RESUMEN
Expression of cytochrome P450-1A1 (CYP1A1) is suppressed under physiologic conditions but is induced (a) by polycyclic aromatic hydrocarbons (PAHs) which can be metabolized by CYP1A1 to carcinogens, and (b) in majority of breast cancers. Hence, phytochemicals or dietary flavonoids, if identified as CYP1A1 inhibitors, may help in preventing PAH-mediated carcinogenesis and breast cancer. Herein, we have investigated the cancer chemopreventive potential of a flavonoid-rich Indian medicinal plant, Pongamia pinnata (L.) Pierre. Methanolic extract of its seeds inhibits CYP1A1 in CYP1A1-overexpressing normal human HEK293 cells, with IC50 of 0.6⯵g/mL. Its secondary metabolites, the furanoflavonoids pongapin/lanceolatin B, inhibit CYP1A1 with IC50 of 20â¯nM. Although the furanochalcone pongamol inhibits CYP1A1 with IC50 of only 4.4⯵M, a semisynthetic pyrazole-derivative P5b, has â¼10-fold improved potency (IC50, 0.49⯵M). Pongapin/lanceolatin B and the methanolic extract of P. pinnata seeds protect CYP1A1-overexpressing HEK293 cells from B[a]P-mediated toxicity. Remarkably, they also block the cell cycle of CYP1A1-overexpressing MCF-7 breast cancer cells, at the G0-G1 phase, repress cyclin D1 levels and induce cellular-senescence. Molecular modeling studies demonstrate the interaction pattern of pongapin/lanceolatin B with CYP1A1. The results strongly indicate the potential of methanolic seed-extract and pongapin/lanceolatin B for further development as cancer chemopreventive agents.
Asunto(s)
Antineoplásicos/farmacología , Benzopiranos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Citocromo P-450 CYP1A1/antagonistas & inhibidores , Flavonas/farmacología , Furanos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Benzopiranos/síntesis química , Benzopiranos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Citocromo P-450 CYP1A1/biosíntesis , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Flavonas/síntesis química , Flavonas/química , Citometría de Flujo , Furanos/síntesis química , Furanos/química , Células HEK293 , Humanos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Prenylated flavonols are known as phytoestrogen and have good bioactivties. However, their abundances in nature are pretty low. It is required to find an efficient synthesis technique. Icariin is a prenylated flavonol glycoside with low cost. It can be used to synthesize different prenylated flavonols. A combination of cellulase and trifluoacetic acid hydrolysis could effectively remove rhamnose and glucose from icariin. Icaritin, anhydroicaritin and wushanicaritin were the leading prenylated flavonol products. Their affinities to estrogen receptors α and ß were predicted by docking study. The weak affinity of wushanicaritin indicated that prenyl hydroxylation impaired its affinity to estrogen receptor ß. The prenyl cyclization led to a loss of affinity to both receptors. The interactions between icaritin and ligand binding cavity of estrogen receptor ß were simulated. π-π stacking and hydrophobic forces were predicted to be the dominant interactions positioning icaritin, which induced the helix (H12) forming an activated conformation.
Asunto(s)
Benzopiranos/síntesis química , Receptor alfa de Estrógeno/química , Receptor beta de Estrógeno/química , Flavonoides/química , Flavonoides/síntesis química , Fitoestrógenos/síntesis química , Benzopiranos/química , Sitios de Unión , Celulasa/química , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/metabolismo , Glucosa/química , Hidrólisis , Interacciones Hidrofóbicas e Hidrofílicas , Hidroxilación , Modelos Moleculares , Simulación del Acoplamiento Molecular , Fitoestrógenos/química , Prenilación , Unión Proteica , Estructura Secundaria de Proteína , Ramnosa/química , Ácido Trifluoroacético/químicaRESUMEN
Metal-ion misregulation and oxidative stress continue to be components of the continually evolving hypothesis describing the molecular origins of Alzheimer's disease. Therefore, these features are viable targets for synthetic chemists to explore through hybridizations of metal-binding ligands and antioxidant units. To date, the metal-binding unit in potential therapeutic small molecules has largely been inspired by clioquinol with the exception of a handful of heterocyclic small molecules and open-chain systems. Heterocyclic small molecules such as cyclen (1,4,7,10-tetraazacyclododecane) have the advantage of straightforward N-based modifications, allowing the addition of functional groups. In this work, we report the synthesis of a triazine bridged system containing two cyclen metal-binding units and an antioxidant coumarin appendage inspired by nature. This new potential therapeutic molecule shows the ability to bind copper in a unique manner compared to other chelates proposed to treat Alzheimer's disease. DPPH and TEAC assays exploring the activity of N-(2-((4,6-di(1,4,7,10-tetraazacyclododecan-1-yl)-1,3,5-triazin-2-yl)amino)ethyl)-2-oxo-2H-chromene-3-carboxamide (molecule 1) show that the molecule is antioxidant. Cellular studies of molecule 1 indicate a low toxicity (EC50 = 80 µM) and the ability to protect HT-22 neuronal cells from cell death induced by Aß + copper(II), thus demonstrating the potential for molecule 1 to serve as a multimodal therapeutic for Alzheimer's disease.
