RESUMEN
In an initial screening, a series of novel Knoevenagel adducts were submitted to the National Cancer Institute for evaluation of antitumor activity in human cell lines. In particular, compound 5f showed remarkable selectivity against IGROV1, an ovarian cancer cell line, without affecting healthy human fibroblast cells. Analyses of cytotoxicity, cell proliferation, cell migration, epigenetic changes, gene expression, and DNA damage were performed to obtain detailed information about its antitumor properties. Our results show that 5f causes proliferation arrest, decrease in motility, histone hyperacetylation, downregulation of cyclin D1 and α5 subunit of integrin ß1 gene transcription. In addition, 5f treatment reduces transcript and protein levels of cyclin D1, which increases sensitivity to ionizing radiation and results in DNA damage comparable to cyclin D1 gene silencing.
Asunto(s)
Antineoplásicos , Proliferación Celular , Humanos , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Indoles/farmacología , Indoles/química , Daño del ADNRESUMEN
Isatin and its derivatives are important heterocycles found in nature and present in numerous bioactive compounds which possess various biological activities. Moreover, it is an essential building block in organic synthesis. The discovery of novel compounds active against human pathogenic bacteria and fungi is an urgent need, and the isatin may represent the suitable scaffold in the design of biologically relevant antimicrobials. A small library of 18 isatin hybrids was synthetized and evaluated for their antimicrobial potential on three reference strains: S. aureus, E. coli, both important human pathogens infamous for causing community- and hospital-acquired severe systemic infections; and C. albicans, responsible for devastating invasive infections, mainly in immunocompromised individuals. The study highlighted two lead compounds, 6k and 6m, endowed with inhibitory activity against S. aureus at very low concentrations (39.12 and 24.83 µg/mL, respectively).
Asunto(s)
Antiinfecciosos , Isatina , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Candida albicans , Escherichia coli , Humanos , Indoles/farmacología , Isatina/farmacología , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus , Relación Estructura-ActividadRESUMEN
G-quadruplex (G4) ligands are investigated to discover new anticancer drugs with increased cell-killing potency. These ligands can induce genome instability and activate innate immune genes at non-cytotoxic doses, opening the discovery of cytostatic immune-stimulating ligands. However, the interplay of G4 affinity/selectivity with cytotoxicity and immune gene activation is not well-understood. We investigated a series of closely related hydrazone derivatives to define the molecular bases of immune-stimulation activity. Although they are closely related to each other, such derivatives differ in G4 affinity, cytotoxicity, genome instability, and immune gene activation. Our findings show that G4 affinity of ligands is a critical feature for immune gene activation, whereas a high cytotoxic potency interferes with it. The balance of G4 stabilization versus cytotoxicity can determine the level of immune gene activation in cancer cells. Thus, we propose a new rationale based on low cell-killing potency and high immune stimulation to discover effective anticancer G4 ligands.
