and 13.1 nm, respectively. The Os-AgNPs:Os-CuNPs nano-composite with a 1:2 ratio exhibited a zone of inhibition ranging from 8 to 12 mm against tested bacterial pathogens. Additionally, the NPs and their composites demonstrated potent antioxidant activity, with notable 2-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity observed in composites with ratios of 2:1 and 1:2. Furthermore, they displayed potential anticancer activity against human leukaemia (Jurkat) cancer cells. Although no distinct difference in anticancer property was observed among the NPs and their composites, our study highlights their well-defined nanostructure and significant biological activity, suggesting their potential as therapeutic agents in the pharmaceutical industry.
Asunto(s)
Antibacterianos , Antineoplásicos , Antioxidantes , Cobre , Tecnología Química Verde , Nanopartículas del Metal , Ocimum sanctum , Extractos Vegetales , Hojas de la Planta , Plata , Nanopartículas del Metal/química , Plata/química , Plata/farmacología , Ocimum sanctum/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Cobre/química , Humanos , Hojas de la Planta/química , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular TumoralRESUMEN
The modern nanomedicine incorporates the multimodal treatments into a single formulation, offering innovative cancer therapy options. Nanosheets function as carriers, altering the solubility, biodistribution, and effectiveness of medicinal compounds, resulting in more efficient cancer treatments and reduced side effects. The non-toxic nature of fluorinated graphene oxide (FGO) nanosheets and their potential applications in medication delivery, medical diagnostics, and biomedicine distinguish them from others. Leveraging the unique properties of Lissachatina fulica snail mucus (LfSM), FGO nanosheets were developed to reveal the novel characteristics. Consequently, LfSM was utilized to create non-toxic, environmentally friendly, and long-lasting FGO nanosheets. Ultraviolet-visible (UV-vis) spectroscopy revealed a prominent absorbance peak at 235 nm. The characterization of the synthesized FGO nanosheets involved X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Raman, scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), high-resolution transmission electron microscopy (HR-TEM), and atomic force microscopy (AFM) analyses. The antimicrobial activity data demonstrated a broad spectrum of antibacterial effects against Escherichia coli, Bacillus subtilis, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The cytotoxicity efficacy of LfSM-FGO nanosheets against pancreatic cancer cell line (PANC1) showed promising results at low concentrations. The study suggests that FGO nanosheets made from LfSM could serve as alternate factors for in biomedical applications in the future.
Asunto(s)
Grafito , Nanoestructuras , Caracoles , Grafito/química , Grafito/farmacología , Animales , Caracoles/química , Humanos , Nanoestructuras/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Pruebas de Sensibilidad Microbiana , Moco/química , Moco/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Halogenación , Supervivencia Celular/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Línea Celular Tumoral , Tamaño de la PartículaRESUMEN
Due to their exceptional physicochemical features, green synthesized silver nanoparticles (AgNPs) have been of considerable interest in cancer treatment. In the present study, for the first time, we aimed to green synthesize AgNPs from Euphorbia retusa and explore their anticancer potential on human breast cancer (MCF-7) cells. First, the green synthesized AgNPs (EU-AgNPs) were well characterized by UV-visible spectroscopy, Fourier transmission infrared (FTIR) spectrum, XRD, scanning and transmission electron microscopy (SEM and TEM), and EDX techniques. The characterization data exhibited that EU-AgNPs were spherical in shape and crystalline in nature with an average size of 17.8 nm. FTIR results established the presence of active metabolites in EU-AgNPs. Second, the anticancer effect of EU-AgNPs was evaluated against MCF-7 cells by MTT and neutral red uptake (NRU) assays. Moreover, morphological changes, ROS production, MMP, and apoptotic marker genes were also studied upon exposure to cytotoxic doses of EU-AgNPs. Our results showed that EU-AgNPs induce cytotoxicity in a concentration-dependent manner, with an IC50 value of 40 µg/mL. Morphological changes in MCF-7 cells exposed to EU-AgNPs also confirm their cytotoxic effects. Increased ROS and decreased MMP levels revealed that EU-AgNPs induced oxidative stress and mitochondrial membrane dysfunction. Moreover, ROS-mediated apoptosis was confirmed by elevated levels of proapoptotic marker genes (p53, Bax, caspase-3, and caspase-9) and reduced levels of an antiapoptotic gene (Bcl-2). Altogether, these findings suggested that EU-AgNPs could induce potential anticancer effects through ROS-mediated apoptosis in MCF-7 cells.