Asunto(s)
Antioxidantes/síntesis química , Benzopiranos/síntesis química , Fármacos Neuroprotectores/síntesis química , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Animales , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacología , Benzopiranos/química , Benzopiranos/metabolismo , Benzopiranos/farmacología , Línea Celular Transformada , Quelantes/síntesis química , Quelantes/metabolismo , Quelantes/farmacología , Cobre/metabolismo , Cobre/toxicidad , Evaluación Preclínica de Medicamentos , Fluorometría , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Peso Molecular , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/toxicidad , Unión Proteica , Conformación Proteica , Relación Estructura-Actividad , Tirosina/análisisRESUMEN
Most chemotherapeutic drugs commonly suffer from several shortcomings, including the lack of aqueous solubility, limited stability and adverse side effects. Although caging strategy has recently been employed as an effective approach to conceal and stabilize these drugs to achieve light-activated cancer therapy, it is plagued by the sophisticated drug modification process and deleterious solvent usage. In addition, using UV or Visible light to remove photocaged group is restricted to its limited tissue penetration ability in and phototoxicity. In this paper, by anchoring photochromic spiropyran on the mesoporous silica coated upconversion nanoparticles (UCNP-SP), we design a NIR-controlled cage mimicking system. Our results indicate that hydrophobic drug can be concealed inside the channels of the nanocarrier with high stability and "uncaged" via NIR irradiation-triggered hydrophobicity-hydrophilicity switch of the spiropyran molecules, finally inducing drug release and recovering their bioactivity. Moreover, under NIR illumination, the UV/Visible emissions from UCNP can also efficaciously initiate the generation of reactive oxygen species (ROS) by Curcumin, further improving the therapeutic efficiency. Both in vitro and in vivo experimental results validate that NIR irradiated nanosystem can produce remarkably enhanced antitumor efficiency.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/efectos de la radiación , Benzopiranos/síntesis química , Benzopiranos/química , Línea Celular Tumoral , Supervivencia Celular , Curcumina/química , Curcumina/farmacología , Liberación de Fármacos , Interacciones Hidrofóbicas e Hidrofílicas , Indoles/síntesis química , Indoles/química , Luz , Sustancias Luminiscentes/química , Ratones , Nanopartículas/química , Nitrocompuestos/síntesis química , Nitrocompuestos/química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/efectos de la radiación , Especies Reactivas de Oxígeno , Dióxido de Silicio/químicaRESUMEN
Herein we report the synthesis of twelve 2,5-substituted 4-(trifluoromethyl)-spirochromeno[4,3-d]pyrimidines (7-10), as well as an evaluation of their analgesic effect in a mouse pain model. The nine new chromeno[4,3-d]pyrimidines (7-9) were synthesized from the cyclocondensation reactions of three 2,2,2-trifluoro-1-(4-methoxyspiro[chromene-2,1'-cycloalkane]-3-yl)ethanones (3) containing 5-, 6- and 7-membered spirocycloalkanes, with some well-known amidine salts (4-6) [NH2CR(NH)]-in which R=Me, Ph, and NH2-at yields of 60-95%. Subsequently, three new 2-(pyrrol-1-yl)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (10) were obtained through a Clauson-Kaas reaction between the respective 2-(amino)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (9) and 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation showed that these 4-(trifluoromethyl)chromeno[4,3-d]pyrimidines (100mg/kg, p.o.) and Ketoprofen (100mg/kg, p.o.) significantly reduced capsaicin-induced spontaneous nociception. Moreover, the 2-pyrrolyl-spirocyclohexane derivative 10b (100 and 300mg/kg, p.o.) had an anti-allodynic effect comparable to Ketoprofen (100 and 300mg/kg, p.o.) in the arthritic pain model, without causing locomotor alterations in the mice. These results suggest that the compound 10b is a promising molecule for new analgesic drugs in the treatment of pathological pain, such as in arthritis.