RESUMEN
Isobavachalcone (IBC) is a flavonoid component of the traditional Chinese medicine Psoraleae Fructus, with a range of pharmacological properties. However, IBC causes some hepatotoxicity, and the mechanism of toxicity is unclear. The purpose of this paper was to investigate the possible mechanism of toxicity of IBC on HepG2 cells and zebrafish embryos. The results showed that exposure to IBC increased zebrafish embryo mortality and decreased hatchability. Meanwhile, IBC induced liver injury and increased expression of ALT and AST activity. Further studies showed that IBC caused the increase of ROS and MDA the decrease of CAT, GSH, and GSH-Px; the increase of Fe2+ content; and the changes of ferroptosis related genes (acsl4, gpx4, and xct) and iron storage related genes (tf, fth, and fpn) in zebrafish embryos. Through in vitro verification, it was found that IBC also caused oxidative stress and increased Fe2+ content in HepG2 cells. IBC caused depolarization of mitochondrial membrane potential (MMP) and reduction of mitochondrial ATP, as well as altered expression of ACSl4, SLC7A11, GPX4, and FTH1 proteins. Treatment of HepG2 cells with ferrostatin-1 could reverse the effect of IBC. Targeting the System Xc--GSH-GPX4 pathway of ferroptosis and preventing oxidative stress damage might offer a theoretical foundation for practical therapy and prevention of IBC-induced hepatotoxicity.
Asunto(s)
Chalconas , Ferroptosis , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Transducción de Señal , Pez Cebra , Pez Cebra/embriología , Animales , Humanos , Chalconas/toxicidad , Chalconas/farmacología , Ferroptosis/efectos de los fármacos , Células Hep G2 , Transducción de Señal/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Embrión no Mamífero/efectos de los fármacos , Glutatión/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Estrés Oxidativo/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
Isobavachalcone (IBC) is a flavonoid component derived from Psoraleae Fructus that can increase skin pigmentation and treat vitiligo. However, IBC has been reported to be hepatotoxic. Current studies on IBC hepatotoxicity are mostly on normal organisms but lack studies on hepatotoxicity in patients. This study established the depigmented zebrafish model by using phenylthiourea (PTU) and investigated the difference in hepatotoxicity between normal and depigmented zebrafish caused by IBC and the underlying mechanism. Morphological, histological, and ultrastructural examination and RT-qPCR verification were used to evaluate the effects of IBC on the livers of zebrafish larvae. IBC significantly decreased liver volume, altered lipid metabolism, and induced pathological and ultrastructural changes in the livers of zebrafish with depigmentation compared with normal zebrafish. The RNA-sequencing and RT-qPCR results showed that the difference in hepatotoxicity between normal and depigmented zebrafish caused by IBC was closely related to the calcium signaling pathway, lipid decomposition and metabolism, and oxidative stress. This work delved into the mechanism of the enhanced IBC-induced hepatotoxicity in depigmented zebrafish and provided a new insight into the hepatotoxicity of IBC.
Asunto(s)
Señalización del Calcio , Chalconas , Enfermedad Hepática Inducida por Sustancias y Drogas , Pez Cebra , Animales , Chalconas/toxicidad , Señalización del Calcio/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Trastornos del Metabolismo de los Lípidos/inducido químicamente , Trastornos del Metabolismo de los Lípidos/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Metabolismo de los Lípidos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
Chalcone is an important scaffold within medicinal and cosmetic chemistry. The structure enables multiple modifications which may result in obtaining compounds with desirable bioactivity. One of the chalcone derivatives, 4-methoxychalcone is a known cosmetic ingredient indexed in Cosing database as an antioxidant, bleaching, and skin conditioning substance. We investigated its in silico and in vitro safety profile. In silico study using Derek Nexus showed its potential of skin sensitisation, equivocal nature of chromosome damage in vitro in mammals, but also no mutagenic properties. In vitro research proved its activity as melanogenesis inhibitor in B16F10 cell line at the doses 12.5-3.125 µM. Evaluations performed in various cell lines showed that the cytotoxic doses were 50-25 µM. Tests in Episkin™ proved its ability to penetrate across epidermis and enabled classification of 2% formulation in PEG as non-irritant. In micronucleus tests it showed no genotoxicity. Studies in Cunninghamella echinulata model proved that 4-methoxychalcone was metabolised to less lipophilic products. 4-methoxychalcone showed phototoxic potential, its EC50(+UV) = 3.57 µg/mL, PIF = 10.19 and MPE = 0.428 were comparable to chlorpromazine. Moreover, 4-methoxychalcone showed ecotoxic potential in Microtox® assay with EC50(5 min) = 0.0047 mg/L and EC50(15 min) = 0.0033 mg/L. Although active doses were lower than toxic ones, some potential safety risks were noticed. Especially, due to the phototoxicity potential of 4-methoxychalcone, its use as depigmenting agent should involve avoidance of sunlight and use of appropriate photoprotection.
