RESUMEN
Breast cancer is the primary contributor to cancer-related deaths among women [...].
Asunto(s)
Proteína BRCA2 , Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapiaRESUMEN
The untypical course of reaction between chalcones and benzenesulfonylaminoguanidines led to the new 3-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-2-(1-phenyl-3-arylprop-2-enylideneamino)guanidine derivatives 8-33. The new compounds were tested in vitro for their impact on the growth of breast cancer cells MCF-7, cervical cancer cells HeLa and colon cancer cells HCT-116 by MTT assay. The results revealed that the activity of derivatives is strongly related to the presence of hydroxy group in the benzene ring at the 3-arylpropylidene fragment. The most cytotoxic compounds 20 and 24 displayed mean IC50 values of 12.8 and 12.7 µM, respectively, against three tested cell lines and were almost 3- and 4-fold more active toward MCF-7 and HCT-116 when compared with non-malignant HaCaT cells. Furthermore, compound 24 induced apoptosis in cancer cells and caused a decrease of mitochondrial membrane potential as well as an increase of cells in sub-G1 phase in contrast to its inactive analog 31. The strongest activity against the most sensitive HCT-116 cell line was found for compound 30 (IC50 = 8 µM), which was 11-fold more effective in the growth inhibition of HCT-116 cells than those of HaCaT cells. Based on this fact, the new derivatives may be promising leading structures for the search for agents for the treatment of colon cancer.
Asunto(s)
Antineoplásicos , Neoplasias del Colon , Humanos , Relación Estructura-Actividad , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/farmacología , Células HeLa , Apoptosis , Guanidinas/farmacología , Estructura Molecular , Línea Celular TumoralRESUMEN
A series of novel 2-alkythio-4-chloro-N-[imino-(heteroaryl)methyl]benzenesulfonamide derivatives, 8-24, were synthesized in the reaction of the N-(benzenesulfonyl)cyanamide potassium salts 1-7 with the appropriate mercaptoheterocycles. All the synthesized compounds were evaluated for their anticancer activity in HeLa, HCT-116 and MCF-7 cell lines. The most promising compounds, 11-13, molecular hybrids containing benzenesulfonamide and imidazole moieties, selectively showed a high cytotoxic effect in HeLa cancer cells (IC50: 6-7 µM) and exhibited about three times less cytotoxicity against the non-tumor cell line HaCaT cells (IC50: 18-20 µM). It was found that the anti-proliferative effects of 11, 12 and 13 were associated with their ability to induce apoptosis in HeLa cells. The compounds increased the early apoptotic population of cells, elevated the percentage of cells in the sub-G1 phase of the cell cycle and induced apoptosis through caspase activation in HeLa cells. For the most active compounds, susceptibility to undergo first-phase oxidation reactions in human liver microsomes was assessed. The results of the in vitro metabolic stability experiments indicated values of the factor t½ for 11-13 in the range of 9.1-20.3 min and suggested the hypothetical oxidation of these compounds to sulfenic and subsequently sulfinic acids as metabolites.
Asunto(s)
Antineoplásicos , Humanos , Estructura Molecular , Relación Estructura-Actividad , Células HeLa , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/química , Línea Celular Tumoral , Apoptosis , Relación Dosis-Respuesta a Droga , BencenosulfonamidasRESUMEN
Breast cancer is the leading cause of cancer-related deaths in the female population [...].
Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Femenino , HumanosRESUMEN
In the search for new compounds with antitumor activity, new potential anticancer agents were designed as molecular hybrids containing the structures of a triazine ring and a sulfonamide fragment. Applying the synthesis in solution, a base of new sulfonamide derivatives 20-162 was obtained by the reaction of the corresponding esters 11-19 with appropriate biguanide hydrochlorides. The structures of the compounds were confirmed by spectroscopy (IR, NMR), mass spectrometry (HRMS or MALDI-TOF/TOF), elemental analysis (C,H,N) and X-ray crystallography. The cytotoxic activity of the obtained compounds toward three tumor cell lines, HCT-116, MCF-7 and HeLa, was examined. The results showed that some of the most active compounds belonged to the R1 = 4-trifluoromethylbenzyl and R1 = 3,5-bis(trifluoromethyl)benzyl series and exhibited IC50 values ranging from 3.6 µM to 11.0 µM. The SAR relationships were described, indicating the key role of the R2 = 4-phenylpiperazin-1-yl substituent for the cytotoxic activity against the HCT-116 and MCF-7 lines. The studies regarding the mechanism of action of the active compounds included the assessment of the inhibition of MDM2-p53 interactions, cell cycle analysis and apoptosis induction examination. The results indicated that the studied compounds did not inhibit MDM2-p53 interactions but induced G0/G1 and G2/M cell cycle arrest in a p53-independent manner. Furthermore, the active compounds induced apoptosis in cells harboring wild-type and mutant p53. The compound design was conducted step by step and assisted by QSAR models that correlated the activity of the compounds against the HCT-116 cell line with molecular descriptors.
Asunto(s)
Antineoplásicos , Bencenosulfonatos , Triazinas , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Bencenosulfonatos/química , Bencenosulfonatos/farmacología , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/química , Triazinas/farmacología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Pyrazine and its derivatives are a large group of compounds that exhibit broad biological activity, the changes of which can be easily detected by a substituent effect or a change in the functional group. The present studies combined theoretical research with the density functional theory (DFT) approach (B3LYP/6-311+G**) and experimental (potentiometric and spectrophotometric) analysis for a thorough understanding of the structure of chlorohydrazinopyrazine, its physicochemical and cytotoxic properties, and the site and nature of interaction with DNA. The obtained results indicated that 2-chloro-3-hydrazinopyrazine (2Cl3HP) displayed the highest affinity to DNA. Cytotoxicity studies revealed that the compound did not exhibit toxicity toward human dermal keratinocytes, which supported the potential application of 2Cl3HP in clinical use. The study also attempted to establish the possible equilibria occurring in the aqueous solution and, using both theoretical and experimental methods, clearly showed the hydrophilic nature of the compound. The experimental and theoretical results of the study confirmed the quality of the compound, as well as the appropriateness of the selected set of methods for similar research.
Asunto(s)
Antineoplásicos , Pirazinas , Antibacterianos/química , Antineoplásicos/química , ADN , Humanos , Pirazinas/química , Pirazinas/farmacología , Agua/químicaRESUMEN
CONTEXT: Bufadienolide compounds occur in many plants and animal species and have strong cardiac and anti-inflammatory properties. The compounds have been recently investigated for cytotoxic and antitumor activity. OBJECTIVE: The cytotoxic effect of bersaldegenin-1,3,5-orthoacetate - a bufadienolide steroid occuring in plants from Kalanchoe genus (Crassulaceae), was evaluated with cervical cancer HeLa cells in vitro. MATERIALS AND METHODS: The cytotoxic activity of the compound (at 0.1-20.0 µg/mL) on the cells was determined by Real-Time Cell Analysis (RTCA) system for 24 h. The estimation of cell cycle arrest, reactive oxygen species (ROS) production, reduction of mitochondrial membrane potential (MMP), and caspases-3/7/9 activity in the HeLa cells treated with the compound was done by flow cytometry and luminometric technique. DNA damage in the cells was estimated by immunofluorescence staining and the comet assay with etoposide as a positive control. RESULTS: The compound had strong effect on the cells (IC50 = 0.55 µg/mL) by the suppression of HeLa cells proliferation in G2/M phase of cell cycle and induction of cell death through double-stranded DNA damage and reactive oxygen species overproduction. Furthermore, we did not observe an increase in the activity of caspase-3/7/9 in the treated cells as well as a decrease in cellular mitochondrial membrane potential. Gene expression analysis revealed the overexpression of NF-Kappa-B inhibitors genes (>2-fold higher than control) in the treated cells. CONCLUSIONS: Bersaldegenin-1,3,5-orthoacetate induces cell cycle arrest and caspase-independent cell death through double-stranded DNA damage. These results are an important step in further studies on cell death signalling pathways induced by bufadienolides.
