RESUMEN
Phosphatidylinositide-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) have recently been identified as potential cancer targets. In our work, a new family of quinoline analogues was designed, developed, and evaluated as dual inhibitors of PI3Kδ/mTOR. The preliminary biological activity analysis led to the discovery of the lead compounds 5h and 5e. Compounds 5h and 5e exhibited excellent anti-tumor potency with IC50 of 0.26 µM and 0.34 µM against Ramos cells, respectively. Importantly, based on the enzymatic activity assay results, compounds 5h and 5e were identified as dual inhibitors of PI3Kδ and mTOR, with IC50 values of 0.042 µM and 0.056 µM for PI3Kδ and 0.059 µM and 0.073 µM for mTOR, respectively. Furthermore, these compounds showed superior selectivity for blocking PI3Kδ compared to other PI3K isoforms (α, ß, and γ), supporting the concept of developing inhibitors that specifically target PI3Kδ/mTOR. The most effective compound 5h was chosen for additional biological testing. At a low dose of 0.5 µM, a western blot investigation confirmed the anticancer effects by inhibiting the PAM cascade, which in turn reduced downstream biomarkers pAkt (Ser473), pAkt (Thr308), and pRPS6 (Ser235/236). Furthermore, it increased apoptosis at the early (10.03 times) and late (17.95 times) stages in the Annexin-V assay as compared to the standard. In addition, the expression of p53, caspase-3, caspase-9, and the Bax/BCl-2 ratio were all significantly increased by compound 5h in the ELISA assay. Based on these results, it appears that 5h may activate the intrinsic apoptosis pathway, which in turn triggers cell death. Furthermore, the anticancer effects could be attributed to the inhibition of PI3Kδ/mTOR, as shown by docking interactions. Lastly, it demonstrated improved in vitro metabolic stability and passed the in silico ADMET/drug-likeness test. This profile recommends 5h for future in vivo PK-PD and efficacy investigations in animal cancer models.
Asunto(s)
Antineoplásicos , Proliferación Celular , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de las Quinasa Fosfoinosítidos-3 , Quinolinas , Serina-Treonina Quinasas TOR , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Proliferación Celular/efectos de los fármacos , Quinolinas/farmacología , Quinolinas/química , Quinolinas/síntesis química , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores mTOR/farmacología , Inhibidores mTOR/síntesis química , Inhibidores mTOR/química , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
Photodynamic therapy (PDT) under hypoxic conditions and drug resistance in chemotherapy are perplexing problems in anti-tumor treatment. In addition, central nervous system neoplasm-targeted nanoplatforms are urgently required. To address these issues, a new multi-functional protein hybrid nanoplatform is designed, consisting of transferrin (TFR) as the multicategory solid tumor recognizer and hemoglobin for oxygen supply (ODP-TH). This protein hybrid framework encapsulates the photosensitizer protoporphyrin IX (PpIX) and chemotherapeutic agent doxorubicin (Dox), which are attached by a glutathione-responsive disulfide bond. Mechanistically, ODP-TH crosses the blood-brain barrier (BBB) and specifically aggregated in hypoxic tumors via protein homology recognition. Oxygen and encapsulated drugs ultimately promote a therapeutic effect by down-regulating the abundance of multidrug resistance gene 1 (MDR1) and hypoxia-inducible factor-1-α (HIF-1α). The results reveal that ODP-TH achieves oxygen transport and protein homology recognition in the hypoxic tumor occupation. Indeed, compared with traditional photodynamic chemotherapy, ODP-TH achieves a more efficient tumor-inhibiting effect. This study not only overcomes the hypoxia-related inhibition in combination therapy by targeted oxygen transport but also achieves an effective treatment of multiple tumors, such as breast cancer and glioma, providing a new concept for the construction of a promising multi-functional targeted and intensive anti-tumor nanoplatform.