Asunto(s)
Chalconas , Cosméticos , Dermatitis Fototóxica , Animales , Chalconas/toxicidad , Antioxidantes , Cosméticos/toxicidad , MamíferosRESUMEN
Isoliquiritigenin, a flavonoid compound, exhibits a variety of pharmacological properties, including anti-inflammatory, anti-oxidative, anti-microbial, anti-viral, and anti-tumor effects. In the past few years, the consumption of isoliquiritigenin-containing dietary supplements has increased due to their health benefits. Although the neuroprotective effects of isoliquiritigenin have been well-investigated, these studies were performed in cells and adult animals. The potential effects of isoliquiritigenin on the development, especially the neurodevelopment, of certain populations, such as zebrafish larvae, have not been investigated. In this study, zebrafish larvae were employed as a model to investigate the effects of isoliquiritigenin on development and neurodevelopment. Zebrafish embryos treated with high concentrations of isoliquiritigenin (10 and 15 µM) exhibited high rates of mortality, hatching, and malformation, indicating that isoliquiritigenin can affect zebrafish development. In addition, isoliquiritigenin impeded the development of central nervous system regions and the length of dopaminergic neurons located in midbrains and thalami of transgenic zebrafish larvae. The locomotor ability of zebrafish larvae exposed to high concentrations of isoliquiritigenin was negatively affected. The total distance and the average velocity significantly decreased, and anxiety-related behaviors were observed under light-dark challenge. Furthermore, the levels of gap43, tuba1b, mbp, hcrt, vmat2, and pomc, which mediate neurodevelopment, neurotoxicity, and anxiety were significantly decreased in zebrafish larvae exposed to isoliquiritigenin. These results indicate that isoliquiritigenin can disrupt the development of dopaminergic neurons and the function of the central nervous system in zebrafish, causing anxiety-like symptoms.
Asunto(s)
Chalconas , Pez Cebra , Animales , Larva , Chalconas/toxicidad , Ansiedad/inducido químicamente , Embrión no MamíferoRESUMEN
Isoliquiritigenin (ISL) is used in many households' personal hygiene and medicinal products, and the average human daily ISL exposure is 1-2 mg/kg. However, the molecular mechanisms of ISL toxicity in zebrafish embryos have not been fully elucidated. We investigated whether exposure to ISL induces oxidative stress and inflammatory responses in zebrafish. And exposure to ISL significantly affects the expression of immune response-related genes in zebrafish embryos following oxidative stress and the release of pro-inflammatory mediators through Toll-like receptor signaling.
Asunto(s)
Chalconas , Pez Cebra , Animales , Humanos , Pez Cebra/metabolismo , Estrés Oxidativo , Chalconas/toxicidad , InmunidadRESUMEN
Chalcones and sulfonamides are well-known chemical groups associated with several biological activities such as antibiotic, anti-inflammatory, and antitumor activities. Over the past few decades, a series of sulfonamide-chalcone hybrids have been synthesized and assessed to develop compounds with interesting biological properties for application in disease therapy. In the present study, a new sulfonamide-chalcone hybrid µ - (2,5-dichloro-N-{4-[(3E)-4-(3-nitrophenyl) buta-1,3-dien-2-yl] phenyl} benzene sulfonamide), or simply CL185, was synthesized, and its angiogenic activity was assessed using the chick embryo chorioallantoic membrane (CAM) assay at different concentrations (12.5, 25, and 50 µg/µL). To further investigate the role of CL185 in the angiogenic process, we evaluated the levels of vascular endothelial growth factor (VEGF) in all treated CAMs. The results showed that all concentrations of CL185 significantly increased tissue vascularization (p < 0.05) as well as the parameters associated with angiogenesis, in which inflammation was the most marked phenomenon observed. In all CAMs treated with CL185, VEGF levels were significantly higher than those in the negative control (p < 0.05), and at the highest concentration, VEGF levels were even higher than in the positive control (p < 0.05). The pronounced angiogenic activity displayed by CL185 may be related to the increase in VEGF levels that were stimulated by inflammatory processes observed in our study. Therefore, CL185 presents a favorable profile for the development of drugs that can be used in pro-angiogenic and tissue repair therapies.