Asunto(s)
Antineoplásicos , Apoptosis , Neoplasias de la Mama , Tecnología Química Verde , Nanopartículas del Metal , Mitocondrias , Especies Reactivas de Oxígeno , Plata , Humanos , Plata/química , Plata/farmacología , Nanopartículas del Metal/química , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células MCF-7 , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Femenino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Euphorbia/química , Relación Dosis-Respuesta a Droga , Supervivencia Celular/efectos de los fármacosRESUMEN
Metal oxide nanoparticles(NPs) contain unique properties which have made them attractive agents in cancer treatment. The CuO nanoparticles were green synthesized using walnut shell powder in different calcination temperatures (400°, 500°, 700°, and 900 °C). The CuO nanoparticles are characterized by FTIR, XRD, BET, SEM and DLS analyses. SEM and DLS analyses showed that by increasing the required calcination temperature for synthesizing the NPs, their size was increased. DPPH analysis displayed no significant anti-oxidative properties of the CuO NPs. The MTT analysis showed that all synthesized CuO NPs exhibited cytotoxic effects on MCF-7, HCT-116, and HEK-293 cell lines. Among the CuO NPs, the CuO-900 NPs showed the least cytotoxic effect on the HEK-293 cell line (IC50 = 330.8 µg/ml). Hoechst staining and real-time analysis suggested that the CuO-900 NPs induced apoptosis by elevation of p53 and Bax genes expression levels. Also, the CuO-900 NPs increased the Nrf-2 gene expression level in MCF-7 cells, despite the HCT-116 cells. As can be concluded from the results, the CuO-900 NPs exerted promising cytotoxic effects on breast and colon cancer cells.
Asunto(s)
Antineoplásicos , Apoptosis , Neoplasias de la Mama , Neoplasias Colorrectales , Cobre , Tecnología Química Verde , Juglans , Nanopartículas del Metal , Humanos , Cobre/química , Cobre/farmacología , Juglans/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Nanopartículas del Metal/química , Células MCF-7 , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Células HCT116 , Femenino , Células HEK293 , Tamaño de la Partícula , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Línea Celular Tumoral , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Supervivencia Celular/efectos de los fármacosRESUMEN
Rho family GTPases regulate cellular processes and promote tumour growth and metastasis; thus, RhoA is a potential target for tumour metastasis inhibition. However, limited progress has been made in the development of RhoA targeting anticancer drugs. Here, we synthesised benzo[b]thiophene-3-carboxylic acid 1,1-dioxide derivatives based on a covalent inhibitor of RhoA (DC-Rhoin), reported in our previous studies. The observed structure-activity relationship (contributed by carboxamide in C-3 and 1-methyl-1H-pyrazol in C-5) enhanced the anti-proliferative activity of the derivatives. Compound b19 significantly inhibited the proliferation, migration, and invasion of MDA-MB-231 cells and promoted their apoptosis. The suppression of myosin light chain phosphorylation and the formation of stress fibres confirmed the inhibitory activity of b19 via the RhoA/ROCK pathway. b19 exhibited a different binding pattern from DC-Rhoin, as observed in molecular docking analysis. This study provides a reference for the development of anticancer agents targeting the RhoA/ROCK pathway.