Asunto(s)
Antineoplásicos , Citostáticos , G-Cuádruplex , Neoplasias , Antineoplásicos/farmacología , Inestabilidad Genómica , Humanos , Hidrazonas/farmacología , Interferón beta/genética , Ligandos , Neoplasias/genéticaRESUMEN
A series of new Knoevenagel adducts, bearing two indolinone systems, has been synthesized and evaluated on 60 human cancer cell lines according to protocols available at the National Cancer Institute (Bethesda, MD, USA). Some derivatives proved to be potent antiproliferative agents, showing GI50 values in the submicromolar range. Compound 5b emerged as the most active and was further studied in Jurkat cells in order to determine the effects on cell-cycle phases and the kind of cell death induced. Finally, oxidative stress and DNA damage induced by compound 5b were also analyzed.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Oxindoles/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales/métodos , Humanos , Células Jurkat , Estructura Molecular , Estrés Oxidativo/efectos de los fármacosRESUMEN
Cystic fibrosis is a genetic disease caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator gene, encoding for CFTR protein. The most frequent mutation is the deletion of phenylalanine at position 508 (F508del), which leads to distinct defects in channel gating and cellular processing. In last years, several thiazole containing small molecules, endowed with dual F508del-CFTR modulator activity, proved to be able to target these defects. In search of new chemical entities able to restore CFTR function, we designed and synthesized a small series of sixteen thiazole derivatives. The designed compounds were studied as correctors and potentiators of F508del-CFTR. Although none of the molecules showed significant corrector activity, compounds 10 and 11 exhibited potentiator effects, thus allowing to determine some basic structural features which enable to obtain F508del-CFTR potentiator activity. In silico ADME studies showed that these derivatives obey Lipinski's rule of five and are expected to be orally bioavailable. Therefore, these molecules may represent a good starting point for the design of analogues endowed with improved CFTR potentiator activity and a good pharmacokinetic profile.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Fibrosis Quística/tratamiento farmacológico , Tiazoles/farmacología , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
Targeting G-quadruplex structures is currently viewed as a promising anticancer strategy. Searching for potent and selective G-quadruplex binders, here we describe a small series of new monohydrazone derivatives designed as analogues of a lead which was proved to stabilize G-quadruplex structures and increase R loop levels in human cancer cells. To investigate the G-quadruplex binding properties of the new molecules, in vitro biophysical studies were performed employing both telomeric and oncogene promoter G-quadruplex-forming sequences. The obtained results allowed the identification of a highly selective G-quadruplex ligand that, when studied in human cancer cells, proved to be able to stabilize both G-quadruplexes and R loops and showed a potent cell killing activity associated with the formation of micronuclei, a clear sign of genome instability.
Asunto(s)
Antineoplásicos/farmacología , Daño del ADN/efectos de los fármacos , ADN/efectos de los fármacos , G-Cuádruplex/efectos de los fármacos , Inestabilidad Genómica/efectos de los fármacos , Hidrazonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Línea Celular Tumoral , ADN/genética , ADN/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Genoma/efectos de los fármacos , Humanos , Hidrazonas/síntesis química , Hidrazonas/metabolismo , Ligandos , Estructuras R-Loop/efectos de los fármacosRESUMEN
Parvovirus B19 (B19V) is a human pathogenic virus associated with a wide range of clinical conditions. Currently, there are no recognized antiviral drugs for B19V treatment; therefore, efforts in the search for compounds inhibiting B19V replication are now being pursued. Coumarins (chromen-2-ones) are considered a privileged structure for designing novel orally bioavailable and non-peptidic antiviral agents. To further contribute to the development of new drugs against B19V, our research was focused on the synthesis, characterization and evaluation of antiviral activity of some new 3-(imidazo[2,1-b]thiazol-6-yl)-2H-chromen-2-one derivatives. The effects of the synthesized compounds on cell viability and viral replication were investigated by employing two relevant cellular systems, the myeloblastoid cell line UT7/EpoS1 and primary erythroid progenitor cells (EPCs). Some of the tested compounds showed inhibitory activity both on cell viability and on viral replication, depending on the cellular system. These results suggest that the mechanism involved in biological activity is sensitive to small structural changes and that it is possible to direct the activity of the 3-(imidazo[2,1-b]thiazol-6-yl)-2H-chromen-2-one core.