Asunto(s)
Inductores de la Angiogénesis/farmacología , Chalconas/farmacología , Membrana Corioalantoides/irrigación sanguínea , Inflamación/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inductores de la Angiogénesis/toxicidad , Animales , Chalconas/toxicidad , Embrión de Pollo , Inflamación/inducido químicamente , Regulación hacia ArribaRESUMEN
OBJECTIVE: To evaluate the toxicity of three synthetic chalcones administered intraperitoneally to BALB/c mice. MATERIALS AND METHODS: The median lethal dose (LD50) was estimated by Dixon's Up-and-Down method. Subchronic toxicity of chalcones was evaluated at 20 and 40 mg/kg for 21 days. Behavioral, physiological, biochemical, and histological toxic effects were evaluated. RESULTS: Chalcone 43 produced mucus in feces, visceral damage (liver) and alterations in organ coefficient (kidney, p = 0.037 and brain, p = 0.008) when compared to the control group. In addition, histological analysis showed that this chalcone produced edema, inflammation and necrosis in the evaluated organs, although there was no significant difference with the control. None of the biochemical parameters differed significantly between the treatment groups at 40 mg/kg dose and the control. CONCLUSIONS: The LD50 for all three chalcones was greater than 550 mg/kg of body weight. Chalcones 40 and 42 were found to be relatively non-toxic. Both can be considered safe for intraperitoneal application in BALB/c mice and, consequently, are potential candidates for use in the treatment of leishmaniasis.
OBJETIVO: Evaluar la toxicidad de tres chalconas sintéticas administradas por vía intraperitoneal en ratones BALB/c. MATERIALES Y MÉTODOS: La dosis letal media (DL50) se estimó por el método Up-and-Down de Dixon. La toxicidad subcrónica de las chalconas se evaluó a 20 y 40 mg/kg por 21 días. Se evaluó el efecto tóxico a nivel de comportamiento, fisiológico, bioquímico e histológico. RESULTADOS: La chalcona 43 generó moco en las heces, daño visceral (hígado) y alteración en el coeficiente de órganos (riñón, p = 0,037 y cerebro, p = 0,008) en comparación con el grupo control. Además, en el análisis histológico se observó que esta chalcona produjo edema, inflamación y necrosis en los órganos evaluados, aunque no hubo diferencia significativa con el control. Todos los parámetros bioquímicos no difirieron significativamente entre los grupos de tratamiento a dosis de 40 mg/kg y el control. CONCLUSIONES: La DL50 para las tres chalconas fue superior a 550 mg/kg de peso corporal. Las chalconas 40 y 42 son relativamente no tóxicas. Ambas pueden considerarse seguras para la aplicación vía intraperitoneal en ratones BALB/c y, en consecuencia, son posibles candidatas para ser usadas en el tratamiento contra las leishmaniosis.
Asunto(s)
Antiprotozoarios , Chalcona , Chalconas , Leishmaniasis , Animales , Antiprotozoarios/uso terapéutico , Chalconas/toxicidad , Ratones , Ratones Endogámicos BALB CRESUMEN
Microbial conjugation studies of licochalcones (1-4) and xanthohumol (5) were performed by using the fungi Mucor hiemalis and Absidia coerulea. As a result, one new glucosylated metabolite was produced by M. hiemalis whereas four new and three known sulfated metabolites were obtained by transformation with A. coerulea. Chemical structures of all the metabolites were elucidated on the basis of 1D-, 2D-NMR and mass spectroscopic data analyses. These results could contribute to a better understanding of the metabolic fates of licochalcones and xanthohumol in mammalian systems. Although licochalcone A 4'-sulfate (7) showed less cytotoxic activity against human cancer cell lines compared to its substrate licochalcone A, its activity was fairly retained with the IC50 values in the range of 27.35-43.07 µM.