Asunto(s)
Bufanólidos/farmacología , Caspasas/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Extractos Vegetales/farmacología , Neoplasias del Cuello Uterino/metabolismo , Animales , Bufanólidos/aislamiento & purificación , Bufanólidos/uso terapéutico , Bufonidae , Puntos de Control del Ciclo Celular/fisiología , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Daño del ADN/fisiología , Femenino , Células HeLa , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
A series of novel 2-[(4-amino-6-R2-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-N-(5-R1-1H-benzo[d]imidazol-2(3H)-ylidene)benzenesulfonamides 6-49 was synthesized by the reaction of 5-substituted ethyl 2-{5-R1-2-[N-(5-chloro-1H-benzo[d]imidazol-2(3H)-ylidene)sulfamoyl]-4-methylphenylthio}acetate with appropriate biguanide hydrochlorides. The most active compounds, 22 and 46, showed significant cytotoxic activity and selectivity against colon (HCT-116), breast (MCF-7) and cervical cancer (HeLa) cell lines (IC50: 7-11 µM; 15-24 µM and 11-18 µM), respectively. Further QSAR (Quantitative Structure-Activity Relationships) studies on the cytotoxic activity of investigated compounds toward HCT-116, MCF-7 and HeLa were performed by using different topological (2D) and conformational (3D) molecular descriptors based on the stepwise multiple linear regression technique (MLR). The QSAR studies allowed us to make three statistically significant and predictive models for them. Moreover, the molecular docking studies were carried out to evaluate the possible binding mode of the most active compounds, 22 and 46, within the active site of the MDM2 protein.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Técnicas de Química Sintética , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ligandos , Conformación Molecular , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/química , BencenosulfonamidasRESUMEN
To learn more about the structure-activity relationships of (E)-3-(5-styryl-1,3,4-oxadiazol-2-yl)benzenesulfonamide derivatives, which in our previous research displayed promising in vitro anticancer activity, we have synthesized a group of novel (E)-5-[(5-(2-arylvinyl)-1,3,4-oxadiazol-2-yl)]-4-chloro-2-R1-benzenesulfonamides 7-36 as well as (E)-4-[5-styryl1,3,4-oxadiazol-2-yl]benzenesulfonamides 47-50 and (E)-2-(2,4-dichlorophenyl)-5-(2-arylvinyl)-1,3,4-oxadiazols 51-55. All target derivatives were evaluated for their anticancer activity on HeLa, HCT-116, and MCF-7 human tumor cell lines. The obtained results were analyzed in order to explain the influence of a structure of the 2-aryl-vinyl substituent and benzenesulfonamide scaffold on the anti-tumor activity. Compound 31, bearing 5-nitrothiophene moiety, exhibited the most potent anticancer activity against the HCT-116, MCF-7, and HeLa cell lines, with IC50 values of 0.5, 4, and 4.5 µM, respectively. Analysis of structure-activity relationship showed significant differences in activity depending on the substituent in position 3 of the benzenesulfonamide ring and indicated as the optimal meta position of the sulfonamide moiety relative to the oxadizole ring. In the next stage, chemometric analysis was performed basing on a set of computed molecular descriptors. Hierarchical cluster analysis was used to examine the internal structure of the obtained data and the quantitative structure-activity relationship (QSAR) analysis with multiple linear regression (MLR) method allowed for finding statistically significant models for predicting activity towards all three cancer cell lines.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , BencenosulfonamidasRESUMEN
ERK is a component of mitogen-activated protein kinases that controls a range of cellular processes including cell proliferation and survival. The upregulation of ERK has been associated with apoptosis inhibition in response to various stimuli including chemotherapeutic agents. Research has suggested that the upregulation of ERK signaling by the anticancer agent paclitaxel leads to acquired resistance of cells to this compound. The presented research focused on determining the role of plumbagin, a naturally derived naphthoquinone, in the sensitization of breast cancer cells to paclitaxel-induced cell death and the involvement of ERK signaling in this process. The results of the study indicated that plumbagin increases the sensitivity of breast cancer cells to paclitaxel. Moreover, a synergistic effect between plumbagin and paclitaxel was observed. Plumbagin was shown to decrease levels of phosphorylated ERK in breast cancer cells and abrogated paclitaxel-induced ERK phosphorylation. The role of ERK in plumbagin-mediated sensitization of breast cancer cells to paclitaxel was shown through the enhancement of the synergistic effect between compounds in cells with decreased ERK expression. Furthermore, plumbagin reduced p-ERK levels in paclitaxel-resistant breast cancer cells and resensitized paclitaxel-resistant cells to this compound. These results imply that plumbagin inhibits ERK activation in breast cancer cells, which plays a role in the sensitization of cells to paclitaxel-induced cell death.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Naftoquinonas/farmacología , Paclitaxel/farmacología , Antineoplásicos Fitogénicos/administración & dosificación , Línea Celular Tumoral , Sinergismo Farmacológico , Activación Enzimática , Femenino , Humanos , Naftoquinonas/administración & dosificación , Paclitaxel/administración & dosificaciónRESUMEN
Rising resistance of pathogenic bacteria reduces the options of treating hospital and non-hospital bacterial infections. There is a need to search for newer chemotherapies that will show antimicrobial ability against planktonic cells as well as bacterial biofilms. We have synthesized a series of N-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)amides, namely, molecular hybrids, which include a 2-mercaptobenzenosulfonamide fragment and either cinnamic or cyclohexylpropionic acid residues. The antimicrobial activity of compounds 8â17 was evaluated on Gram-positive, Gram-negative bacteria and fungal species. Experiments took into account investigation of antibacterial activity against planktonic cells as well as biofilms. Compounds 8â17 showed high bacteriostatic activity against staphylococci, with the most active molecules 10 and 16 presenting low MIC values of 4-8 µg/mL against reference methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) strains as well as clinical isolates. Compounds 10 and 16 also showed an ability to inhibit biofilms formed by MRSA and MSSA. The potential of 10 and 16 as antibiofilm agents was supported by cytotoxicity assays that indicated no cytotoxic effect either on normal cells of human keratinocytes or on human cancer cells, including cervical, colon, and breast cancer lines.
Asunto(s)
Amidas/farmacología , Antiinfecciosos/farmacología , Staphylococcus aureus/efectos de los fármacos , Biopelículas/efectos de los fármacos , Línea Celular Tumoral , Células HCT116 , Células HeLa , Humanos , Células MCF-7 , Pruebas de Sensibilidad Microbiana/métodos , Plancton/efectos de los fármacosRESUMEN
A series of N-(aryl/heteroaryl)-4-(1H-pyrrol-1-yl)benzenesulfonamides were synthesized from 4-amino-N-(aryl/heteroaryl)benzenesulfonamides and 2,5-dimethoxytetrahydrofuran. All the synthesized compounds were evaluated for their anticancer activity on HeLa, HCT-116, and MCF-7 human tumor cell lines. Compound 28, bearing 8-quinolinyl moiety, exhibited the most potent anticancer activity against the HCT-116, MCF-7, and HeLa cell lines, with IC50 values of 3, 5, and 7 µM, respectively. The apoptotic potential of the most active compound (28) was analyzed through various assays: phosphatidylserine translocation, cell cycle distribution, and caspase activation. Compound 28 promoted cell cycle arrest in G2/M phase in cancer cells, induced caspase activity, and increased the population of apoptotic cells. Relationships between structure and biological activity were determined by the QSAR (quantitative structure activity relationships) method. Analysis of quantitative structure activity relationships allowed us to generate OPLS (Orthogonal Projections to Latent Structure) models with verified predictive ability that point out key molecular descriptors influencing benzenosulfonamide's activity.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Técnicas de Química Sintética , Estructura Molecular , Sulfonamidas/química , Sulfonamidas/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Relación Estructura-Actividad Cuantitativa , Sulfonamidas/síntesis química , BencenosulfonamidasRESUMEN