Asunto(s)
Antivirales/síntesis química , Benzopiranos/síntesis química , Cumarinas/química , Parvovirus B19 Humano/fisiología , Antivirales/química , Antivirales/farmacología , Benzopiranos/química , Benzopiranos/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Humanos , Estructura Molecular , Infecciones por Parvoviridae , Parvovirus B19 Humano/efectos de los fármacos , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
In the present work we describe the synthesis, characterization and evaluation of neuroprotective effects of a focused library of 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines. Furthermore, the new dihydropyridines were subjected to functional in vitro assays in cardiac tissues and vascular smooth muscle to determine their possible selectivity in counteracting the effects of neurodegeneration. In particular the strategy adopted for designing the compounds involves the imidazo[2,1-b]thiazole nucleus. The observed properties show that substituents at C2 and C6 of the bicyclic scaffold are able to influence the cardiovascular parameters and the neuroprotective activity. In comparison to nifedipine, a set of derivatives such as compound 6, showed a neuroprotective profile of particular interest.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Sistema Cardiovascular/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Canales de Calcio/metabolismo , Sistema Cardiovascular/metabolismo , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Ratas , Ratas Wistar , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A small library of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones has been synthesized and screened according to protocols available at the National Cancer Institute (NCI). Some derivatives were potent antiproliferative agents, showing GI50 values in the nanomolar range. Remarkably, when most active compounds against leukemia cells were tested in human peripheral blood lymphocytes from healthy donors, were 100-200 times less cytotoxic. Some compounds, selected by the Biological Evaluation Committee of NCI, were examined to determine tubulin assembly inhibition. Furthermore, flow cytometric studies performed on HeLa, HT-29, and A549â¯cells, showed that compounds 14 and 25 caused a block in the G2/M phase. Interestingly, these derivatives induced apoptosis through the mitochondrial death pathway, causing in parallel significant activation of both caspase-3 and -9, PARP cleavage and down-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1. Finally, compound 25 was also tested in vivo in the murine BL6-B16 melanoma and E0771 breast cancer cells, causing in both cases a significant reduction in tumor volume.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Indoles/síntesis química , Indoles/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Activación Enzimática/efectos de los fármacos , Fase G2/efectos de los fármacos , Células HeLa , Humanos , Indoles/química , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Relación Estructura-ActividadRESUMEN
A fluorescent derivative of trehalose with two dansyl groups (DAT) has been synthesized. It is characterised by a large Stokes shift, good permeability in human living cells and a well detectable fluorescent signal within the cells. Notably, in intestinal cells DAT is sequestered in vesicles induced by trehalose pre-treatment and colocalizes with lipid droplets.
RESUMEN
The rhizome of the Zingiber officinale Roscoe, a biennial herb growing in South Asia, is commonly known as ginger. Ginger is used in clinical disorders, such as constipation, dyspepsia, diarrhoea, nausea and vomiting and its use is also recommended by the traditional medicine for cardiopathy, high blood pressure, palpitations and as a vasodilator to improve the circulation. The decoction of ginger rhizome is widely used in Ayurvedic medicine. In this papery by high-performance liquid chromatography, we have seen that its main phytomarkers were 6-gingerol, 8-gingerol and 6-shogaol and we report the effects of the decoction of ginger rhizome on cardiovascular parameters and on vascular and intestinal smooth muscle. In our experimental models, the decoction of ginger shows weak negative inotropic and chronotropic intrinsic activities but a significant intrinsic activity on smooth muscle with a potency on ileum is greater than on aorta: EC50 = 0.66 mg/mL versus EC50 = 1.45 mg/mL.
Asunto(s)
Medicina Ayurvédica/métodos , Zingiber officinale/química , Asia , Sistema Cardiovascular/efectos de los fármacos , Catecoles , Cromatografía Líquida de Alta Presión , Alcoholes Grasos , Humanos , Músculo Liso/efectos de los fármacos , Extractos Vegetales/química , Rizoma/químicaRESUMEN
BACKGROUND: Fused five-membered heterocyclic rings containing bridgehead nitrogen atom are particularly versatile in the field of medicinal chemistry because of their different biological activities. Among them, the imidazo[2,1-b]thiazole is an attractive fused heterocyclic core that has been extensively studied. OBJECTIVE: The aim of the current study was to study the therapeutic applications of imidazo[2,1- b]thiazole derivatives as antimicrobial agents for the treatment of genitourinary infections. METHOD: A traditional synthetic methodology was involved to obtain a small series of imidazothiazole derivatives. RESULTS: Herein, we report the antimicrobial activity of the imidazo[2,1-b]thiazole or imidazo[2,1- b]thiazolidine derivatives against selected fungi, Gram-positive and Gram-negative bacteria. Moreover, experiments were carried out to investigate the interference towards the endogenous microbiota. CONCLUSION: The most interesting of the series are the thiocyano derivatives (19, 23) showing a good profile for the treatment of genitourinary infections: a spectrum of activity covering both bacteria and fungi together with a reduced impact versus critical lines of Lactobacillus exerting defense against pathogens.