Asunto(s)
Absidia/metabolismo , Chalconas/química , Flavonoides/química , Mucor/metabolismo , Propiofenonas/química , Células A549 , Absidia/química , Antineoplásicos/química , Antineoplásicos/toxicidad , Proliferación Celular/efectos de los fármacos , Chalconas/metabolismo , Chalconas/toxicidad , Flavonoides/metabolismo , Flavonoides/toxicidad , Humanos , Células MCF-7 , Metaboloma , Mucor/química , Propiofenonas/metabolismo , Propiofenonas/toxicidadRESUMEN
Hydroxylated chalcones are phytochemicals which are biosynthetic precursors of flavonoids and their 1,3-diaryl-prop-2-en-1-one structure is used as a scaffold for drug development. In this study, the structure-dependent activation of aryl hydrocarbon receptor (AhR)-responsive CYP1A1, CYP1B1, and UGT1A1 genes was investigated in Caco2 colon cancer cells and in non-transformed young adult mouse colonocytes (YAMC) cells. The effects of a series of di- and trihydroxychalcones as AhR agonists was structure dependent with maximal induction of CYP1A1, CYP1B1, and UGT1A1 in Caco2 cells observed for compounds containing 2,2'-dihydroxy substituents and this included 2,2'-dihydroxy-, 2,2',4'-trihydroxy-, and 2,2',5'-trihydroxychalcones. In contrast, 2',4,5'-, 2'3',4'-, 2',4,4'-trihydroxy, and 2',3-, 2',4-, 2',4'-, and 2',5-dihydroxychalcones exhibited low to non-detectable AhR activity in Caco2 cells. In addition, all of the hydroxychalcones exhibited minimal to non-detectable activity in YAMC cells, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced CYP1A1, CYP1B1, and UGT1A1 in Caco2 and YAMC cells. The activity of AhR-active chalcones was confirmed by determining their effects in AhR-deficient Caco2 cells. In addition, 2,2'-dihydroxychalcone induced CYP1A1 protein and formation of an AhR-DNA complex in an in vitro assay. Simulation and modeling studies of hydroxylated chalcones confirmed their interactions with the AhR ligand-binding domain and were consistent with their structure-dependent activity as AhR ligands. Thus, this study identifies hydroxylated chalcones as AhR agonists with potential for these phytochemicals to impact AhR-mediated colonic pathways.
Asunto(s)
Chalconas , Dibenzodioxinas Policloradas , Animales , Células CACO-2 , Chalconas/toxicidad , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Humanos , Ratones , Unión Proteica , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismoRESUMEN
Being crucial part of plant-based novel discovery of drug from natural resources, a study was done to explore the antibacterial potential of curcumin mimics in combination with antibiotics against multidrug resistant isolates of Pseudomonas aeruginosa. The best candidate Van D, a curcumin mimics reduced the MIC of tetracycline (TET) up to 16 folds against multidrug resistant clinical isolates. VanD further inhibited the efflux pumps as evident by ethidium bromide efflux and by in-silico docking studies. In another experiment, it was also found that Van D inhibits biofilm synthesis. This derivative kills the KG-P2, an isolate of P. aeruginosa in a time dependent manner, the post-antibiotic effect (PAE) of tetracycline was extended as well as mutant prevention concentration (MPC) of TET was also decreased. In Swiss albino mice, Van D reduced the proinflammatory cytokines concentration. In acute oral toxicity study, this derivative was well tolerated and found to be safe up to 1000 mg/kg dose. To the best of our knowledge, this is the first report on curcumin mimics as synergistic agent via inhibition of efflux pump.