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Benzopiranos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Dolor/tratamiento farmacológico , Pirimidinas/uso terapéutico , Compuestos de Espiro/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/síntesis química , Artritis/inducido químicamente , Artritis/tratamiento farmacológico , Artritis/fisiopatología , Benzopiranos/administración & dosificación , Benzopiranos/síntesis química , Capsaicina , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Cetoprofeno/administración & dosificación , Cetoprofeno/farmacología , Ratones , Nocicepción/efectos de los fármacos , Dolor/inducido químicamente , Dolor/fisiopatología , Pirimidinas/administración & dosificación , Pirimidinas/síntesis química , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/síntesis químicaRESUMEN
Aldose reductase (ALR2) inhibitors provide a viable mode to fight against diabetic complications. ALR2 exhibit plasticity in the active site vicinities and possible shifts in the nearby two supporting alpha helices. Therefore, a novel series of amino acid conjugates of chromene-3-imidazoles (13-15) were designed and synthesized based on natural isoflavonoids. The compounds were identified on the basis of spectral (1H NMR, 13C NMR and MS) data and tested in vitro for ALR2 inhibitory activity with an IC50 value ranges from 0.031 ± 0.082 µM to 4.29 ± 0.55 µM. Our in silico and biochemical studies confirmed that 15e has the best inhibition activity among the synthesized compounds with a high selective index against the Aldehyde reductase (ALR1). Supplementation of 15e to STZ induced rats decreased the blood glucose levels and delayed the progression of cataract in a dose-dependent manner. The present study thus provides novel series of compounds with a promising inhibitor to prevent or delay the cataract progression.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Aminoácidos/síntesis química , Aminoácidos/farmacología , Diseño de Fármacos , Imidazoles/química , Aminoácidos/química , Animales , Benzopiranos/síntesis química , Benzopiranos/química , Benzopiranos/farmacología , Glucemia/efectos de los fármacos , Dominio Catalítico , Catarata/tratamiento farmacológico , Catarata/etiología , Complicaciones de la Diabetes/tratamiento farmacológico , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Over the last twenty years, tocotrienol analogues raised great interest because of their higher level and larger domain of biological activities when compared with tocopherols. Amongst the most promising therapeutic application, anti-inflammatory potency has been evaluated through the inhibition of various mediators of inflammation. Here, we worked on the isolation of two natural isoforms of garcinoic acid (i.e., δ and γ) from two different sources, respectively, Garcinia kola seeds and Garcinia amplexicaulis bark. We also developed semisynthetic strategies to access the other two non-natural α- and ß-garcinoic acid isoforms. In the next stage of our work, microsomal prostaglandin E2 synthase was defined as a target to evaluate the anti-inflammatory potential of the four garcinoic acid isomers. Both dimethylated isoforms, ß- and γ-garcinoic acid, exhibited the lowest IC50, 2.8 µM and 2.0 µM, respectively. These results showed that the affinity of tocotrienol analogues to microsomal prostaglandin E2 synthase-1 most probably contributes to the anti-inflammatory potential of this class of derivatives.
Asunto(s)
Benzopiranos/aislamiento & purificación , Garcinia/química , Extractos Vegetales/aislamiento & purificación , Prostaglandina-E Sintasas/antagonistas & inhibidores , Benzopiranos/síntesis química , Benzopiranos/química , Línea Celular , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Humanos , Isomerismo , Corteza de la Planta/química , Extractos Vegetales/farmacologíaRESUMEN
The synthesis of oolongtheanins (1a-d) was accomplished from EGC and/or EGCg in three steps. Oolongtheanin-3'-O-gallate (1b) showed more potent inhibitory activity on micellar cholesterol solubility than did EGCg.
