RESUMEN
Gyrase and topoisomerase IV are the cellular targets for fluoroquinolones, a critically important class of antibacterial agents used to treat a broad spectrum of human infections. Unfortunately, the clinical efficacy of the fluoroquinolones has been curtailed by the emergence of target-mediated resistance. This is especially true for Neisseria gonorrhoeae, the causative pathogen of the sexually transmitted infection gonorrhea. Spiropyrimidinetriones (SPTs), a new class of antibacterials, were developed to combat the growing antibacterial resistance crisis. Zoliflodacin is the most clinically advanced SPT and displays efficacy against uncomplicated urogenital gonorrhea in human trials. Like fluoroquinolones, the primary target of zoliflodacin in N. gonorrhoeae is gyrase, and topoisomerase IV is a secondary target. Because unbalanced gyrase/topoisomerase IV targeting has facilitated the evolution of fluoroquinolone-resistant bacteria, it is important to understand the underlying basis for the differential targeting of zoliflodacin in N. gonorrhoeae. Therefore, we assessed the effects of this SPT on the catalytic and DNA cleavage activities of N. gonorrhoeae gyrase and topoisomerase IV. In all reactions examined, zoliflodacin displayed higher potency against gyrase than topoisomerase IV. Moreover, zoliflodacin generated more DNA cleavage and formed more stable enzyme-cleaved DNA-SPT complexes with gyrase. The SPT also maintained higher activity against fluoroquinolone-resistant gyrase than topoisomerase IV. Finally, when compared to zoliflodacin, the novel SPT H3D-005722 induced more balanced double-stranded DNA cleavage with gyrase and topoisomerase IV from N. gonorrhoeae, Escherichia coli, and Bacillus anthracis. This finding suggests that further development of the SPT class could yield compounds with a more balanced targeting against clinically important bacterial infections.
Asunto(s)
Antibacterianos , Girasa de ADN , Topoisomerasa de ADN IV , Neisseria gonorrhoeae , Inhibidores de Topoisomerasa II , Neisseria gonorrhoeae/efectos de los fármacos , Neisseria gonorrhoeae/enzimología , Topoisomerasa de ADN IV/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Topoisomerasa de ADN IV/genética , Girasa de ADN/metabolismo , Girasa de ADN/genética , Girasa de ADN/química , Antibacterianos/farmacología , Antibacterianos/química , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/química , Humanos , Oxazolidinonas/farmacología , Oxazolidinonas/química , Barbitúricos/farmacología , Barbitúricos/química , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Bacteriana , Isoxazoles , Morfolinas , Compuestos de EspiroRESUMEN
Uracil DNA glycosylase (UDG or Ung) is a key enzyme involved in uracil excision from the DNA as a repair mechanism. Designing Ung inhibitors is thus a promising strategy to treat different cancers and infectious diseases. The uracil ring and its derivatives have been shown to inhibit Mycobacterium tuberculosis Ung (MtUng), resulting from specific and strong binding with the uracil-binding pocket (UBP). To design novel MtUng inhibitors, we screened several non-uracil ring fragments hypothesised to occupy MtUng UBP due to their high similarity to the uracil structural motif. These efforts have resulted in the discovery of novel MtUng ring inhibitors. Here we report the co-crystallised poses of these fragments, confirming their binding within the UBP, thus providing a robust structural framework for the design of novel lead compounds. We selected the barbituric acid (BA) ring as a case study for further derivatisation and SAR analysis. The modelling studies predicted the BA ring of the designed analogues to interact with the MtUng UBP much like the uracil ring. The synthesised compounds were screened in vitro using radioactivity and a fluorescence-based assay. These studies led to a novel BA-based MtUng inhibitor 18a (IC50 = 300 µM) displaying â¼24-fold potency over the uracil ring.