Asunto(s)
Antibacterianos/uso terapéutico , Chalconas/uso terapéutico , Farmacorresistencia Bacteriana/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Antibacterianos/metabolismo , Antibacterianos/toxicidad , Proteínas de la Membrana Bacteriana Externa/metabolismo , Biopelículas/efectos de los fármacos , Chalconas/síntesis química , Chalconas/metabolismo , Chalconas/toxicidad , Curcumina/química , Curcumina/farmacología , Diseño de Fármacos , Sinergismo Farmacológico , Femenino , Masculino , Proteínas de Transporte de Membrana/metabolismo , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Unión Proteica , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/fisiología , Tetraciclina/farmacologíaRESUMEN
Chalcones are a group of natural products with many recognized biological activities, including antiparasitic activity. Although a lot of chalcones have been synthetized and assayed against parasites, the number of structural features known to be involved in this biological property is small. Thus, in the present study, 21 chalcones were synthesized to determine the effect of substituents in the A and B rings on the activity against Leishmania braziliensis, Trypanosoma cruzi, and Plasmodium falciparum. The compounds were active against L. braziliensis in a structure-dependent manner. Only one compound was very active against T. cruzi, but none of them had a significant antiplasmodial activity. The electron-donating substituents in ring B and the hydrogen bonds at C-2' with carbonyl affect the antiparasitic activity.
Asunto(s)
Chalconas/farmacología , Leishmania braziliensis/efectos de los fármacos , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Antimaláricos/síntesis química , Antimaláricos/farmacología , Supervivencia Celular/efectos de los fármacos , Chalconas/síntesis química , Chalconas/toxicidad , Diseño de Fármacos , Humanos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/efectos de los fármacos , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/toxicidad , Células U937RESUMEN
Isoliquiritigenin (ISL) is an emerging natural flavonoid found in the roots of licorice, exhibits antioxidant, anti-cancer, anti-inflammatory, anti-allergic, cardioprotective, hepatoprotective and neuroprotective properties. However, the effect of ISL in embryonic development is yet to be elucidated, and the mechanisms underlying its target-organ toxicity and harmful side effects are still unclear. In the present study, we employed zebrafish embryos to study the developmental toxicity effect of ISL and its underlying mechanisms. Zebrafish embryos upon treatment with either vehicle control (0.1% DMSO) or ISL solutions for 4-96 h post fertilization (hpf) showed that ISL exposure instigated severe developmental toxicity in heart, liver, and nervous system. Mortality and morphological abnormalities were also observed. High concentrations of ISL exposure resulted in abnormal phenotypes and embryonic malformations including pericardial edema, swim bladder defects, yolk retention, curved body shape and shortening of body length. Moreover, ISL exposure led to significant loss of dopaminergic neurons accompanied by reduced locomotor behaviour. Apoptotic cells were predominantly located in the heart area of 96 hpf embryo. Additionally, ISL significantly increased the levels of reactive oxygen species, lipid peroxidation content and decreased antioxidant enzyme activities. The expressions pattern of apoptosis-related genes Bad, Cyto c, Caspase-9, Caspase-3 and Bax/Bcl-2 indicated that the oxidative stress-induced apoptosis triggered by ISL suggest involvement of Nrf2-HO1/JNK-ERK/mitochondrion pathways. In conclusion, here we provide first evidence that demonstrate ISL-induced dose-dependent developmental toxicity in zebrafish embryos. Furthermore, gene expression patterns in the embryos correlate the above and reveal potential genetic mechanisms of developmental toxicity.
Asunto(s)
Chalconas/toxicidad , Inhibidores Enzimáticos/toxicidad , Animales , Apoptosis/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacos , Larva/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mitocondrias/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Pez Cebra/embriología , Pez Cebra/metabolismoRESUMEN
The incubation system of CYP2E1 and CYP3A4 enzymes in rat liver microsomes was established to investigate the effects of psoralidin, isobavachalcone, neobavaisoflavone and daidzein from Fructus Psoraleae in vitro. The relevant metabolites were measured by the method of high performance liquid chromatography (HPLC), after probe substrates of 4-nitrophenol, testosterone and the drugs at different concentrations were added to the incubation systems. In addition, real-time RT-PCR was performed to determine the effect of psoralidin, neobavaisoflavone and daidzein on the mRNA expression of CYP3A4 in rat liver. The results suggested that psoralidin, isobavachalcone and neobavaisoflavone were Medium-intensity inhibitors of CYP2E1 with Ki values of 2.58, 1.28 and 19.07 µM, respectively, which could inhibit the increase of CYP2E1 and reduce diseases caused by lipid peroxidation. Isobavachalcone (Ki = 37.52 µM) showed a weak competitive inhibition on CYP3A4. Psoralidin and neobavaisoflavone showed obvious induction effects on CYP3A4 in the expression level of mRNA, which could accelerate the effects of drug metabolism and lead to the risk of inducing DDIs and serious adverse reactions. The results could be used for guideline of Fructus Psoraleae in clinic, which aimed to calculate the drug toxicity by studying the drug-drug interactions caused by the induction and inhibition of CYP450.