Asunto(s)
Antineoplásicos , Apoptosis , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Tiofenos , Quinasas Asociadas a rho , Proteína de Unión al GTP rhoA , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Proteína de Unión al GTP rhoA/antagonistas & inhibidores , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Apoptosis/efectos de los fármacos , Tiofenos/farmacología , Tiofenos/química , Tiofenos/síntesis química , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Simulación del Acoplamiento MolecularRESUMEN
Pyridazinone derivatives have been extensively used as anticancer agents. IMB5036 is a structure specific pyridazinone compound with potential antitumor activity via targeting KSRP protein which controls gene expression at multiple levels. In this study, fifteen IMB5036 analogues were synthesized and preliminary structure-activity relationships were explored. Among them, compounds 8 and 10 exhibited remarkably anti-proliferation of various cancer cells and a good cancer cell selectivity (against human fetal hepatocyte L02 cells). More detailed investigation was included that both 8 and 10 inhibited colony formation and migration in concentration-dependent mode against MCF-7 cells. Additionally, 8 and 10 induced apoptosis and cell cycle arrest, decreased mitochondrial membrane potential, damaged DNA, and increased reactive oxygen species. Moreover, 8 displayed a potent antitumor efficacy (TGI = 74.2 %, at a dose of 30 mg/kg) in MCF-7 xenograft model by i.p. injection. Further, we synthesized a biotinylated probe 16 for identifying the detail domain of KSRP. Through pull down assay and molecular docking study, we validated that the KH23 domain functioned as the binding pocket for the compounds. Thus, compound 8 was identified as a novel targeting KSRP pyridazinone-based compound and exhibited excellent antitumor activity both in vitro and in vivo.
Asunto(s)
Antineoplásicos , Apoptosis , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Piridazinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Piridazinas/farmacología , Piridazinas/química , Piridazinas/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Animales , Apoptosis/efectos de los fármacos , Ratones , Estructura Molecular , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Femenino , Ratones Desnudos , Ratones Endogámicos BALB C , Línea Celular TumoralRESUMEN
Tumor proliferation and metastasis are intricately linked to blood vessel formation, with vascular endothelial growth factor (VEGF) playing a pivotal role in orchestrating angiogenesis throughout tumor progression. Pseudolaric acid B (PAB) has emerged as a potent inhibitor of tumor cell proliferation, migration, and angiogenesis. In efforts to enhance its efficacy, 37 derivatives of PAB were synthesized and assessed for their capacity to suppress VEGF secretion in SiHa cells under hypoxic conditions. Notably, majority of these derivatives exhibited significant inhibition of VEGF protein secretion without inducing cytotoxicity. Among them, compound M2 displayed the most potent inhibitory activity, with an IC50 value of 0.68 µM, outperforming the lead compound PAB (IC50 = 5.44 µM). Compound M2 not only curbed the migration and angiogenesis of HUVECs under hypoxic conditions but also hindered the invasion of SiHa cells. Mechanistic investigations unveiled that compound M2 may impede the accumulation and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) in SiHa cells, thereby downregulating VEGF expression. This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis. Furthermore, compound M2 was observed to modulate the PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells, thereby regulating HIF-1α translation and synthesis. In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis.
Asunto(s)
Inhibidores de la Angiogénesis , Antineoplásicos , Proliferación Celular , Diterpenos , Diseño de Fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Factor A de Crecimiento Endotelial Vascular , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Diterpenos/farmacología , Diterpenos/síntesis química , Diterpenos/química , Transducción de Señal/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Animales , Movimiento Celular/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismoRESUMEN
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and STAT3 has emerged as an effective drug target for TNBC treatment. Herein, we employed a scaffold-hopping strategy of natural products to develop a series of naphthoquinone-furopiperidine derivatives as novel STAT3 inhibitors. The in vitro assay showed that compound 10g possessed higher antiproliferative activity than Cryptotanshinone and Napabucasin against TNBC cell lines, along with lower toxicity and potent antitumor activity in a TNBC xenograft model. Mechanistically, 10g could inhibit the phosphorylation of STAT3 and the binding affinity was determined by the SPR assay (KD = 8.30 µM). Molecule docking studies suggested a plausible binding mode between 10g and the SH2 domain, in which the piperidine fragment and the terminal hydroxy group of 10g played an important role in demonstrating the success of this evolution strategy. These findings provide a natural product-inspired novel STAT3 inhibitor for TNBC treatment.