Asunto(s)
Benzopiranos/química , Catequina/química , Colesterol/química , Polifenoles/química , Benzopiranos/síntesis química , Camellia sinensis/química , Técnicas In Vitro , Micelas , Polifenoles/síntesis química , SolubilidadRESUMEN
Hydroxylated 6H-benzo[c]chromen-6-one derivatives (i.e., urolithins) are the main bioavailable metabolites, and biomarkers of ellagitannins present in various nutrition. Although these dietaries, the sources of urolithins, are employed in folk medicine as cognitive enhancer in the treatment of Alzheimer's Disease, urolithins have negligible potential to inhibit acetylcholinesterase and butyrylcholinesterase enzymes, the validated targets of Alzheimer's Disease. Therefore, within this research, a series of 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives has been designed, synthesized, and their biological activities were evaluated as potential acetylcholinesterase and butyrylcholinesterase inhibitors. The compounds synthesized exerted comparable activity in comparison to rivastigmine, galantamine, and donepezil both in in vitro and in vivo studies.
Asunto(s)
Acetilcolinesterasa/metabolismo , Benzopiranos/farmacología , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Benzopiranos/síntesis química , Benzopiranos/química , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
The dwindling supply of antibiotics that remain effective against drug-resistant bacterial pathogens has precipitated efforts to identify new compounds that inhibit bacterial growth using untapped mechanisms of action. Here, we report both (1) a high-throughput screening methodology designed to discover chemical perturbants of the essential, yet unexploited, process of bacterial iron homeostasis, and (2) our findings from a small-molecule screen of more than 30,000 diverse small molecules that led to the identification and characterization of two spiro-indoline-thiadiazoles that disrupt iron homeostasis in bacteria. We show that these compounds are intracellular chelators with the capacity to exist in two isomeric states. Notably, these spiroheterocyles undergo a transition to an open merocyanine chelating form with antibacterial activity that is specifically induced in the presence of its transition-metal target.
Asunto(s)
Escherichia coli/efectos de los fármacos , Homeostasis/efectos de los fármacos , Quelantes del Hierro/química , Quelantes del Hierro/farmacología , Hierro/metabolismo , Compuestos Organometálicos/farmacología , Elementos de Transición/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Benzopiranos/síntesis química , Benzopiranos/química , Benzopiranos/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Escherichia coli/metabolismo , Ensayos Analíticos de Alto Rendimiento , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Quelantes del Hierro/síntesis química , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Bibliotecas de Moléculas Pequeñas , Compuestos de Espiro/química , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazoles/química , Factores de Transcripción/antagonistas & inhibidores , Elementos de Transición/químicaRESUMEN
We have synthesized and characterized a variety of fat-soluble, low-melting and medicinally useful 4-aryl-4H-chromenes from H-cardanol (side-chain perhydrogenated cardanol, 3-pentadecylphenol), a renewable and low-cost product from locally grown cashew nut trees (Anacardium occidentale L.). We incorporated H-cardanol into the aromatic rings of either 4H-chromene or phenol, or both. Substitution of C4SMe in N-methyl-4-(methylthio)-3-nitro-4H-chromene-2-amines with H-cardanol was regio-specific at the C6 position.
Asunto(s)
Benzopiranos/química , Fenoles/química , Anacardium/química , Benzopiranos/síntesis química , Estructura MolecularRESUMEN
AIM: In a search for new cardiovascular drug candidates, a series of novel oxime ethers derived from a natural isochroman-4-one were synthesized. METHOD: Compounds 3 and 6, derived from the natural antihypertensive compound 7, 8-dihydroxy-3-methyl-isochroman-4-one (XJP), were designed and synthesized. Subsequently, a series of novel isochroman-4-one oxime ether hybrids were prepared by hybridizing various N-substituted isopropanolamine functionalities to isochroman-4-one oxime. Furthermore, ß1-adrenergic blocking activities of the synthesized compounds were assayed using the isolated rat left atria. RESULTS: Twenty target compounds were obtained, and the preliminary structure-activity relationships were deduced. The most promising compound Ic exhibited ß1-adrenoceptor blocking activity (inhibition: 52.2%) at 10(-7) mol·L(-1), which was superior to that of propranolol (inhibition: 49.7%). CONCLUSION: The results suggested that natural product XJP/isopropanolamine moiety hybrids may provide a promising approach for the discovery of novel cardiovascular drug candidates.