Asunto(s)
Mycobacterium tuberculosis , Uracil-ADN Glicosidasa , Uracil-ADN Glicosidasa/química , Uracil-ADN Glicosidasa/metabolismo , Uracilo/farmacología , Barbitúricos/farmacología , Reparación del ADNRESUMEN
Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, novel easy-to-prepare benzimidazole-linked (thio)barbiturate derivatives were designed and synthesized as HDAC6 inhibitors. The proposed structures of the title compounds were confirmed based on their spectral data and elemental analyses. The newly synthesized compounds were screened in vitro against HDAC6. All tested compounds showed potent HDAC6 inhibition at the nanomolar level. Several compounds displayed a remarkable HDAC6 inhibitory activity (IC50 = 48.85-75.62 nM), superior to that of the reference drug suberoylanilide hydroxamic acid (SAHA; IC50 = 91.73 nM). The most potent derivatives were further assessed for their in vitro anticancer activity against two human leukemia cell lines. Thiobarbiturate 3e was two times more potent than SAHA against the tested cells. The detailed structure-activity relationship was also described. Furthermore, molecular docking simulation revealed the ability of the title compounds to chelate the catalytic Zn+2 ion located within the binding pocket of HDAC6. In silico evaluation of physicochemical properties indicated that the target compounds are promising candidates in terms of pharmacokinetic aspects.
Asunto(s)
Antineoplásicos , Leucemia , Humanos , Relación Estructura-Actividad , Antineoplásicos/química , Simulación del Acoplamiento Molecular , Inhibidores de Histona Desacetilasas , Línea Celular Tumoral , Ácidos Hidroxámicos/farmacología , Vorinostat/farmacología , Barbitúricos/farmacología , Bencimidazoles/farmacología , Diseño de Fármacos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Histona Desacetilasa 6RESUMEN
An amphipathic barbiturate mimic of the marine eusynstyelamides is reported as a promising class of antimicrobial agents. We hereby report a detailed analysis of the structure-activity relationship for cationic amphipathic N,N'-dialkylated-5,5-disubstituted barbiturates. The influence of various cationic groups, hydrocarbon linkers and lipophilic side chains on the compounds' antimicrobial potency and haemolytic activity was studied. A comprehensive library of 58 compounds was prepared using a concise synthetic strategy. We found cationic amine and guanidyl groups to yield the highest broad-spectrum activity and cationic trimethylated quaternary amine groups to exert narrow-spectrum activity against Gram-positive bacteria. n-Propyl hydrocarbon linkers proved to be the best compromise between potency and haemolytic activity. The combination of two different lipophilic side chains allowed for further fine-tuning of the biological properties. Using these insights, we were able to prepare both, the potent narrow-spectrum barbiturate 8a and the broad-spectrum barbiturates 11lG, 13jA and 13jG, all having low or no haemolytic activity. The guanidine derivative 11lG demonstrated a strong membrane disrupting effect in luciferase-based assays. We believe that these results may be valuable in further development of antimicrobial lead structures.
Asunto(s)
Antiinfecciosos , Bacterias Gramnegativas , Aminas , Antibacterianos/química , Antibacterianos/farmacología , Antiinfecciosos/química , Antiinfecciosos/farmacología , Barbitúricos/farmacología , Cationes/química , Cationes/farmacología , Hemólisis , Humanos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
BACKGROUND: Etomidate, barbiturates, alfaxalone, and propofol are anesthetics that allosterically modulate γ-aminobutyric acid type A (GABAA) receptors via distinct sets of molecular binding sites. Two-state concerted coagonist models account for anesthetic effects and predict supra-additive interactions between drug pairs acting at distinct sites. Some behavioral and molecular studies support these predictions, while other findings suggest potentially complex anesthetic interactions. We therefore evaluated interactions among four anesthetics in both animals and GABAA receptors. METHODS: The authors used video assessment of photomotor responses in zebrafish larvae and isobolography to evaluate hypnotic drug pair interactions. Voltage clamp electrophysiology and allosteric shift analysis evaluated coagonist interactions in α1ß3γ2L receptors activated by γ-aminobutyric acid (GABA) versus anesthetics [log(d, AN):log(d, GABA) ratio]. Anesthetic interactions at concentrations relevant to zebrafish were assessed