Asunto(s)
Carcinoma , Fotoquimioterapia , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/terapia , Carcinoma/tratamiento farmacológico , Carcinoma/terapia , Hipoxia , Oxígeno/farmacología , Oxígeno/uso terapéutico , Fármacos Fotosensibilizantes/química , Fotoquimioterapia/instrumentación , Fotoquimioterapia/métodos , Nanotecnología/instrumentación , Nanotecnología/métodos , Nanomedicina/instrumentación , Nanomedicina/métodosRESUMEN
Ferroptosis is an iron-dependent, non-apoptotic form of programmed cell death driven by excessive lipid peroxidation (LPO). Mounting evidence suggests that the unique modality of cell death is involved in the development and progression of several diseases including cancer, cardiovascular diseases (CVDs), neurodegenerative disorders, etc. However, the pathogenesis and signalling pathways of ferroptosis are not fully understood, possibly due to the lack of robust tools for the highly selective and sensitive imaging of ferroptosis analytes in complex living systems. Up to now, various small-molecule fluorescent probes have been applied as promising chemosensors for studying ferroptosis through tracking the biomolecules or microenvironment-related parameters in vitro and in vivo. In this review, we comprehensively reviewed the recent development of small-molecule fluorescent probes for studying ferroptosis, with a focus on the analytes, design strategies and bioimaging applications. We also provided new insights to overcome the major challenges in this emerging field.
Asunto(s)
Ferroptosis , Muerte Celular , Colorantes Fluorescentes , Hierro/metabolismo , Peroxidación de LípidoRESUMEN
Recently, hypothermal photothermal therapy (HPTT) seemed essential for the future clinical transformation of cancer optical therapies. However, at a lower working temperature, heat shock proteins (HSPs) seriously affect the anti-tumor effect of HPTT. This work reports a reasonable design of a dual-responsive nanoplatform for the synergistic treatment of chemotherapy and HPTT. We adopted a one-step method to wrap indocyanine green (ICG) into imidazole skeleton-8 (ZIF-8) and further loaded it with the chemotherapy drug doxorubicin (DOX). Furthermore, we introduced Hsp-70 siRNA to block the affection of HSPs at an upstream node, thereby avoiding the side effects of traditional heat shock protein inhibitors. The prepared ZIF-8@ICG@DOX@siRNA nanoparticles (ZID-Si NPs) could significantly improve the stability of siRNA to effectively down-regulate the expression of HSP70 protein during the photothermal therapy, thus realizing the pH-controlled and NIR-triggered release of the chemotherapeutical drug DOX. Moreover, tumors were also imaged accurately by ICG wrapped in ZID-Si nanoparticles. After the evaluation of the in vitro and in vivo photothermal effect as well as the anti-tumor activity, we found that the added Hsp-70 siRNA enhanced the synergistic anti-cancer activity of HPTT and chemotherapy. In summary, this work holds great potential in cancer treatment, and suggests better efficacy of synergistic chemo/HPTT than the single-agent therapy.
Asunto(s)
Hipertermia Inducida , Nanopartículas , Doxorrubicina , Liberación de Fármacos , Verde de Indocianina , Terapia Fototérmica , ARN Interferente Pequeño/genéticaRESUMEN
BACKGROUND: Heterocyclic compounds, also called heterocycles, are a major class of organic chemical compound that plays a vital role in the metabolism of all living cells. The heterocyclic compound, indazole, has attracted more attention in recent years and is widely present in numerous commercially available drugs. Indazole-containing derivatives, representing one of the most important heterocycles in drug molecules, are endowed with a broad range of biological properties. METHODS: A literature search was conducted in PubMed, Google Scholar and Web of Science regarding articles related to indazole and its therapeutic application. RESULTS: The mechanism and structure-activity relationship of indazole and its derivatives were described. Based on their versatile biological activities, the compounds were divided into six groups: anti-inflammatory, antibacterial, anti-HIV, antiarrhythmic, antifungal and antitumour. At least 43 indazole-based therapeutic agents were found to be used in clinical application or clinical trials. CONCLUSION: This review is a guide for pharmacologists who are in search of valid preclinical/clinical drug compounds where the progress of approved marketed drugs containing indazole scaffold is examined from 1966 to the present day. Future direction involves more diverse bioactive moieties with indazole scaffold and greater insights into its mechanism.
Asunto(s)
Antibacterianos/farmacología , Antiinfecciosos/farmacología , Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Indazoles/farmacología , Antibacterianos/química , Antiinfecciosos/química , Antiinflamatorios/química , Antineoplásicos/química , Relación Dosis-Respuesta a Droga , Humanos , Indazoles/química , Estructura MolecularRESUMEN
In recent decades, much attention has been given to cyclopropyl scaffolds, which commonly exist in natural products and synthetic organic molecules. Clinical drug molecules with cyclopropyl rings are an area of focus in therapeutic research due to their interesting chemical properties and unique pharmacology activity. These molecular drugs against different targets are applicable in some therapeutic treatment fields including cancer, infection, respiratory disorder, cardiovascular and cerebrovascular diseases, dysphrenia, nervous system disorders, endocrine and metabolic disorders, skin disease, digestive disorders, urogenital diseases, otolaryngological and dental diseases, and eye diseases. This review is a guide for pharmacologists who are in search of valid preclinical/clinical drug compounds where the progress, from 1961 to the present day, of approved marketed drugs containing cyclopropyl scaffold is examined.