Asunto(s)
Antineoplásicos , Productos Biológicos , Proliferación Celular , Simulación del Acoplamiento Molecular , Naftoquinonas , Piperidinas , Factor de Transcripción STAT3 , Neoplasias de la Mama Triple Negativas , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/síntesis química , Naftoquinonas/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Piperidinas/uso terapéutico , Animales , Femenino , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones , Relación Estructura-Actividad , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Descubrimiento de Drogas , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
A series of new gold(I) and silver(I) N-heterocyclic carbenes bearing a 1-thio-ß-d-glucose tetraacetate moiety was synthesized and chemically characterized. The compounds' stability and solubility in physiological conditions were investigated employing a multitechnique approach. Interaction studies with biologically relevant proteins, such as superoxide dismutase (SOD) and human serum albumin (HSA), were conducted via UV-vis absorption spectroscopy and high-resolution ESI mass spectrometry. The biological activity of the compounds was evaluated in the A2780 and A2780R (cisplatin-resistant) ovarian cancer cell lines and the HSkMC (human skeletal muscle) healthy cell line. Inhibition studies of the selenoenzyme thioredoxin reductase (TrxR) were also carried out. The results highlighted that the gold complexes are more stable in aqueous environment and capable of interaction with SOD and HSA. Moreover, these carbenes strongly inhibited the TrxR activity. In contrast, the silver ones underwent structural alterations in the aqueous medium and showed greater antiproliferative activity.
Asunto(s)
Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Oro , Compuestos Heterocíclicos , Metano , Plata , Reductasa de Tiorredoxina-Disulfuro , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Plata/química , Plata/farmacología , Oro/química , Oro/farmacología , Metano/análogos & derivados , Metano/química , Metano/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Proliferación Celular/efectos de los fármacos , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Estructura Molecular , Relación Estructura-Actividad , Línea Celular Tumoral , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/antagonistas & inhibidoresRESUMEN
Given the extensive role of lipids in cancer development, there is substantial clinical interest in developing therapies that target lipid metabolism. In this study, we identified one cyclometalated iridium complex (Ir2) that exhibits potent antiproliferation activity in MIA PaCa-2 cells by regulating fatty acid metabolism and sphingolipid metabolism simultaneously. Ir2 also efficiently overcomes cisplatin resistance in vitro. Satisfyingly, the generated Ir2@F127 carriers, as a temperature-sensitive in situ gelling system of Ir2, showed effective cancer treatment with minimal side effects in an in vivo xenograft study. To the best of our knowledge, Ir2 is the first reported cyclometalated iridium complex that exerts anticancer activity in MIA PaCa-2 cells by intervening in lipid metabolism, which provides an alternative pathway for the anticancer mechanism of cyclometalated iridium complexes.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Ácidos Grasos , Iridio , Esfingolípidos , Humanos , Iridio/química , Iridio/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Animales , Ácidos Grasos/metabolismo , Ácidos Grasos/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Línea Celular Tumoral , Esfingolípidos/metabolismo , Ratones , Oxidación-Reducción , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto , Reprogramación MetabólicaRESUMEN
The synthesis of bioinspired metal-organic frameworks (MOFs) performed in mild conditions with a high quality is greatly demanded. Moreover, the influence of the morphology and structure of bio-MOFs on the cell interaction and toxicity is important to determine. In this work, we developed an ultrasound (US)-assisted synthesis of HKUST-1 MOFs under mild conditions and investigated the influence of the parameters of synthesis on the morphology, structure, and biological properties of the developed MOFs. It was found that the US power, reaction time, temperature, and type of solvent composition would affect the morphology, size, and yield of the obtained crystals. Employing the optimal synthetic conditions, five types of HKUST-1 MOFs were prepared, achieving highest yields (67.8-96.2%) and different morphologies (octahedral, dodecahedral, icosahedral). The relationship between the morphological features and biological properties of developed bio-MOFs was evaluated and discussed. The cellular association and cytotoxicity of MOF@US and MOF@US-PARG were studied on various cell cultures, i.e. normal mouse embryonic fibroblasts (MEF NF2), chronic myeloid leukemia (K562), and mouse melanoma (B16-F10). The experimental results showed that MOF@US-PARG has a higher percentage of association compared to MOF@US. It has also been shown that the cytotoxicity depends on the concentration and surface modification of the developed MOFs.