in receptors activated with low GABA. RESULTS: In zebrafish larvae, etomidate interacted additively with both propofol and the barbiturate R-5-allyl-1-methyl m-trifluoromethyl mephobarbital (R-mTFD-MPAB; mean ± SD α = 1.0 ± 0.07 and 0.96 ± 0.11 respectively, where 1.0 indicates additivity), while the four other drug pairs displayed synergy (mean α range 0.76 to 0.89). Electrophysiologic allosteric shifts revealed that both propofol and R-mTFD-MPAB modulated etomidate-activated receptors much less than GABA-activated receptors [log(d, AN):log(d, GABA) ratios = 0.09 ± 0.021 and 0.38 ± 0.024, respectively], while alfaxalone comparably modulated receptors activated by GABA or etomidate [log(d) ratio = 0.87 ± 0.056]. With low GABA activation, etomidate combined with alfaxalone was supra-additive (n = 6; P = 0.023 by paired t test), but etomidate plus R-mTFD-MPAB or propofol was not. CONCLUSIONS: In both zebrafish and GABAA receptors, anesthetic drug pairs interacted variably, ranging from additivity to synergy. Pairs including etomidate displayed corresponding interactions in animals and receptors. Some of these results challenge simple two-state coagonist models and support alternatives where different anesthetics may stabilize distinct receptor conformations, altering the effects of other drugs.
Asunto(s)
Anestésicos , Etomidato , Propofol , Animales , Etomidato/farmacología , Etomidato/metabolismo , Pez Cebra/metabolismo , Receptores de GABA/metabolismo , Mefobarbital , Receptores de GABA-A , Anestésicos/farmacología , Propofol/farmacología , Barbitúricos/farmacología , Sitios de Unión , Hipnóticos y Sedantes/farmacología , Ácido gamma-Aminobutírico , ElectrofisiologíaRESUMEN
Myocardial ischemia/reperfusion (MI/R) has been a challenge for global public health. Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling could attenuate MI/R injury by maintaining cell redox balance and reducing oxidative damage. Cinnamamide derivatives have been proven to be a class of potential Nrf2 activators and cardioprotective agents. The development of novel cinnamamide derivatives to combat oxidative stress in cardiomyocytes is highly desirable. In this study, twenty-three cinnamamide-barbiturate hybrids were studied. Cell-based assays showed that most of the compounds exhibited excellent protective activity against H2O2-induced oxidative injury in H9c2 cells. Notably, compound 7w, which had the highest activity and low cytotoxicity, was demonstrated to remarkably reduce intracellular ROS accumulation by activating the mRNA expression of Nrf2 and its downstream antioxidant gene HO-1, indicating a novel promising antioxidant and Nrf2 activator. The probable binding mode between protein Keap1 and compound 7w was also studied via molecule docking. Furthermore, we found that the administration of compound 7w could significantly reduce the cardiac infarct size and improve the cardiac function against MI/R injury in rats, as well as decrease cardiac oxidative stress. Taken together, we report, for the first time, that cinnamamide-barbiturate hybrids are a novel class of potential cardioprotective agents. The excellent cardioprotective action of such compounds rely on enhancing the endogenous antioxidative system by upregulating the Nrf2 signaling pathway in vitro and in vivo against MI/R damage. These findings provide a new perspective for designing cinnamamide-barbiturate hybrids as a novel class of Nrf2 activator against cardiovascular diseases.
Asunto(s)
Daño por Reperfusión Miocárdica , Animales , Antioxidantes/farmacología , Barbitúricos/farmacología , Cardiotónicos/metabolismo , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Cinamatos , Peróxido de Hidrógeno/farmacología , Proteína 1 Asociada A ECH Tipo Kelch , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , RatasRESUMEN
The electrochemical thiocyanation of barbituric acids with NH4SCN was disclosed in an undivided cell under constant current conditions. The electrosynthesis is the most efficient at a record high current density (janode ≈50-70 mA cm-2). NH4SCN has a dual role as the source of the SCN group and as the electrolyte. Electrochemical thiocyanation of barbituric acids starts with the generation of (SCN)2 from the thiocyanate anion. The addition of thiocyanogen to the double bond of the enol tautomer of barbituric acid gives thiocyanated barbituric acid. A variety of thiocyanated barbituric acids bearing different functional groups were obtained in 18-95% yields and were shown to exhibit promising antifungal activity.