Asunto(s)
Benzofuranos/toxicidad , Chalconas/toxicidad , Cumarinas/toxicidad , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Isoflavonas/toxicidad , Microsomas Hepáticos/metabolismo , Animales , Benzofuranos/metabolismo , Chalconas/metabolismo , Cumarinas/metabolismo , Inhibidores del Citocromo P-450 CYP2E1/metabolismo , Inhibidores del Citocromo P-450 CYP2E1/toxicidad , Inhibidores del Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Interacciones Farmacológicas , Isoflavonas/metabolismo , Ratas Sprague-DawleyRESUMEN
New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10⯵M against sixty different human cancer cell lines (one-dose trial). Chalcones 8b and 9b satisfied the pre-determined threshold inhibition criteria and were selected for screening at five different concentrations (100, 10, 1.0, 0.1, and 0.01⯵M). Compound 8b exhibited remarkable GI50 values ranging from 0.57 to 12.4⯵M, with cytotoxic effects being observed in almost all cases, especially against the cell lines K-562 of Leukemia and LOX IMVI of Melanoma with GI50â¯=â¯0.57 and 1.28⯵M, respectively. Moreover, all compounds were screened against Mycobacterium tuberculosis H37Rv, chalcones 8a-c and 9a-c were the most active showing MIC values between 14 and 42⯵M, and interestingly they were devoid of antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus. These antituberculosis hits showed however low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells. The chalcone-sulfonamide hybrids 8a-f and 9a-f resulted to be appealing cytotoxic agents with significant antituberculosis activity.
Asunto(s)
Antineoplásicos/farmacología , Antituberculosos/farmacología , Chalconas/farmacología , Sulfonamidas/farmacología , Células 3T3 , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Antituberculosos/síntesis química , Antituberculosos/química , Antituberculosos/toxicidad , Línea Celular Tumoral , Chalconas/síntesis química , Chalconas/química , Chalconas/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/toxicidadRESUMEN
Angiogenesis plays an essential role in tumourigenesis and tumour progression, and anti-angiogenesis therapies have shown promising antitumour effects in solid tumours. 2-Methoxyestradiol (2ME2), an endogenous metabolite of estradiol, has been regarded as a potential antitumour agent mainly targeting angiogenesis. Here we synthesized a novel series of chalcones based on 2-methoxyestradiol and evaluated their potential activities against tumours. Compound 11e was demonstrated to have potent antiangiogenic activity. Further studies showed that 11e suppressed tumour growth in human breast cancer (MCF-7) xenograft models without obvious side effects. Evaluation of the mechanism revealed that 11e targeted the epithelial to mesenchymal transition (EMT) process in MCF-7â¯cells and inhibited HUVEC migration and then contributed to hindrance of angiogenesis. Thus, 11e may be a promising antitumour agent with excellent efficacy and low toxicity.