Asunto(s)
Antagonistas Adrenérgicos beta/síntesis química , Antagonistas Adrenérgicos beta/farmacología , Benzopiranos/síntesis química , Benzopiranos/farmacología , Medicamentos Herbarios Chinos/síntesis química , Medicamentos Herbarios Chinos/farmacología , Hipertensión/tratamiento farmacológico , Oximas/química , Antagonistas Adrenérgicos beta/química , Animales , Antihipertensivos/síntesis química , Antihipertensivos/química , Antihipertensivos/farmacología , Benzopiranos/química , Medicamentos Herbarios Chinos/química , Humanos , Hipertensión/fisiopatología , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Helicobacter pylori (Hp) infection affects one-half of the human population and produces a variety of diseases from peptic ulcer to cancer. Current eradication therapies achieve modest success rates (around 70%), resistance to the antibiotics of choice is on the rise, and vaccination has not proved to be successful yet. Using an essential Hp protein, flavodoxin, as target, we identified three low-molecular-weight flavodoxin inhibitors with bactericidal anti-Hp properties. To improve their therapeutic indexes, we have now identified and tested 123 related compounds. We have first tested similar compounds available. Then we have designed, synthesized, and tested novel variants for affinity to flavodoxin, MIC for Hp, cytotoxicity, and bactericidal effect. Some are novel bactericidal inhibitors with therapeutic indexes of 9, 38 and 12, significantly higher than those of their corresponding leads. Developing novel Hp-specific antibiotics will help fighting Hp resistance and may have the advantage of not generally perturbing the bacterial flora.
Asunto(s)
Antibacterianos/síntesis química , Flavodoxina/antagonistas & inhibidores , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Antibacterianos/química , Antibacterianos/farmacología , Benzopiranos/síntesis química , Benzopiranos/química , Benzopiranos/farmacología , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Oxadiazoles/síntesis química , Oxadiazoles/química , Oxadiazoles/farmacología , Unión Proteica , Relación Estructura-Actividad , Estirenos/síntesis química , Estirenos/química , Estirenos/farmacologíaRESUMEN
The small chemical compound 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as an inhibitor of the phosphoinositide 3-kinase (PI3K). In the present study, we designed a novel synthesis of S14161 and prepared a series of its analogues via the oxa-Michael-Henry reaction in the presence of catalytic amounts of l-proline and triethylamine. Further structural simplification led to the identification of 6-bromo-8-ethoxy-3-nitro-2H-chromene (BENC-511) that exhibited potent antiproliferative activities against a panel of 12 tumor cell lines. Compared with S14161, BENC-511 was more potent in blocking the AKT phosphorylation and inducing cancer cell apoptosis. BENC-511 also displayed more potent effects on human umbilical vein epithelial cells (HUVEC) migration, suggesting its anti-angiogenesis activity.
Asunto(s)
Antineoplásicos/síntesis química , Benzopiranos/química , Benzopiranos/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Antineoplásicos/química , Antineoplásicos/toxicidad , Benzopiranos/farmacología , Sitios de Unión , Catálisis , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Células Endoteliales de la Vena Umbilical Humana , Humanos , Simulación del Acoplamiento Molecular , Neovascularización Fisiológica/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Piperazinas/química , Prolina/química , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
A series of 3,3-dimethyl-3Hbenzothieno[3,2-f][1]-benzopyran analogues modified at the pyran 1,2-double bond were synthesized. The corresponding dihydro and (+/-)-cis-diol derivatives were converted into diacetate and cyclic carbonate upon acylation. The title compounds were characterized by spectroscopic analysis and screened for their antimicrobial activity in vitro.
Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Benzopiranos/síntesis química , Benzopiranos/farmacología , Azufre/química , Antiinfecciosos/química , Benzopiranos/química , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Estructura MolecularRESUMEN
Three-component reaction of 1-(6-hydroxy-2-isopropenyl-1-benzofuran-yl)-1-ethanone, dialkyl acetylenedicarboxylates and isocyanides in water was described as efficient and green synthetic procedure for preparation of 9Hfuro[ 2,3-f]chromene-8,9-dicarboxylates in excellent yield. In these reactions, 1-(6-hydroxy-2-isopropenyl-1-benzofuranyl)- 1-ethanone was extracted from rhizomes of Petasites hybridus from northern Iran. The structure of this compound was determined by 1H, 13C-NMR and IR spectroscopy and confirmed by X-ray diffraction analysis. This procedure provides rapid access to novel and diversely substituted 9H-furo[2,3-f]chromene-8,9-dicarboxylate derivatives.