A series of novel 5-substituted 2-(arylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl) benzenesulfonamide derivatives 27-60 have been synthesized by the reaction of aminoguanidines with an appropriate phenylglyoxal hydrate in glacial acetic acid. A majority of the compounds showed cytotoxic activity toward the human cancer cell lines HCT-116, HeLa and MCF-7, with IC50 values below 100 µM. It was found that for the analogues 36-38 the naphthyl moiety contributed significantly to the anticancer activity. Cytometric analysis of translocation of phosphatidylserine as well as mitochondrial membrane potential and cell cycle revealed that the most active compounds 37 (HCT-116 and HeLa) and 46 (MCF-7) inhibited the proliferation of cells by increasing the number of apoptotic cells. Apoptotic-like, dose dependent changes in morphology of cell lines were also noticed after treatment with 37 and 46. Moreover, triazines 37 and 46 induced caspase activity in the HCT-116, HeLa and MCF-7 cell lines. Selected compounds were tested for metabolic stability in the presence of pooled human liver microsomes and NADPH, both R² and Ar = 4-CF3-C6H4 moiety in 2-(R²-methylthio)-N-(5-aryl-1,2,4-triazin-3-yl)benzenesulfonamides simultaneously increased metabolic stability. The results pointed to 37 as a hit compound with a good cytotoxicity against HCT-116 (IC50 = 36 µM), HeLa (IC50 = 34 µM) cell lines, apoptosis-inducing activity and moderate metabolic stability.
Asunto(s)
Antineoplásicos/administración & dosificación , Proliferación Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Células HeLa , Humanos , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , BencenosulfonamidasRESUMEN
Bacterial cell envelope is generally accepted as the primary target for a photo-induced oxidative stress. It is plausible that DNA damage occurs during the antimicrobial photoinactivation. Here we investigate the correlation between DNA damage and photoinactivation by evaluating the level of RecA-based DNA repair system in Staphylococcus aureus. By using exogenous photosensitizers (new methylene blue (NMB), toluidine blue O (TBO), 5,10,15,20-tetrakis(1-methyl-4-pyridinio)porphyrin tetra(p-toluenesulfonate) (TMPyP), zinc phthalocyanine (ZnPc), Rose Bengal (RB)) and ALA-induced endogenous porphyrin-dependent blue light (405 nm), several outcomes were observed: (i) an increase of DNA damage (from gel electrophoresis in DNA damage assay), (ii) an increase of recA expression (luminescence assay in recA-lux strain), and (iii) an increase of RecA protein level (Western blotting). When recA expression was repressed by novobiocin, or abolished by deleting the gene, S. aureus susceptibility towards photoinactivation was increased at approximately a hundred-fold. The absence of RecA increases DNA damage to yield bactericidal effect. In novobiocin-resistant mutant (gyrB), as opposed to wild type, neither RecA protein level nor cell's susceptibility was affected by photoinactivation (when novobiocin is present). This is to suggest that GyrB-dependent inhibition mediated recA repression. Therefore, we have established the role of RecA in DNA damage during photoinactivation. With the use of rifampicin mutation frequency and Ames tests, we demonstrated that photoinactivation did not increase S. aureus mutagenesis and potentially is not mutagenic toward eukaryotic cells. The results suggest that the treatment is considered safe. In conclusion, we provide an evidence that recA inhibitor may serve as therapeutic adjuvant for antimicrobial photoinactivation. Clinical relevance of our findings warrants further investigations.