Asunto(s)
Materiales Biocompatibles , Ensayo de Materiales , Estructuras Metalorgánicas , Tamaño de la Partícula , Ratones , Animales , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Estructuras Metalorgánicas/síntesis química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/síntesis química , Humanos , Supervivencia Celular/efectos de los fármacos , Ondas Ultrasónicas , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Propiedades de Superficie , Proliferación Celular/efectos de los fármacos , Línea Celular TumoralRESUMEN
Using the principle of "Magic Bullet", a cisplatin-derived platinum(IV) prodrug heterobimetallic Pt(IV)-Ru(II) complex, cis,cis,trans-[Pt(NH3)2Cl2{Ru(tpy-BODIPY)(tpy-COO)}(biotin)]Cl2 (Pt-Ru-B, 2), having two axial ligands, namely, biotin as water-soluble B-vitamin for enhanced cellular uptake and a BODIPY-ruthenium(II) (Ru-B, 1) photosensitizer having N,N,N-donor tpy (4'-phenyl-2,2':6',2â³-terpyridine) bonded to boron-dipyrromethene (BODIPY), is developed as a "Platin Bullet" for targeted photodynamic therapy (PDT). Pt-Ru-B exhibited intense absorption near 500 nm and emission near 513 nm (λex = 488 nm) in a 10% dimethyl sulfoxide-Dulbecco's phosphate-buffered saline medium (pH 7.2). The BODIPY complex on light activation generates singlet oxygen as the reactive oxygen species (ROS) giving a quantum yield (ΦΔ) of â¼0.64 from 1,3-diphenylisobenzofuran experiments. Pt-Ru-B exhibited preferential cellular uptake in cancer cells over noncancerous cells. The dichlorodihydrofluorescein diacetate assay confirmed the generation of cellular ROS. Confocal images revealed its mitochondrial internalization. Pt-Ru-B showed submicromolar photocytotoxicity in visible light (400-700 nm) in A549 and multidrug-resistant MDA-MB-231 cancer cells. It remained nontoxic in the dark and less toxic in nontumorigenic cells. Cellular apoptosis and alteration of the mitochondrial membrane potential were evidenced from the respective Annexin V-FITC/propidium iodide assay and JC-1 dye assay. A wound healing assay using A549 cells and Pt-Ru-B revealed inhibition of cancer cell migration, highlighting its potential as an antimetastatic agent.