Asunto(s)
Ciclopropanos/química , Antibacterianos/química , Antibacterianos/farmacología , Ciprofloxacina/química , Ciprofloxacina/farmacología , Ciclopropanos/metabolismo , Evaluación Preclínica de Medicamentos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Humanos , Oligopéptidos/química , Oligopéptidos/metabolismo , Oligopéptidos/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismoRESUMEN
As an essential enzyme with a variety of physiological functions, Cyclooxygenase-2 (COX-2) is also closely related to carcinoma due to the observed overexpression. In this work, a novel series of sulfonamide-containing aminophosphonate derivatives (A1-A25) were developed as selective COX-2 inhibitors and anti-cancer candidates. The top hit compound A23 presented applicative COX-2 inhibitory activity (IC50 = 0.28 µM) and anti-proliferative capability against several cancer cell lines (IC50 = 2.34-16.43 µM for HeLa, MCF-7, HCT116 and HepG2 cells). Among them, A23 has the most significant inhibitory effect on HCT116 cells, which were comparable with that of the positive controls respectively (eg: IC50 = 8.73 µM for HCT116). The binding pattern of A23 was inferred by the molecular docking simulation. Moreover, A23 could induce the apoptosis via a mitochondrion-dependent mode and cause the arrest of the cell-cycle in G1 stage. A further investigation in the checkpoints of apoptosis indicated that the node Bcl-2 might connect the selective COX-2 inhibition and the anti-tumor activity. Therefore, this work brought new information for developing COX-2 inhibitors in anti-tumor therapies in future.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Descubrimiento de Drogas , Organofosfonatos/farmacología , Sulfonamidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Simulación del Acoplamiento Molecular , Estructura Molecular , Organofosfonatos/síntesis química , Organofosfonatos/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
An efficient and concise synthesis of 2-methoxyestradiol (4) from 17ß-estradiol (1) has been achieved in three synthetic steps with a 63.3% overall yield. The key step was the palladium-catalyzed direct C(sp2)-H methoxylation of 2-aryloxypyridines. Using 2-pyridyloxyl as the directing group, Pd(OAc)2 as the catalyst, PhI(OAc)2 as the oxidant and methanol as both the methoxylation reagent and solvent, the methoxy group could be handily installed at the 2-position of 3-(2-pyridoxy) estradiol (2). Subsequently, the pyridyl group could be easily removed by nucleophilic substitution with a methoxy anion after being oxidized to a pyridyl N-oxide by m-chloroperoxybenzoic acid, delivering the target product 2-methoxyestradiol (4) in quantitative yield. In contrast, when the pyridyl directing group was removed by the TfOMe-NaOMe/MeOH system as reported in the literature, TfOMe inevitably methylated the 17-OH of 2-methoxy-3-(2-pyridoxy) estradiol (3). In effect, we have fortuitously found a new method to cleave the pyridyl directing group, which is highly suitable for substrates bearing hydroxy groups.
Asunto(s)
Carbono/química , Estradiol/química , Estradiol/síntesis química , Técnicas de Química Sintética , EstereoisomerismoRESUMEN
Sulfur-containing species are essential in the composition and the metabolism of the organisms, thus developing a full set of implements to cover all of them is still a favorable choice. Herein, we chose imidazo [1,5-α]pyridine moiety as the basic fluorophore for the detection of sulfite, and preliminarily completed the toolset since biothiols (GSH, Cys, Hcy), H2S, and PhSH could be detected by sensors based on the same backbone. The designed sensor, IPD-SFT, with structural novelty and large Stokes shift (130 nm), indicated the most attractive advantages of remarkably rapid response period (within 1 min) and high selectivity for sulfite from all the sulfur-containing species. Other practical properties included high sensitivity (LOD = 50 nM) and wide pH adaptability (5.0-11.0). Furthermore, IPD-SFT could monitor both exogenous and endogenous sulfite. It not only raised a potential tool for sulfite detection, but also preliminarily completed the toolset for all the sulfur-containing species. The development of such toolsets might reveal the sulfur-containing metabolism and corresponding physiology and pathological procedures.