Asunto(s)
Antibacterianos/metabolismo , Daño del ADN/efectos de la radiación , Fármacos Fotosensibilizantes/metabolismo , Rec A Recombinasas/metabolismo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/efectos de la radiación , Girasa de ADN/genética , Eliminación de Gen , Novobiocina/metabolismo , Rec A Recombinasas/genética , Staphylococcus aureus/enzimología , Staphylococcus aureus/genéticaRESUMEN
A family of N-methylpyrrolidinium fullerene iodide salts has been intensively studied to determine their applicability in antimicrobial photodynamic therapy (APDT). This study examined in vitro the efficacy of a C60 fullerene functionalized with one methylpyrrolidinium group to kill upon irradiation with white light gram-negative and gram-positive bacteria, as well as fungal cells, and the corresponding mechanism of the fullerene bactericidal action. The in vitro studies revealed that the high antistaphylococcal efficacy of functionalized fullerene could be linked to their ability to photogenerate singlet oxygen and superoxide anion. Following Staphylococcus aureus photoinactivation, no modifications of its genomic DNA were detected. In contrast, photodamage of the cell envelope seemed to be a dominant mechanism of bactericidal action. In in vivo studies, a 2 log10 reduction in the average bioluminescent radiance between treated and non-treated mice was reached. One day post APDT treatment, moist and abundant growth of bacteria could be observed on wounds of non-fulleropyrrolidine and dark control mice. APDT-treated wounds stayed visibly clear up to the third day. Moreover, cytotoxicity test on human dermal keratinocytes revealed great safety of using the sensitizer toward eukaryotic cells. These data indicate potential application of functionalized fullerene as antistaphylococcal sensitizer for superficial infections.
Asunto(s)
Fulerenos/farmacología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Pirrolidinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/toxicidad , Carga Bacteriana , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Fulerenos/administración & dosificación , Fulerenos/toxicidad , Queratinocitos/efectos de los fármacos , Queratinocitos/fisiología , Luz , Ratones , Viabilidad Microbiana/efectos de los fármacos , Fotoquimioterapia/efectos adversos , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/toxicidad , Pirrolidinas/administración & dosificación , Pirrolidinas/toxicidad , Infecciones Estafilocócicas/tratamiento farmacológico , Infección de Heridas/tratamiento farmacológicoRESUMEN
A new lignan from the non-transformed root in vitro cultures of Phyllanthus amarus was isolated. The structure of the compound was established on the basis of one- and two-dimensional NMR, as well as mass spectrometry data, as 7'-oxocubebin dimethylether (1,4-bis(benzo[d][1,3]dioxol-5-yl)-2,3-bis(methoxymethyl)butan-1-on). The non-transformed root cultures of P. amarus showed to be a selective source of this compound. The lignan revealed strong cytotoxic activity against HeLa cell line with an IC50 value of 3.8 µg/mL.
Asunto(s)
Lignanos/química , Lignanos/farmacología , Phyllanthus/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Raíces de Plantas/química , Línea Celular Tumoral , Células HeLa , Humanos , Espectroscopía de Resonancia Magnética/métodos , Fitoterapia/métodosRESUMEN
A series of novel 3-/2,3-substituted pyrido[4,3-e][1,2,4]triazino[3,2-c][1,2,4]thiadiazine 6,6-dioxides 4-28 have been synthesized by the reaction of 3-amino-2-(4-thioxo-1,4-dihydropyridin-3-yl-sulfonyl)guanidine with either 2-oxoalkanoic acids and its esters, or phenylglyoxylic hydrates in glacial acetic acid. Some of them exhibited reasonable or moderate anticancer activity toward human cancer cell lines, HCT-116, MCF-7 and HeLa. The structure of this novel heterocyclic ring system was confirmed by ¹D-NMR and ²D-NMR spectroscopic data including COSY, ROESY and HMBC, elemental analyses and MS spectrometry.