Asunto(s)
Antineoplásicos , Biotina , Fotoquimioterapia , Fármacos Fotosensibilizantes , Profármacos , Rutenio , Humanos , Profármacos/farmacología , Profármacos/química , Profármacos/síntesis química , Rutenio/química , Rutenio/farmacología , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Biotina/química , Biotina/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Compuestos de Boro/química , Compuestos de Boro/farmacología , Compuestos de Boro/síntesis química , Porfobilinógeno/análogos & derivados , Porfobilinógeno/química , Porfobilinógeno/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Platino (Metal)/química , Platino (Metal)/farmacología , Estructura Molecular , Supervivencia Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Cisplatino/farmacología , Cisplatino/químicaRESUMEN
The synthesis and characterization of metal complexes have garnered significant attention due to their versatile applications in scientific and biomedical fields. In this research, two novel copper (Cu) complexes, [Cu(L)(L')(H2O)2] (1) and [Cu(L)(Im)H2O] (2), where L = pyridine-2,6-dicarboxylic acid, L' = 2,4-diamino-6-hydroxypyrimidine, and Im = imidazole, were investigated concerning their sonochemical synthesis, spectroscopic analysis, and biological activity. The complexes' structural characterization was achieved using analytical techniques, including single-crystal X-ray structure determination, FTIR, PXRD, TGA and DTA, SEM, TEM, and EDS. Complex (1) displayed a six-coordinated Cu2+ ion, while complex (2) exhibited a five-coordinated Cu2+ ion. The crystal structures revealed monoclinic (C2/c) and triclinic (P-1) space groups, respectively. Both complexes showcased zero-dimensional (0D) supramolecular networks, primarily driven by hydrogen bonding and π-π stacking interactions, which played pivotal roles in stabilizing the structures and shaping the unique supramolecular architecture. Both complexes demonstrated significant antioxidant activity, suggesting their capability to neutralize free radicals and mitigate oxidative stress-related diseases. Hemolysis percentages were less than 2%, per the ASTM F756-00 standard, indicating non-hemolytic behavior. Low cytotoxicity was observed against fibroblast and MCF-7 cell lines. They do not exhibit antibacterial activity against Escherichia coli and Staphylococcus aureus. These findings suggest that the synthesized Cu2+âcomplexes hold considerable promise for applications in drug delivery and cancer treatment. This research contributes to the advancement of supramolecular chemistry and the development of multifunctional materials for diverse scientific and medical applications.
Asunto(s)
Complejos de Coordinación , Cobre , Cobre/química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Humanos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Cristalografía por Rayos X , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Células MCF-7 , Hemólisis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis químicaRESUMEN
The pyrimidine heterocycle plays an important role in anticancer research. In particular, the pyrimidine derivative families of uracil show promise as structural scaffolds relevant to cervical cancer. This group of chemicals lacks data-driven machine learning quantitative structure-activity relationships (QSARs) that allow for generalization and predictive capabilities in the search for new active compounds. To achieve this, a dataset of pyrimidine and uracil compounds from ChEMBL were collected and curated. A workflow was developed for data-driven machine learning QSAR using an intuitive dataset design and forwards selection of molecular descriptors. The model was thoroughly externally validated against available data. Blind validation was also performed by synthesis and antiproliferative evaluation of new synthesized uracil-based and pyrimidine derivatives. The most active compound among new synthesized derivatives, 2,4,5-trisubstituted pyrimidine was predicted with the QSAR model with differences of 0.02 compared to experimentally tested activity.