Asunto(s)
2-Metoxiestradiol/análogos & derivados , 2-Metoxiestradiol/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Chalconas/uso terapéutico , Transición Epitelial-Mesenquimal/efectos de los fármacos , 2-Metoxiestradiol/síntesis química , 2-Metoxiestradiol/toxicidad , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/toxicidad , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Chalconas/síntesis química , Chalconas/química , Chalconas/toxicidad , Pollos , Membrana Corioalantoides/efectos de los fármacos , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones Desnudos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Estereoisomerismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The present study investigated the antimicrobial, anti-adhesion and anti-biofilm activity of the modified synthetic molecules nitrochalcone (NC-E05) and pentyl caffeate (C5) against microorganisms which have a high incidence in hospital-acquired infections. The compounds were further tested for their preliminary systemic toxicity in vivo. NC-E05 and C5 showed antimicrobial activity, with minimum inhibitory concentrations (MICs) ranging between 15.62 and 31.25 µg ml-1. Treatment with NC-E05 and C5 at 1 × MIC and/or 10 × MIC significantly reduced mono or mixed-species biofilm formation and viability. At MIC/2, the compounds decreased microbial adhesion to HaCaT keratinocytes from 1 to 3 h (p < 0.0001). In addition, NC-E05 and C5 demonstrated low toxicity in vivo in the Galleria mellonella model at anti-biofilm concentrations. Thus, the chemical modification of these molecules proved to be effective in the proposed anti-biofilm activity, opening opportunities for the development of new antimicrobials.
Asunto(s)
Antiinfecciosos/farmacología , Adhesión Bacteriana/efectos de los fármacos , Biopelículas/efectos de los fármacos , Ácidos Cafeicos/farmacología , Chalconas/farmacología , Animales , Antibacterianos/farmacología , Antibacterianos/toxicidad , Antiinfecciosos/toxicidad , Antifúngicos/farmacología , Antifúngicos/toxicidad , Biopelículas/crecimiento & desarrollo , Ácidos Cafeicos/toxicidad , Candida albicans/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Chalconas/toxicidad , Infección Hospitalaria/prevención & control , Humanos , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Mariposas Nocturnas/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacosRESUMEN
Eleven 4'-alkoxy chalcones were synthesized and biologically evaluated for their antiproliferative activity against four human tumor cell lines (PC-3, MCF-7, HF-6, and CaSki). Compounds 3a-3d and 3f were selective against PC-3, with IC50 values ranging from 8.08 to 13.75⯵M. In addition, chalcones 3a-3c did not affect the normal fibroblasts BJ cells. The most active and selective compounds were further evaluated for their effect on the progression of cell cycle in PC-3 cells, and chalcones 3a and 3c induced a G2/M phase arrest. Furthermore, it was found that these three chalcones induced the mitochondrial apoptotic pathway by regulating Bax and Bcl-2 transcripts and by increasing caspase 3/7 activation. Otherwise, the QSAR model indicates that the double bond of the α,ß-unsaturated carbonyl, as well as the planar structure geometry, are important to the biological activity of the synthetized chalcones. Based on these studies, it was concluded that withdrawing substituents in ring A, decrease the antiproliferative activity. This is related to the possible mechanism of action of these compounds, where a Michael addition needs to take place in order to be a potent anticancer agent.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Chalconas/farmacología , Mitocondrias/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Chalconas/síntesis química , Chalconas/química , Chalconas/toxicidad , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Mitocondrias/metabolismo , Estructura Molecular , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Relación Estructura-Actividad Cuantitativa , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Staphylococcus aureus is the leading cause of bacteraemia and the dwindling supply of effective antibacterials has exacerbated the problem of managing infections caused by this bacterium. Isoliquiritigenin (ISL) is a plant flavonoid that displays therapeutic potential against S. aureus. The present study identified a novel mannich base derivatives of ISL, IMRG4, active against Vancomycin intermediate S. aureus (VISA). IMRG4 damages the bacterial membranes causing membrane depolarization and permeabilization, as determined by loss of salt tolerance, flow cytometric analysis, propidium idodie and fluorescent microscopy. It reduces the intracellular invasion of HEK-293 cells by S. aureus and decreases the staphylococcal load in different organs of infected mice models. In addition to anti-staphylococcal activity, IMRG4 inhibits the multidrug efflux pump, NorA, which was determined by molecular docking and EtBr efflux assays. In combination, IMRG4 significantly reduces the MIC of norfloxacin for clinical strains of S. aureus including VISA. Development of resistance against IMRG4 alone and in combination with norfloxacin was low and IMRG4 prolongs the post-antibiotic effect of norfloxacin. These virtues combined with the low toxicity of IMRG4, assessed by MTT assay and haemolysis, makes it an ideal candidate to enter drug development pipeline against S. aureus.