Asunto(s)
Antibacterianos/farmacología , Imidazoles/farmacología , Tiazoles/farmacología , Antibacterianos/síntesis química , Antifúngicos/síntesis química , Antifúngicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Bifidobacterium/efectos de los fármacos , Econazol/farmacología , Células HeLa , Humanos , Imidazoles/síntesis química , Lactobacillus/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Tiazoles/síntesis química , Sistema Urogenital/microbiologíaRESUMEN
Background Community acquired urinary tract infections (caUTI) in adults are common ailments. Older adults are prone to infectious diseases, diagnosis can be difficult, their etiologic and antimicrobial resistance are poorly known. Objectives To evaluate the incidence discriminated by sex, symptoms, and to determine pathogens and their antimicrobial resistance rate. Methods A retrospective, descriptive and comparative study. We analyze uricultures among 2013 in the Hospital Nacional de Clinicas (Córdoba-Argentina). Patients over 65 years old, admitted with a caUTI diagnose were included; we exclude those with urinary catheter. Variables used: Sex, symptoms, pathogen isolation, antimicrobial resistance. For symptom variable was performed a comparative test. Descriptive statistics were used to analyze remaining variables. Results Were analyzed 349 patients: 1) Positive uricultures 191 (case), negative 158 (control). 2) Average age 77 (76% women, 24% men). 3) Symptoms: fever (45%), sepsis criteria (17%), altered mental status (14%), heart failure (11%). 4) Uriculture: monomicrobial 95.29%. 5) Isolation and resistance rate: Escherichia coli (67,7%): ampicillin/sulbactam 52.7%, ciprofloxacin 51.9%, trimethoprim/sulfamethoxazole 45.7%, cefotaxime: 12,9 %, amikacin: 3,9 %, Klebsiella pneumoniae (11,97%): ciprofloxacin 60.8%, trimethoprim/ sulfamethoxazole 50%, cefotaxime 47.8%, amikacin 4.7%. Enterococcus spp. (9,89%): ampicillin 0%, vancomycin 0%. Also isolated: Cándida spp. (3.66%), Proteus mirabilis (2,6%), Staphylococcus aureus (2,6%), Enterobacter cloacae (1,56%), Pseudomonas aeruginosa (1,56%). There were no imipenem resistances among gram negatives. Conclusions Isolations were mostly monomicrobial and at female gender. E. coli was the main uropathogen. The elevated resistance rate to ciprofloxacin, ampicillin/sulbactam and trimethoprim/sulfamethoxazole is remarkable. We suggest to avoid their empiric use in this population.
Asunto(s)
Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Infecciones Urinarias/microbiología , Anciano , Anciano de 80 o más Años , Antibacterianos/farmacología , Argentina/epidemiología , Estudios de Casos y Controles , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/microbiología , Femenino , Bacterias Gramnegativas/aislamiento & purificación , Bacterias Grampositivas/aislamiento & purificación , Humanos , Incidencia , Masculino , Pruebas de Sensibilidad Microbiana , Estudios Retrospectivos , Infecciones Urinarias/epidemiologíaRESUMEN
BACKGROUND: Despite the fact that in recent years, a substantial progress has been made in the treatment of pulmonary hypertension, it is still a severe disease characterized by poor prognosis, and the search for new drugs remains a priority. Current remedies address mainly the vasoconstrictor/ vasodilator imbalance in the pulmonary circulation, while the causes of the disease are only moderately affected. Recently, the role of receptor and non receptor kinases in pulmonary hypertension has emerged and these targets were extensively considered for the development of new therapeutic strategies. This review discusses the patents on small-molecules targeting kinases involved in the proliferation/apoptosis imbalance, typically present in pulmonary hypertension. METHODS: Bibliographic research for the inventions was carried out using Espacenet and Sci-Finder databases, "pulmonary hypertension and kinases" as research query and the range from 2010 to 2015. Only patents published in English were considered. A qualitative analysis of the contents of each patent was made to examine the reported compounds, the studies performed and the resulting conclusions. RESULTS: The review includes about thirty applications. Moreover, in order to illustrate the pathophisiology of the disease and the mechanisms of the targets, about forty additional papers were reported. Considering that imatinib, a PDGF receptor inhibitor, entered the clinical trials for the treatment of pulmonary hypertension, the first patents were devoted to inhibitors of tyrosine kinase receptors, such as PDGFR and c-Kit. Subsequently, in addition to kinase receptors, the role of other pathways involved in pulmonary hypertension has emerged, and some research groups have focused