Asunto(s)
Antineoplásicos/farmacología , Óxidos Heterocíclicos/síntesis química , Tiadiazinas/síntesis química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células HCT116 , Células HeLa , Óxidos Heterocíclicos/farmacología , Humanos , Células MCF-7 , Relación Estructura-Actividad , Tiadiazinas/farmacologíaRESUMEN
A series of new 6-chloro-3-(2-arylmethylene-1-methylhydrazino)-1,4,2-benzodithiazine 1,1-dioxide derivatives were effectively synthesized from N-methyl-N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)hydrazines. The intermediate compounds as well as the products, were evaluated for their cytotoxic effects toward three human cancer cell lines. All compounds shown moderate or weak cytotoxic effects against the tested cancer cell lines, but selective cytotoxic effects were observed. Compound 16 exhibited the most potent cytotoxic activity against the HeLa cell line, with an IC50 value of 10 µM, while 14 was the most active against the MCF-7 and HCT-116 cell lines, affording IC50 values of 15 µM and 16 µM, respectively. The structure-activity relationship was evaluated based on QSAR methodology. The QSAR MCF-7 model indicated that natural charge on carbon atom C13 and energy of highest occupied molecular orbital (HOMO) are highly involved in cytotoxic activity against MCF-7 cell line. The cytotoxic activity of compounds against HCT-116 cell line is dependent on natural charge on carbon atom C13 and electrostatic charge on nitrogen atom N10. The obtained QSAR models could provide guidelines for further development of novel anticancer agents.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Tiazinas/química , Tiazinas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Células MCF-7 , Neoplasias/patología , Relación Estructura-Actividad Cuantitativa , Relación Estructura-Actividad , Tiazinas/síntesis químicaRESUMEN
A series of novel N-acyl-4-chloro-5-methyl-2-(R¹-methylthio)benzenesulfonamides 18-47 have been synthesized by the reaction of N-[4-chloro-5-methyl-2-(R¹-methylthio) benzenesulfonyl]cyanamide potassium salts with appropriate carboxylic acids. Some of them showed anticancer activity toward the human cancer cell lines MCF-7, HCT-116 and HeLa, with the growth percentages (GPs) in the range from 7% to 46%. Quantitative structure-activity relationship (QSAR) studies on the cytotoxic activity of N-acylsulfonamides toward MCF-7, HCT-116 and HeLa were performed by using topological, ring and charge descriptors based on the stepwise multiple linear regression technique (MLR). The QSAR studies revealed three predictive and statistically significant models for the investigated compounds. The results obtained with these models indicated that the anticancer activity of N-acylsulfonamides depends on topological distances, number of ring system, maximum positive charge and number of atom-centered fragments. The metabolic stability of the selected compounds had been evaluated on pooled human liver microsomes and NADPH, both R¹ and R² substituents of the N-acylsulfonamides simultaneously affected them.
Asunto(s)
Antineoplásicos/síntesis química , Derivados del Benceno/síntesis química , Sulfonamidas/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Derivados del Benceno/metabolismo , Derivados del Benceno/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Semivida , Células HeLa , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Células MCF-7 , Microsomas Hepáticos/metabolismo , Conformación Molecular , Relación Estructura-Actividad Cuantitativa , Sulfonamidas/metabolismo , Sulfonamidas/farmacologíaRESUMEN
A series of N-substituted N'-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)guanidine derivatives bearing sulfonamide moiety have been screened in vitro for antibacterial activity against isolates from patients with infections of oral cavity, respiratory tract and intestinal tract. The majority of compounds exhibited good antibacterial potency. 1-[4-Chloro-5-methyl-2-(4-trifluoromethylbenzylthio)benzenesulfonyl]-3-(3-sulfamoylphenyl)guanidine (13) showed very strong activity, with MIC ≤ 6.2 µg/ml against eleven bacteria strains belonged to Gram-positive anaerobes and aerobes. Furthermore, compound 13 exhibited promising activity toward highly resistant microorganisms such as methicillin-resistant Staphylococcus aureus and Enterococcusfaecalis. It was found that Parvimonas micra, Finegoldia magna, Peptostreptococcus anaerobius, Propionibacterium acnes showed the highest susceptibility toward the investigated guanidines.