Asunto(s)
Barbitúricos , Barbitúricos/química , Barbitúricos/farmacologíaRESUMEN
BACKGROUND: Barbituric acid and its derivatives have gained significant attention for several years as an indispensable class of compounds in the pharmaceutical industry due to their various biological activities, such as anticonvulsants, hypnotics, anti-diabetic, antiviral, anti-AIDS, anti-cancer, anti-microbial, and antioxidant, etc. A plethora of studies has shed light on the properties, synthesis, and reactivity of these compounds. The depiction of multiple biological activities by barbiturates compelled us, and by virtue of which herein we have mediated over the progress of synthesis of numerous kinds of compounds derived from barbituric acid with well-known and typical examples from 2016 to the present. OBJECTIVES: This review focuses on the advancements in methods of synthesis of barbituric acid derivatives and their applications as antimicrobial agents. CONCLUSION: This review will help future researchers to analyze the previous studies and explore new compounds for the development of efficient antimicrobial drugs.
Asunto(s)
Antiinfecciosos , Barbitúricos , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Anticonvulsivantes , Antioxidantes , Barbitúricos/farmacologíaRESUMEN
BACKGROUND: Cancer is one of the most important reasons for mortality worldwide. Several synthetic products have shown valuable efficiency as an anticancer medicines. Chromene derivatives have long been used as the promising compounds which are potent in inhibition of the growth of tumors. METHODS AND RESULTS: In this study, we investigate an anticancer activity of barbituric/thiobarbituric acid-based chromene derivates. For this purpose, viability, antioxidant and apoptotic assays were conducted using three different cancer cell lines (A2780, MCF7, and A549). In most cases, the antiproliferative activity of barbituric acid-based derivatives was higher than that of thiobarbituric acid-based compounds. Among 14 compounds, compound 4g was the most potent one, which showed the highest effect on cells by increasing the accumulation of ROS (up to 540% increase), increasing the level of caspase-3 and caspase-9 (~ 35% increase), and decreasing the mitochondrial membrane potential (2.5 folds reduction). To characterize the type of cell death involved into our experiment Annexin V/PI double staining of compound 4g was performed. The results showed that the number of late apoptotic and/or necrotic cells (Ann V + /PI +) increased fourfold upon treatment with IC50 concentration of 4g. CONCLUSIONS: Overall, the anti-proliferative activity of barbituric acid-based derivatives was higher than that of thiobarbituric acid compounds, and compound 4g can be introduced as a potential candidate to prevent various cancers.
Asunto(s)
Barbitúricos/farmacología , Benzopiranos/farmacología , Neoplasias/tratamiento farmacológico , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Barbitúricos/química , Benzopiranos/química , Caspasa 3 , Caspasa 9 , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Humanos , Neoplasias/metabolismo , Especies Reactivas de Oxígeno , Relación Estructura-Actividad , Tiobarbitúricos/química , Tiobarbitúricos/farmacologíaRESUMEN
We report a series of synthetic cationic amphipathic barbiturates inspired by the pharmacophore model of small antimicrobial peptides (AMPs) and the marine antimicrobials eusynstyelamides. These N,N'-dialkylated-5,5-disubstituted barbiturates consist of an achiral barbiturate scaffold with two cationic groups and two lipophilic side chains. Minimum inhibitory concentrations of 2-8 µg/mL were achieved against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum ß-lactamase-carbapenemase production. The guanidine barbiturate 7e (3,5-di-Br) demonstrated promising in vivo antibiotic efficacy in mice infected with clinical isolates of Escherichia coli and Klebsiella pneumoniae using a neutropenic peritonitis model. Mode of action studies showed a strong membrane disrupting effect and was supported by nuclear magnetic resonance and molecular dynamics simulations. The results express how the pharmacophore model of small AMPs and the structure of the marine eusynstyelamides can be used to design highly potent lead peptidomimetics against multi-resistant bacteria.