their attention also on non-receptor kinases. Fifteen patents on this topic reported these new targets and new derivatives. However, in most of the inventions, although the pulmonary hypertension is among the treatable diseases, the compounds were subjected only to antiproliferative assays and not to specific tests on animal models. CONCLUSION: The studies reported in this review confirm the continuous research efforts aimed to identify new targets and new drugs for the treatment of pulmonary hypertension. Several inhibitors of kinase were described. These compounds could inhibit mainly important branching processes and pathological growth of blood vessels, thereby might increase the lifespan of patients.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas Receptoras/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Animales , Presión Sanguínea/efectos de los fármacos , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Inhibidores de la Captación de Neurotransmisores/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Vasodilatadores/química , Vasodilatadores/farmacología , Vasodilatadores/uso terapéuticoRESUMEN
G-Quadruplex-binding compounds are currently perceived as possible anticancer therapeutics. Here, starting from a promising lead, a small series of novel hydrazone-based compounds were synthesized and evaluated as G-quadruplex binders. The in vitro G-quadruplex-binding properties of the synthesized compounds were investigated employing both human telomeric and oncogene promoter G-quadruplexes with different folding topologies as targets. The present investigation led to the identification of potent G-quadruplex stabilizers with high selectivity over duplex DNA and preference for one G-quadruplex topology over others. Among them, selected derivatives have been shown to trap G-quadruplex structures in the nucleus of cancer cells. Interestingly, this behavior correlates with efficient cytotoxic activity in human osteosarcoma and colon carcinoma cells.
Asunto(s)
G-Cuádruplex/efectos de los fármacos , Hidrazonas/farmacología , Proliferación Celular/efectos de los fármacos , ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
INTRODUCTION: 2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done on this bicyclic structure by academic and company researchers to synthesize compounds directed to a plethora of molecular targets in order to discover new drug leads. This review presents up-to-date information in the field of cancer therapy research based on this small building block. AREAS COVERED: The present review gives an account of the recent patent literature (2008-2014) describing the discovery of 2-indolinone derivatives with selected therapeutic activities. In this period, a large amount of patents were published on this topic. We have limited the analysis to 37 patents on 2-indolinone derivatives having potential clinical application as chemotherapeutic agents. In this review, the therapeutic applications of 2-indolinone derivatives for the treatment of cancer reported in international patents have been discussed. EXPERT OPINION: 2-Indolinone is the scaffold of the compounds considered from a medicinal chemistry perspective. Many of them have been developed and marketed for therapeutic use. In cancer chemotherapy, progress has been made in designing selective 2-indolinone derivatives. Some of them show preclinical efficacy. However, 2-indolinone has not exhausted all of its potential in the development of new compounds for clinical applications and remains a great tool for future research.
Asunto(s)
Antineoplásicos/farmacología , Indoles/farmacología , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Indoles/síntesis química , Indoles/química , Terapia Molecular Dirigida , Oxindoles , Patentes como AsuntoRESUMEN
Cancer is a disease of remarkable importance in the world today and is projected to become the primary cause of death within the coming years, therefore the design and development of new antitumor agents is one of the most pressing research areas in medicinal chemistry. Considering the importance of thiazole ring as scaffold present in a wide range of therapeutic agents, the medicinal chemists have been encouraged to synthesize a large number of novel antitumors bearing this heterocycle, which furnish extensive synthetic possibilities due to the presence of several reaction sites. The present review describes the patents from 2008 to present concerning new thiazole compounds useful for the development of new drug molecules. It has been divided according to the molecular target and describes the pathways involved in the biological activities and the structure of the most potent compounds, together with the screening results.