RESUMEN
Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure-activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.
Asunto(s)
Triazoles , Proteolisis , Relación Estructura-Actividad , Triazoles/química , UbiquitinaciónRESUMEN
OBJECTIVE: To explore the clinical and pathologic features as well as prognosis of systemic EBV-positive T-cell lymphoma in children. METHODS: The clinical data including clinical manifestation, pathologic changes and treatment in 16 patients with children's systemic EBV-positive T-cell lymphoma were analyzed retrospectively, and follow-up of patients were carried out. RESULTS: The 16 cases included 12 males and 4 females with median age of 3.3 years old. It was demonstrated that the clinical and pathological features of the children's systemic EBV-positive T-cell lymphoma were as followed fever, hepatosplenomegaly, cytopenia, lymphadenopathy, and hemophagocytosis in bone marrow or organ. Histologically, the structures of lymph node was normal, partially or completely destoryed. The paracortical zone was expanded with prominent infiltration of small to medium-sized atypical lymphocytes. The major immunophenotypic characteristics were as follows: (1) Almost all biopsies exhibited prominent T cell proliferation. (2) CD3 was expressed in 16 patients (100%, 16/16), CD4 in 5 patients (31.3%, 5/16)ï¼CD5 in 13 patients (81.3%, 13/16)ï¼CD7 was expressed in 11 patients (68.8%, 11/16)ï¼CD8 in 15 patients (93.8%, 15/16)ï¼CD4 and CD8 were expressed in 5 patients (31.3%, 5/16)ï¼CD4 and CD8 double-negative in patients (6.3%, 1/16)ï¼16 patients were CD56 negative (100%, 16/16). (3) TCR gene cloning rearrangement in 16 patients (93.8%, 15/16). (4) EBV-EBER was expressed in 16 patients (100%, 16/16). 11 out of 16 cases died, 1 cese failed to be followed up, 1 case relapsedï¼and 3 cases survived, reseptively. The media survival time was 4 months. CONCLUSION: Systemic EBV-positive T-cell lymphoma predominantly occurred in childhood and early teen-age, and lacks specific clinic features, usually combined with hemophagocytic syndrome. The confirmed diagnosis requires comprehensive analysis of clinical manifestation, pathomorphology, immunohistochemical detection, EBV-EBER insite hybridization, and TCR gene test. The overall prognosis of the disease is poor and the fatality rate is high.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Linfoma de Células T , Adolescente , Preescolar , Infecciones por Virus de Epstein-Barr/complicaciones , Femenino , Herpesvirus Humano 4 , Humanos , Linfoma de Células T/etiología , Masculino , Estudios Retrospectivos , Linfocitos TRESUMEN
All the heritable alterations in gene expression and chromatin structure due to chemical modifications that do not involve changes in the primary gene nucleotide sequence are referred to as epigenetics. DNA methylation, histone modifications, and non-coding RNAs are distinct types of epigenetic inheritance. Epigenetic patterns have been linked to the developmental stages, environmental exposure, and diet. Therapeutic strategies are now being developed to target human diseases such as cancer with mutations in epigenetic regulatory genes using specific inhibitors. Within the past two decades, seven epigenetic drugs have received regulatory approval and many others show their candidature in clinical trials. The current article represents a review of epigenetic heritance, diseases connected with epigenetic alterations and regulatory approved epigenetic drugs as future medicines.