Asunto(s)
Antibacterianos/farmacología , Barbitúricos/farmacología , Productos Biológicos/farmacología , Guanidinas/farmacología , Indoles/farmacología , Proteínas Citotóxicas Formadoras de Poros/farmacología , Tensoactivos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Barbitúricos/síntesis química , Barbitúricos/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Guanidinas/síntesis química , Guanidinas/química , Indoles/síntesis química , Indoles/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Proteínas Citotóxicas Formadoras de Poros/síntesis química , Proteínas Citotóxicas Formadoras de Poros/química , Relación Estructura-Actividad , Tensoactivos/síntesis química , Tensoactivos/químicaRESUMEN
Interactions between phospholipid membranes and selected drugs affecting the central nervous system (CNS) were investigated. Small, unilamellar liposomes were used as biomimetic cell membrane models. Microelectrophoretic experiments on two-component liposomes were performed using the electrophoretic light scattering technique (ELS). The effect of both positively (perphenazine, PF) and negatively (barbituric acid, BA) charged drugs on zwitterionic L-α-phosphatidylcholine (PC) membranes were analyzed. Experimental membrane surface charge density (δ) data were determined as a function of pH. Quantitative descriptions of the adsorption equilibria formed due to the binding of solution ions to analyzed two-component membranes are presented. Binding constants of the solution ions with perphenazine and barbituric acid-modified membranes were determined. The results of our research show that both charged drugs change surface charge density values of phosphatidylcholine membranes. It can be concluded that perphenazine and barbituric acid are located near the membrane surface, interacting electrostatically with phosphatidylcholine polar heads.
Asunto(s)
Barbitúricos/farmacología , Sistema Nervioso Central/fisiología , Electricidad , Perfenazina/farmacología , Fosfatidilcolinas/metabolismo , Animales , Aniones , Cationes , Sistema Nervioso Central/efectos de los fármacos , Pollos , Punto Isoeléctrico , Liposomas , Membranas Artificiales , Modelos Biológicos , Dispersión de Radiación , Soluciones , Electricidad EstáticaRESUMEN
BACKGROUND: The aim was to study the effects of barbiturate coma treatment (BCT) on intracranial pressure (ICP) and intracranial compensatory reserve (RAP index) in children (< 17 years of age) with traumatic brain injury (TBI) and refractory intracranial hypertension (RICH). METHODS: High-resolution monitoring data were used to study the effects of BCT on ICP, mean arterial pressure (MAP), cerebral perfusion pressure (CPP), and RAP index. Four half hour long periods were studied: before bolus injection and at 5, 10, and 24 hours thereafter, respectively, and a fifth tapering period with S-thiopental between < 100 and < 30 µmol/L. S-thiopental concentrations and administered doses were registered. RESULTS: Seventeen children treated with BCT 2007-2017 with high-resolution data were included; median age 15 (range 6-17) and median Glasgow coma score 7 (range 3-8). Median time from trauma to start of BCT was 44.5 h (range 2.5-197.5) and from start to stop 99.0 h (range 21.0-329.0). Median ICP was 22 (IQR 20-25) in the half hour period before onset of BCT and 16 (IQR 11-20) in the half hour period 5 h later (p = 0.011). The corresponding figures for CPP were 65 (IQR 62-71) and 63 (57-71) (p > 0.05). The RAP index was in the half hour period before onset of BCT 0.6 (IQR 0.1-0.7), in the half hour period 5 h later 0.3 (IQR 0.1-0.7) (p = 0.331), and in the whole BCT period 0.3 (IQR 0.2-0.4) (p = 0.004). Eighty-two percent (14/17) had favorable outcome (good recovery = 8 patients and moderate disability = 6 patients). CONCLUSION: BCT significantly reduced ICP and RAP index with preserved CPP. BCT should be considered in case of RICH.