Asunto(s)
Antineoplásicos , Proliferación Celular , Pirimidinas , Relación Estructura-Actividad Cuantitativa , Uracilo , Uracilo/química , Uracilo/análogos & derivados , Uracilo/farmacología , Uracilo/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Aprendizaje Automático , Línea Celular TumoralRESUMEN
A new complex of copper(II) with methyl-5-(trifluoromethyl)pyrazol-3-yl-ketazine (H2L) was synthesized with the composition [Cu2L2]âC2H5OH (1). Recrystallization of the sample from DMSO yielded a single crystal of the composition [Cu2L2((CH3)2SO)] (2). The coordination compounds were studied by single-crystal X-ray diffraction analysis, IR spectroscopy, and static magnetic susceptibility method. The data obtained indicate that the polydentate ligand is coordinated by both acyclic nitrogen and heterocyclic nitrogen atoms. The cytotoxic activity of the ligand and complex 1 was investigated on human cell lines MCF7 (breast adenocarcinoma), Hep2 (laryngeal carcinoma), A549 (lung carcinoma), HepG2 (hepatocellular carcinoma), and MRC5 (non-tumor lung fibroblasts). The complex was shown to have a pronounced dose-dependent cytotoxicity towards these cell lines with LC50 values in the range of 0.18-4.03 µM.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Cobre , Hidrazonas , Humanos , Cobre/química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Cristalografía por Rayos X , Estructura Molecular , Ligandos , Células MCF-7 , Células Hep G2RESUMEN
Cancer continues to be a major global health issue, ranking among the top causes of death worldwide. To develop novel antitumor agents, this study focused on the synthesis of a series of 21 novel furanopyridinone derivatives through structural modifications and functional enhancements. The in vitro anti-tumor activities of these compounds were investigated through the cytotoxicity against KYSE70 and KYSE150 and led to the identification of compound 4c as the most potent compound. At a concentration of 20 µg/mL, compound 4c demonstrated a remarkable 99% inhibition of KYSE70 and KYSE150 cell growth after 48 h. IC50 was 0.655 µg/mL after 24 h. Additionally, potential anti-tumor cellular mechanisms were explored through molecular docking, which was used to predict the binding mode of 4c with METAP2 and EGFR, suggesting that the C=O part of the pyridone moiety likely played a crucial role in binding. This study provided valuable insights and guidance for the development of novel anticancer drugs with novel structural scaffolds.
Asunto(s)
Antineoplásicos , Proliferación Celular , Neoplasias Esofágicas , Simulación del Acoplamiento Molecular , Piridonas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Piridonas/farmacología , Piridonas/química , Piridonas/síntesis química , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Apoptosis/efectos de los fármacosRESUMEN
In the following study, a series of new lupeol-3-carbamate derivatives were synthesized, and the structures of all the newly derived compounds were characterized. The new compounds were screened to determine their anti-proliferative activity against human lung cancer cell line A549, human liver cancer cell line HepG2, and human breast cancer cell line MCF-7. Most of the compounds were found to show better anti-proliferative activity in vitro than lupeol. Among them, obvious anti-proliferation activity (IC50 = 5.39~9.43 µM) was exhibited by compound 3i against all three tumor cell lines. In addition, a salt reaction was performed on compound 3k (IC50 = 13.98 µM) and it was observed that the anti-proliferative activity and water solubility of compound 3k·CH3I (IC50 = 3.13 µM), were significantly enhanced subsequent to the salt formation process. The preliminary mechanistic studies demonstrated that apoptosis in HepG2 cells was induced by compound 3k·CH3I through the inhibition of the PI3K/AKT/mTOR pathway. In conclusion, a series of new lupeol-3-carbamate derivatives were synthesized via the structural modification of the C-3 site of lupeol, thus laying a theoretical foundation for the design of this new anticancer drug.
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Antineoplásicos , Apoptosis , Carbamatos , Proliferación Celular , Triterpenos Pentacíclicos , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/síntesis química , Triterpenos Pentacíclicos/química , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Carbamatos/farmacología , Carbamatos/química , Carbamatos/síntesis química , Células Hep G2 , Relación Estructura-Actividad , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Células A549 , Células MCF-7 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , LupanosRESUMEN
Lamellarins are natural products with a [3,4]-fused pyrrolocoumarin skeleton possessing interesting biological properties. More than 70 members have been isolated from diverse marine organisms, such as sponges, ascidians, mollusks, and tunicates. There is a continuous interest in the synthesis of these compounds. In this review, the synthetic strategies for the synthesis of the title compounds are presented along with their biological properties. Three routes are followed for the synthesis of lamellarins. Initially, pyrrole derivatives are the starting or intermediate compounds, and then they are fused to isoquinoline or a coumarin moiety. Second, isoquinoline is the starting compound fused to an indole moiety. In the last route, coumarins are the starting compounds, which are fused to a pyrrole moiety and an isoquinoline scaffold. The synthesis of isolamellarins, azacoumestans, isoazacoumestans, and analogues is also described. The above synthesis is achieved via metal-catalyzed cross-coupling, [3 + 2] cycloaddition, substitution, and lactonization reactions. The title compounds exhibit cytotoxic, multidrug resistance (MDR), topoisomerase I-targeted antitumor, anti-HIV, antiproliferative, anti-neurodegenerative disease, and anti-inflammatory activities.