Asunto(s)
Antineoplásicos/uso terapéutico , Tiazoles/uso terapéutico , Animales , Antineoplásicos/farmacología , Descubrimiento de Drogas , Humanos , Metaloproteinasas de la Matriz/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Patentes como Asunto , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
A series of 2,5,6-substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives have been prepared and were tested for antiproliferative activity on cancer cells at the National Cancer Institute. Results showed that molecules with a benzyl group at position 2, exhibited an increase in activity for the introduction of a formyl group at the 5 position. The compound 2-benzyl-5-formyl-6-(4-bromophenyl)imidazo[2,1-b][1,3,4]thiadiazole 22 has been chosen for understanding the mechanism of action by various molecular and cellular biology studies. Results obtained from cell cycle evaluation analysis, analysis of mitochondrial membrane potential and Annexin V-FITC by flow cytometric analysis, ROS production and expression of apoptotic and DNA-repair proteins suggested that compound 22 induced cytotoxicity by activating extrinsic pathway of apoptosis, however, without affecting cell cycle progression.
Asunto(s)
Antineoplásicos/farmacología , Imidazoles/farmacología , Tiadiazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/químicaRESUMEN
Electronic nose and capillary electrophoresis were applied in quality control of green tea samples subjected to long-term storage. Twelve representative green teas were considered, available as an "aged" (tea leaves stored during a long-term period of two years) and/or "not aged" (fresh products) samples. Their infusions were analyzed by an electronic nose, equipped with an array of six metal oxide semiconductor (MOS) sensors to obtain olfactive fingerprints of the volatile compounds in the infusions headspace. Upon training and chemometric analysis of acquired data (linear discriminant analysis), the electronic nose was found to be able in correctly classifying unknown samples as "aged" or "not aged". Concomitantly, the infusion samples were analyzed by Cyclodextrin-modified Micellar Electrokinetic Chromatography (CD-MEKC) for determination of catechins. The analysis of seven most represented catechins and the methylxanthines theobromine and caffeine revealed a general loss of the polyphenols in each of the considered aged samples (up to 45%, w/w). In addition, the applied enantioselective method based on (2-hydroxypropyl)-ß-cyclodextrin (HP-ßCD) as chiral selector, was exploited for the estimation of (+)-Gallocatechin in the presence of (-)-Gallocatechin; the latter, as the non-native enantiomer, can be associated to the epimerisation of (-)-Epigallocatechin and was assumed as a marker occurring in case of uncorrected storage conditions of tea leaves. Interestingly, it was observed that epimerization did not significantly occur during aging. The application of CD-MEKC and electronic nose allowed for a fast characterization of green teas taking into account that the aroma is a decisive parameter for the acceptance of the product, whereas the catechins content is associated to the biological value.
Asunto(s)
Nariz Electrónica , Electroforesis Capilar/métodos , Análisis de los Alimentos/métodos , Té , Cafeína/química , Calibración , Catequina/análogos & derivados , Catequina/química , Cromatografía/métodos , Cromatografía Capilar Electrocinética Micelar/métodos , Ciclodextrinas/química , Metales/química , Odorantes , Óxidos/química , Hojas de la Planta/química , Polifenoles/química , Control de Calidad , Semiconductores , Estereoisomerismo , Teobromina/química , Factores de Tiempo , Xantinas/químicaRESUMEN
Bis-indolinone derivatives having either 2,6-disubstituted pyridine core (1a and 1b) or 1,10-disubstituted phenanthroline core (2a and 2b), already known to have antitumor activity, have been tested as potential G-quadruplex binders. Compounds 2a and 2b are able to selectively stabilize G-quadruplex over duplex DNA, and also to discriminate among different G-quadruplex structures, having a particular affinity for the parallel form of the human telomeric G-quadruplex. Both compounds are also able to induce telomeric DNA damage that may explain the activity of these compounds.