Asunto(s)
Barbitúricos/farmacología , Lesiones Traumáticas del Encéfalo/terapia , Coma/inducido químicamente , Terapia Convulsiva/métodos , Hipertensión Intracraneal/terapia , Presión Intracraneal/efectos de los fármacos , Adolescente , Anticonvulsivantes/uso terapéutico , Presión Arterial/efectos de los fármacos , Barbitúricos/administración & dosificación , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Circulación Cerebrovascular/efectos de los fármacos , Niño , Femenino , Humanos , Hipertensión Intracraneal/tratamiento farmacológico , Hipertensión Intracraneal/etiología , Masculino , Estudios Retrospectivos , Tiopental/uso terapéuticoRESUMEN
The ability of chemo-radiation therapy to control locally advanced stage III non-small cell lung cancer (NSCLC) is poor. While addition of consolidation immunotherapy has improved outcomes in subsets of patients there is still an urgent need for new therapeutic targets. Emerging research indicates that nucleophosmin1 (NPM1) is over-expressed in NSCLC, promotes tumor growth and that over-expression correlates with a lower survival probability. NPM1 is critical for APE1 base excision activity and for RAD51-mediated repair of DNA double strand breaks (DSBs). YTR107 is a small molecule radiation sensitizer that has been shown to bind to NPM1, suppressing pentamer formation. Here we show that in irradiated cells YTR107 inhibits SUMOylated NPM1 from associating with RAD51, RAD51 foci formation and repair of DSBs. YTR107 acts synergistically with the PARP1/2 inhibitor ABT 888 to increase replication stress and radiation-induced cell lethality. YTR107 was found to radiosensitize tumor initiating cells. Congruent with this knowledge, adding YTR107 to a fractionated irradiation regimen diminished NSCLC xenograft growth and increased overall survival. These data support the hypothesis that YTR107 represents a therapeutic target for control of NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Proteínas Nucleares/genética , Recombinasa Rad51/genética , Barbitúricos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de la radiación , Reparación del ADN/efectos de los fármacos , Reparación del ADN/efectos de la radiación , Humanos , Indoles/farmacología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/radioterapia , Nucleofosmina , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/genética , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Sumoilación/efectos de los fármacos , Sumoilación/efectos de la radiaciónRESUMEN
BACKGROUND: Cancer Stem Cells (CSCs) are a subpopulation within the tumor that play a role in the initiation, progression, recurrence, resistance to drugs and metastasis of cancer. It is well known that epigenetic changes lead to tumor formation in cancer stem cells and show drug resistance. Epigenetic modulators and /or their combination with different agents have been used in cancer therapy. OBJECTIVE: In our study, we scope out the effects of a combination of a histone deacetylases inhibitor, Valproic Acid (VPA), and Cu(II) complex [Cu(barb-κN)(barb-κ2N,O)(phen-κN,N')]·H2O] on cytotoxicity/apoptosis in a stem-cell enriched population (MCF-7s) obtained from parental breast cancer cell line (MCF-7). METHODS: The viability of the cells was measured by the ATP assay. Apoptosis was elucidated via the assessment of caspase-cleaved cytokeratin 18 (M30 ELISA) and a group of flow cytometry analysis (caspase 3/7 activity, phosphatidylserine translocation by annexin V-FITC assay, DNA damage and oxidative stress) and 2',7'- dichlorofluorescein diacetate staining. RESULTS: The VPA combined with Cu(II) complex showed anti-proliferative activity on MCF-7s cells in a doseand time-dependent manner. Treatment with a combination of 2.5 mM VPA and 3.12 µM Cu(II) complex induced oxidative stress in a time-dependent manner, as well as apoptosis evidenced by the increase in caspase 3/7 activity, positive annexin-V-FITC, and increase in M30 levels. CONCLUSION: The results suggest that the combination therapy induces apoptosis following increased oxidative stress, thereby making it a possible promising therapeutic strategy for which further analysis is required.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Barbitúricos/farmacología , Complejos de Coordinación/farmacología , Cobre/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Ácido Valproico/farmacología , Antineoplásicos/química , Barbitúricos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Cobre/química , Daño del ADN , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas/química , Humanos , Células MCF-7 , Células Tumorales Cultivadas , Ácido Valproico/químicaRESUMEN
Development and progression of metastasis comprises synchronized erroneous expressions of several composite pathways, which are difficult to manage simultaneously with the representative anticancer molecules. The emergence of the drug resistance and the complex interplay between these pathways further potentiates cancer related complexities. Barbiturates and their derivatives present a commendable anticancer profile by attenuating the cancer manifesting metabolic and enzymatic pathways including, but not limited to matrix metalloproteinases, xanthine oxidase, amino peptidases, histone deacetylases, and Ras/mitogen-activated protein kinase. The derivatization and conjugation of barbiturates with pharmacophores delivers a suitable hybrid profile in containing the anomalous expression of these pathways. The present report presents a succinct collation of the barbiturates and their derivatives in managing the various cancer causing pathways.