Asunto(s)
Antibacterianos/farmacología , Chalconas/farmacología , Fluoroquinolonas/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Antibacterianos/toxicidad , Proteínas Bacterianas/antagonistas & inhibidores , Adhesión Celular/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Chalconas/síntesis química , Chalconas/toxicidad , Farmacorresistencia Bacteriana/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Fluoroquinolonas/síntesis química , Fluoroquinolonas/toxicidad , Células HEK293 , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Norfloxacino/farmacologíaRESUMEN
The emergence of antimicrobial resistance and rapid acclimation allows Vibrio vulnificus to rapidly propagate in the host. This problematic pathological scenario can be circumvented by employing an antivirulence strategy, treating Vibrio infections without hindering the bacterial growth. We developed a genome-integrated orthogonal inhibitor screening platform in E. coli to identify antivirulence agents targeting a master virulence regulator of V. vulnificus. We identified 2',4'-dihydroxychalcone (DHC) from the natural compound library and verified that it decreases the expression of the major toxin network which is equivalent to the ∆hlyU deletion mutant. 2',4'-DHC also reduced the hemolytic activity of V. vulnificus which was tested as an example of virulence phenotype. The electrophoretic mobility shift assay confirmed that 2',4'-DHC specifically targeted HlyU and inhibited its binding to PrtxA1 promoter. Under in vivo conditions, a single dose of 2',4'-DHC protected ~50% wax-worm larvae from V. vulnificus infection at a non-toxic concentration to both V. vulnificus and wax-worm larvae. In the current study, we demonstrated that an orthogonal reporter system is suitable for the identification of antivirulence compounds with accuracy, and identified 2',4'-DHC as a potent antivirulence agent that specifically targets the HlyU virulence transcriptional regulator and significantly reduces the virulence and infection potential of V. vulnificus.
Asunto(s)
Antivirales/farmacología , Proteínas Bacterianas/metabolismo , Chalconas/farmacología , Factores de Transcripción/metabolismo , Vibrio vulnificus/efectos de los fármacos , Animales , Antivirales/química , Antivirales/toxicidad , Proteínas Bacterianas/genética , Productos Biológicos/química , Supervivencia Celular , Chalconas/química , Chalconas/toxicidad , Escherichia coli , Regulación Bacteriana de la Expresión Génica , Células HEK293 , Humanos , Larva , Mariposas Nocturnas/efectos de los fármacos , Mariposas Nocturnas/microbiología , Regiones Promotoras Genéticas , Bibliotecas de Moléculas Pequeñas/química , Factores de Transcripción/genética , Vibrio vulnificus/fisiología , Virulencia/efectos de los fármacos , Factores de Virulencia/genética , Factores de Virulencia/metabolismo , Activación ViralRESUMEN
Toxoplasma gondii, an obligate intracellular protozoan, is the causative agent of toxoplasmosis, which can cause serious public health problems. The current drugs used to treat toxoplasmosis have many limitations. This study evaluated the anti-T. gondii activity and potential mechanism of Licochalcone A (Lico A) in vitro and in vivo. The safe concentration of Lico A in HFF cells was determined by MTT cell viability assays. The presence of T. gondii was assessed by qPCR and Giemsa staining. Azithromycin and sulfadiazine, commonly used effective treatments, served as drug controls. T. gondii ultrastructural alterations were observed by electron microscopy. The anti-T. gondii activity of Lico A was evaluated using an in vivo mouse infection model. In vitro, Lico A had no negative effect on host cell viability at concentrations below 9⯵g/mL; however, it did inhibit T. gondii proliferation in a dose-dependent manner, with a 50% inhibitory concentration (IC50) of 0.848⯵g/mL. Electron microscopy analyses indicated substantial structural and ultrastructural changes in tachyzoites after Lico A treatment. Nile Red staining assays demonstrated that Lico A caused lipid accumulation. Lico A treatment significantly increased the survival rate of BALB/c mice infected with T. gondii. Lico A achieved the same therapeutic effect as a commonly used clinical drugs (combination of sulfadiazine, pyrimethamine and folinic acid). In conclusion, Lico A has strong anti-T. gondii activity in vitro and in vivo and might be developed into a new anti-T. gondii drug. Moreover, Lico A may exert these effects by interfering with lipid metabolism in the parasite.