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Cumarinas , Cumarinas/química , Cumarinas/síntesis química , Cumarinas/farmacología , Humanos , Animales , Productos Biológicos/química , Productos Biológicos/síntesis química , Productos Biológicos/farmacología , Isoquinolinas/química , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Pirroles/química , Pirroles/síntesis química , Pirroles/farmacología , Estructura Molecular , Compuestos Heterocíclicos de 4 o más AnillosRESUMEN
A series of new unique acetylene derivatives of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonamide 3a-f and 6a-f were prepared by reactions of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonyl chlorides with acetylene derivatives of amine. A series of new hybrid systems containing quinoline and 1,2,3-triazole systems 7a-h were obtained by reactions of acetylene derivatives of quinoline-5-sulfonamide 6a-d with organic azides. The structures of the obtained compounds were confirmed by 1H and 13C NMR spectroscopy and HR-MS spectrometry. The obtained quinoline derivatives 3a-f and 6a-f and 1,2,3-triazole derivatives 7a-h were tested for their anticancer and antimicrobial activity. Human amelanotic melanoma cells (C-32), human breast adenocarcinoma cells (MDA-MB-231), and human lung adenocarcinoma cells (A549) were selected as tested cancer lines, while cytotoxicity was investigated on normal human dermal fibroblasts (HFF-1). All the compounds were also tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis. Only the acetylene derivatives of 8-hydroxyquinoline-5-sulfonamide 3a-f were shown to be biologically active, and 8-hydroxy-N-methyl-N-(prop-2-yn-1-yl)quinoline-5-sulfonamide (3c) showed the highest activity against all three cancer lines and MRSA isolates. Its efficacies were comparable to those of cisplatin/doxorubicin and oxacillin/ciprofloxacin. In the non-cancer HFF-1 line, the compound showed no toxicity up to an IC50 of 100 µM. In additional tests, compound 3c decreased the expression of H3, increased the transcriptional activity of cell cycle regulators (P53 and P21 proteins), and altered the expression of BCL-2 and BAX genes in all cancer lines. The unsubstituted phenolic group at position 8 of the quinoline is the key structural fragment necessary for biological activity.
Asunto(s)
Antibacterianos , Antineoplásicos , Pruebas de Sensibilidad Microbiana , Quinolinas , Sulfonamidas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Línea Celular Tumoral , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Diseño de Fármacos , Relación Estructura-Actividad , Staphylococcus aureus/efectos de los fármacos , Enterococcus faecalis/efectos de los fármacos , Estructura MolecularRESUMEN
The enmein-type diterpenoids are a class of anticancer ent-Kaurane diterpnoids that have received much attention in recent years. Herein, a novel 1,14-epoxy enmein-type diterpenoid 4, was reported in this project for the first time. A series of novel enmein-type diterpenoid derivatives were also synthesized and tested for anticancer activities. Among all the derivatives, compound 7h exhibited the most significant inhibitory effect against A549 cells (IC50 = 2.16 µM), being 11.03-folds better than its parental compound 4. Additionally, 7h exhibited relatively weak anti-proliferative activity (IC50 > 100 µM) against human normal L-02 cells, suggesting that it had excellent anti-proliferative selectivity for cancer cells. Mechanism studies suggested that 7h induced G0/G1 arrest and apoptosis in A549 cells by inhibiting the PI3K/AKT/mTOR pathway. This process was associated with elevated intracellular ROS levels and collapsed MMP. In summary, these data identified 7h as a promising lead compound that warrants further investigation of its anticancer properties.