Asunto(s)
Antineoplásicos/farmacología , Barbitúricos/farmacología , Neoplasias/tratamiento farmacológico , Aminopeptidasas/metabolismo , Apoptosis/efectos de los fármacos , Histona Desacetilasas/metabolismo , Humanos , Metaloproteinasas de la Matriz/metabolismo , Neoplasias/enzimología , Xantina Oxidasa/metabolismoRESUMEN
BACKGROUND/AIM: Previously, we reported the identification of a cytotoxic chemotype compound CC-I (1a), a derivative of thiobarbituric acid. We also reported the anticancer activity of a series of novel thio- and seleno-barbituric acid analogs. MATERIALS AND METHODS: We herein evaluated the effect of 1a and its modified compounds on in vitro and in vivo lung cancer models. RESULTS: The compounds 1b and 2a showed more potent cytotoxicity than 1a to lung cancer cells. Moreover, 1b did not have any cytotoxicity on normal cells, such as fibroblasts. In the human lung cancer A549 mouse tumor xenograft model, 1b and 2a showed more pronounced antitumor effects than 1a In the A549 lung cancer cells, 1a induced cell death mainly via JNK and p38 MAPK activation. However, compound 1b and 2a induced lung cancer cell death mostly through JNK activation. CONCLUSION: The results suggest that 1b and 2a can be useful therapeutic agents for lung cancer.
Asunto(s)
Barbitúricos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Tiobarbitúricos/uso terapéutico , Células A549 , Barbitúricos/síntesis química , Barbitúricos/química , Barbitúricos/farmacología , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Fosforilación/efectos de los fármacos , Tiobarbitúricos/química , Tiobarbitúricos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Six series based on barbituric acid 5a-e, 10a-d; thiobarbituric acid 6a-e, 11a-d and 1,3-dimethylbarbituric acid 7a-e, 12a-d were prepared and screened for their in vitro PARP1 inhibition. They revealed promising inhibition at nanomolar level especially compounds 5c, 7b, 7d and 7e (IC50â¯=â¯30.51, 41.60, 41.53 and 36.33â¯nM) with higher potency than olaparib (IC50â¯=â¯43.59â¯nM). Moreover, compounds 5b, 5d, 7a, 12a and 12c exhibited good comparable activity (IC50â¯=â¯65.93, 58.90, 66.57, 45.40 and 50.62â¯nM, respectively). Furthermore, the most active compounds 5c, 7b, 7d, 7e, 12a and 12c against PARP1 in vitro were evaluated in the BRCA1 mutated triple negative breast cancer cell line MDA-MB-436 where 5c and 12c showed higher potency compared to olaparib and result in cell cycle arrest at G2/M phase. 5c and 12c showed apoptotic effects in MDA-MB-436 and potentiated the cytotoxicity of temozolomide in A549 human lung epithelial cancer cell line. Compounds 5c and 12c represent interesting starting points towards PARP1 inhibitors.