Asunto(s)
Antineoplásicos , Epigénesis Genética/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Metilación de ADN/efectos de los fármacos , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Epigenómica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Código de Histonas/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , ARN no Traducido/efectos de los fármacosRESUMEN
In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against cancer cell lines (IC50â¯=â¯6.43-10.97⯵M for F10, HeLa, A549 and MCF-7â¯cells), lower toxicity to non-cancer cells than celecoxib (A33: IC50â¯=â¯194.01⯵M vs.celecoxib: IC50â¯=â¯97.87⯵M for 293T cells), and excellent inhibitory activities on COX-2 (IC50â¯=â¯0.17⯵M) and 5-LOX (IC50â¯=â¯0.68⯵M). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced apoptosis of F10â¯cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising candidate for cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Azoles/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Morfolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Azoles/síntesis química , Azoles/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Humanos , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Modelos Moleculares , Estructura Molecular , Morfolinas/química , Relación Estructura-ActividadRESUMEN
A series of rhodanine derivatives RB1-RB23 were synthesized through a two-round screening. Their Mycobacterial tuberculosis (Mtb) InhA inhibitory activity and Mtb growth blocking capability were evaluated. The most potent hit compound RB23 indicated comparable InhA inhibiton (IC50â¯=â¯2.55⯵M) with the positive control Triclosan (IC50â¯=â¯6.14⯵M) and Isoniazid (IC50â¯=â¯8.29⯵M). Its improved growth-blocking effect on Mtb and low toxicity were attractive for further development. The docking simulation revealed the possible binding pattern of this series and picked the key interacted residues as Ser20, Phe149, Lys165 and Thr196. The 3D-QSAR model visualized the SAR discussion and hinted new information. Modifying the surroundings near rhodanine moiety might be promising attempts in later investigations.
Asunto(s)
Proteínas Bacterianas/metabolismo , Oxidorreductasas/metabolismo , Rodanina/química , Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Sitios de Unión , Evaluación Preclínica de Medicamentos , Isoniazida/farmacología , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/metabolismo , Oxidorreductasas/antagonistas & inhibidores , Estructura Terciaria de Proteína , Relación Estructura-Actividad Cuantitativa , Rodanina/metabolismo , Rodanina/farmacologíaRESUMEN
Epigenetics is defined as the stable and heritable alternations in gene expression without changing the DNA nucleotide sequence. The initiation and progression of cancer result from not only genetic mutation, but also aberrant epigenetic regulation, such as DNA methylation and histones acetylation. Although Genetic alternations cannot be reversed, epigenetic modification is a dynamic and reversible process. Over the past few decades, much progress has been made in the research of epigenetic medications and a variety of drugs have been developed targeting at epigenetic regulatory proteins, which are capable of restoring malignant cancer cells to the normal state. The epigenetic drugs currently approved for cancer treatment mainly target at DNA methylation and histones acetylation. In addition, there are a great many epigenetic drugs in clinical trials for cancer therapy, such as inhibitors of DNA methyltransferases, histone deacetylases, histone methyltransferases, lysine specific demethylases, and BET (bromodomain and extra-terminal domain) family proteins. We will discuss the latest developments of these inhibitors and their applications in cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Acetilación/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Código de Histonas/efectos de los fármacos , Histonas/metabolismo , Humanos , Neoplasias/genéticaRESUMEN
The overexpress of COX-2 was clearly associated with carcinogenesis and COX-2 as a possible target has long been exploited for cancer therapy. In this work, we described the design and synthesis of a series of diarylpyrazole derivatives integrating with chrysin. Among them, compound e9 exhibited the most potent inhibitory activity against COX-2 and antiproliferative activity against Hela cells with IC50 value of 1.12⯵M. Further investigation revealed that e9 could induce apoptosis of Hela cells by mitochondrial depolarization and block the G1 phase of cell cycle in a dose-dependent manner. Besides, molecular docking simulation results was further confirmed that e9 could bind well with COX-2. In summary, compound e9 may be promising candidates for cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Diseño de Fármacos , Flavonoides/farmacología , Pirazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Flavonoides/síntesis química , Flavonoides/química , Células HEK293 , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-ActividadRESUMEN