Asunto(s)
Antineoplásicos/farmacología , Barbitúricos/farmacología , Diseño de Fármacos , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Barbitúricos/síntesis química , Barbitúricos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Daprodustat (DUVROQ) is a small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (PHD) developed by GlaxoSmithKline for the treatment of anaemia in patients with chronic kidney disease (CKD). Inhibition of PHD prevents degradation of hypoxia-inducible factor (HIF), leading to the production of erythropoietin and subsequent induction of erythropoiesis. In June, daprodustat received its first approval in Japan for the treatment of renal anaemia. Clinical studies of daprodustat are underway in multiple countries worldwide. This article summarizes the milestones in the development of daprodustat leading to this first approval for the treatment of renal anaemia.
Asunto(s)
Anemia/tratamiento farmacológico , Barbitúricos/farmacología , Aprobación de Drogas , Glicina/análogos & derivados , Prolil Hidroxilasas/metabolismo , Inhibidores de Prolil-Hidroxilasa/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Anemia/metabolismo , Animales , Barbitúricos/química , Glicina/química , Glicina/farmacología , Humanos , Japón , Estructura Molecular , Inhibidores de Prolil-Hidroxilasa/química , Insuficiencia Renal Crónica/metabolismoRESUMEN
Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABAA) receptors to dampen neuronal activity in the brain1-5. However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABAA receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABAA receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABAA receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.
Asunto(s)
Anestésicos Generales/química , Anestésicos Generales/farmacología , Barbitúricos/química , Barbitúricos/farmacología , Benzodiazepinas/química , Benzodiazepinas/farmacología , Microscopía por Crioelectrón , Receptores de GABA-A/química , Regulación Alostérica/efectos de los fármacos , Anestésicos Generales/metabolismo , Barbitúricos/metabolismo , Benzodiazepinas/metabolismo , Bicuculina/química , Bicuculina/metabolismo , Bicuculina/farmacología , Sitios de Unión , Unión Competitiva/efectos de los fármacos , Diazepam/química , Diazepam/metabolismo , Diazepam/farmacología , Electrofisiología , Etomidato/química , Etomidato/metabolismo , Etomidato/farmacología , Flumazenil/farmacología , Antagonistas de Receptores de GABA-A/química , Antagonistas de Receptores de GABA-A/metabolismo , Antagonistas de Receptores de GABA-A/farmacología , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Simulación de Dinámica Molecular , Fenobarbital/química , Fenobarbital/metabolismo , Fenobarbital/farmacología , Picrotoxina/química , Picrotoxina/metabolismo , Picrotoxina/farmacología , Propofol/química , Propofol/metabolismo , Propofol/farmacología , Receptores de GABA-A/metabolismo , Receptores de GABA-A/ultraestructura , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Two novel multi-hydroxyl N-halamine precursors were successfully synthesized in a green and facile way via Knoevenagel condensation reaction between barbituric acid and an aldehyde (citral or cinnamaldehyde), followed by a hydroxylation reaction with hydrogen peroxide. 1H-NMR and FT-IR spectral analyses confirmed their formation. Through the melt-blending process, the multi-hydroxyl derivatives of barbituric acid were introduced via transesterification into poly(ethylene terephthalate) (PET) at 265 °C in a rheometer. The crystallization behaviors of the modified PET samples were investigated using X-ray diffraction (XRD), differential scanning calorimetry (DSC), and polarized optical microscopy (POM) analyses. The results showed that the crystallization temperature and crystallization rate of PET were significantly improved upon the introduction of the precursor. Meanwhile, the relative crystallinity of the modified PET samples increased with an increase in the dosage of the N-halamine precursor. After the treatment with sodium hypochlorite solution, the PET surfaces modified with N-halamine derivatives would impart powerful antibacterial properties and achieve 100% killing of Staphylococcus aureus (ATCC 6538) and Escherichia coli (CMCC44103) cells within 30 min. Therefore, the multi-hydroxyl N-halamine precursors exhibit great potential as bifunctional additives (nucleating and antibacterial agents) in the manufacturing of functional PET materials.