Microtubules are essential for the mitotic division of cells and have become an attractive target for anti-tumour drugs due to the increased incidence of cancer and significant mitosis rate of tumour cells. In this study, a total of six indole 1-position modified 1-indolyl acetate-5-nitroimidazole derivatives were designed, synthesized, and evaluated for their ability to inhibit tubulin polymerization caused by binding to the colchicine-binding site of tubulin. Among them, compound 3 displayed the best ability to inhibit tubulin polymerization; it also exhibited better anti-proliferative activities than colchicine against a panel of human cancer cells (with IC50 values ranging from 15 to 40nM), especially HeLa cells (with IC50 values of 15nM), based on the cellular cytotoxicity assay results. Moreover, cellular mechanism studies indicated that compound 3 could induce G2/M phase arrest and apoptosis of HeLa and MCF-7 cells, which were associated with alterations in the expression of cell cycle-checkpoint related proteins (Cyclin B1, Cdc2, and P21) and a reduction in the mitochondrial membrane potential as well as alterations in the levels of apoptosis-related proteins (PARP, Caspase 9, Bcl-2, and Bax) of these cells, respectively. Importantly, in vivo studies further revealed that compound 3 could dramatically suppress HeLa cell xenograft tumour growth compared with vehicle and CA-4 phosphate (CA-4P), and no signs of toxicity were observed in these mice. Collectively, these in vitro and in vivo results indicated that compound 3 might be a promising lead compound for further development as a potential anti-cancer drug.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Nitroimidazoles/farmacología , Estilbenos/farmacología , Moduladores de Tubulina/farmacología , Células A549 , Animales , Antineoplásicos Fitogénicos/química , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Células HEK293 , Células HT29 , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Nitroimidazoles/química , Estructura Secundaria de Proteína , Distribución Aleatoria , Estilbenos/química , Moduladores de Tubulina/química , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Recently, various nanomaterials have been used in many organic transformations as efficient catalysts. The development of new catalysts by nanoscale design has emerged as a fertile field for research and innovation. The ability of nanotechnology to enhance catalytic activity opens the potential to replace expensive catalysts with lower amounts of inexpensive nanocatalysts. Besides, development of efficient and environmentally friendly synthetic methodologies for the synthesis of compound libraries of medicinal scaffolds is an attractive area of research in both academic and pharmaceutical industry. According to above reports and needs, this review deals with applications of nanoparticles as catalysts in various organic syntheses. We detail the topic of organic transformations using nanoparticles: Metal Nanoparticles and Metal Oxide Nanoparticles. In the latter part, different Metal Oxide Nanoparticles, such as ZnO Nanoparticle, TiO2 Nanoparticle, and CuO Nanoparticle are discussed.
Asunto(s)
Técnicas de Química Sintética , Metales/química , Nanopartículas/química , Compuestos Orgánicos/síntesis química , Óxidos/química , Catálisis , Compuestos Orgánicos/químicaRESUMEN
A series of 12 novel acylhydrazone, chalcone and amide-bridged analogues of combretastatin A-4 were designed and synthesized toward tubulin. All these compounds were determined by elemental analysis, (1)H NMR, and MS. Among them, compound 7 with acylhydrazone-bridge, bearing a benzyl at the indole-N position, was identified as a potent antiproliferative agent against a panel of cancer cell lines with IC50 values ranging from 0.08 to 35.6 µM. In contrast, its cytotoxic effects on three normal human cells were minimal. Cellular studies have revealed that the induction of apoptosis by compound 7 was associated with a collapse of mitochondrial membrane potential, accumulation of reactive oxygen species, alterations in the expression of some cell cycle-related proteins (Cyclin B1, Cdc25c, Cdc2, P21) and some apoptosis-related proteins (Bax, PARP, Bcl-2, Caspase3). The docking mode showed the binding posture of CA-4 and compound 7 are similar in the colchicine-binding pocket of tubulin, as confirmed by colchicine-tubulin competitive binding assay, tubulin polymerization inhibitory activity, extracellular protein expression determination assay and confocal immunofluorescence microscopy. In vivo study, compound 7 effectively inhibited A549 xenograft tumor growth without causing significant loss of body weight suggesting that compound 7 is a promising new antimitotic agent with clinical potential.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Estilbenos/síntesis química , Moduladores de Tubulina/síntesis química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Chalcona/química , Ensayos de Selección de Medicamentos Antitumorales/métodos , Humanos , Hidrazonas/química , Ratones , Neoplasias/patología , Estilbenos/química , Relación Estructura-Actividad , Tubulina (Proteína)/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of novel pyrazole-nitroimidazole derivatives had been arranged and evaluated for their EGFR/HER-2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on four kinds of cancer cell lines (MCF-7, Hela, HepG2, B16-F10). The bioassay results showed most of the designed compounds exhibited potential antiproliferation activity, with the IC50 values ranging from 0.13µM to 128.06µM in four tumor cell lines. Among them, compound 5c exhibited remarkable inhibitory activity against EGFR/HER-2 tyrosine kinase with IC50 value of 0.26µM/0.51µM, respectively, comparable to the positive control erlotinib (IC50=0.41µM for HER-2 and IC50=0.20µM for EGFR) and lapatinib (IC50=0.54µM for HER-2 and IC50=0.28µM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity of the proposed compounds and activity relationship (SAR) of these pyrazole-nitroimidazole derivatives.