Asunto(s)
Benzopiranos/química , Cianuros/química , Extractos Vegetales/química , Benzopiranos/síntesis química , Ácidos Carboxílicos/síntesis química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Petasites/metabolismo , Rizoma/química , Agua/química , Difracción de Rayos XRESUMEN
By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family of tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H -chromene was chosen for its radical capture and ß-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine-4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-permeable properties.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Antioxidantes/síntesis química , Benzopiranos/síntesis química , Inhibidores de la Colinesterasa/síntesis química , Cromonas/síntesis química , Tacrina/análogos & derivados , Tacrina/síntesis química , Acetilcolinesterasa/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Animales , Antioxidantes/química , Antioxidantes/farmacología , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Benzopiranos/química , Benzopiranos/farmacología , Barrera Hematoencefálica/metabolismo , Butirilcolinesterasa/química , Dominio Catalítico , Bovinos , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Cromonas/química , Cromonas/farmacología , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Humanos , Membranas Artificiales , Permeabilidad , Relación Estructura-Actividad , Tacrina/química , Tacrina/farmacologíaRESUMEN
Targeting androgen receptor (AR) signaling with agents distinct from current antagonist drugs remains a rational approach to the prevention and treatment of prostate cancer (PCa). Our previous studies have shown that decursin and isomer decursinol angelate (DA), isolated from the Korean medicinal herb Angelica gigas Nakai, interrupt AR signaling and possess anti-PCa activities in vitro. In the LNCaP PCa cell model, these pyranoccoumarin compounds exhibit properties distinct from currently used antagonists (e.g., Casodex). However, both are rapidly de-esterified to decursinol, a partial AR agonist. We report here that a synthetic decursin analog, decursinol phenylthiocarbamate (DPTC), has greater in vivo stability than the parent compounds. DPTC-decursinol conversion was undetectable in mice. Furthermore, in LNCaP cells, DPTC decreased prostate specific antigen (PSA) expression, down-regulated AR abundance and mRNA and inhibited AR nuclear translocation. The effect of DPTC on AR and PSA mRNA and protein abundance was also observed in VCaP cells expressing wild type AR. DPTC inhibited growth of both PCa cell lines through G(1) cell cycle arrest and apoptosis, as did decursin and DA. Furthermore, i.p. administration of DPTC for 3 weeks suppressed the expression of AR target genes probasin and Nkx3.1 in mouse prostate glands. Overall, our data suggest that DPTC represents a prototype lead compound for development of in vivo stable and active novel decursin analogs for the prevention or therapy of PCa.
Asunto(s)
Antagonistas de Receptores Androgénicos/síntesis química , Antagonistas de Receptores Androgénicos/farmacología , Benzopiranos/farmacología , Butiratos/farmacología , Receptores Androgénicos/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Benzopiranos/síntesis química , Benzopiranos/química , Butiratos/síntesis química , Butiratos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Fase G1/efectos de los fármacos , Fase G1/genética , Humanos , Isotiocianatos/química , Masculino , Ratones , Ratones Endogámicos C57BL , Fenilcarbamatos/síntesis química , Fenilcarbamatos/química , Antígeno Prostático Específico/genética , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Mensajero/genética , Distribución Aleatoria , Receptores Androgénicos/genética , Transducción de Señal/genética , Tiocarbamatos/síntesis química , Tiocarbamatos/químicaRESUMEN
Function-oriented design and synthesis of chiral small molecules with novel activity is a key goal in modern organic chemistry. As multiple antibiotic-resistant pathogens are emerging and causing serious diseases, the need for practical routes for the development of new types of antibacterial agents is very urgent. Herein, we present a highly efficient process for the synthesis of optically active pyranocoumarins and 2-amino-4H-chromenes through an organocatalytic Knoevenagel/Michael/cyclization sequence, and the preliminary biological studies of these new heterocyclic compounds revealed potent antibacterial activity. This study provides a novel strategy for further research and development of new types of antibacterial agents effective against human pathogens.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Benzopiranos/síntesis química , Piranocumarinas/síntesis química , Aminas/química , Animales , Antibacterianos/síntesis química , Técnicas de Química Sintética , Ciclización , Evaluación Preclínica de Medicamentos/métodos , Eritrocitos/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Células HeLa/efectos de los fármacos , Humanos , Células Jurkat/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Pruebas de Toxicidad CrónicaRESUMEN
Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified. Evaluation of the structure-activity relationships of a substituent on this scaffold, with an emphasis on improving the pharmacokinetic profile led to the discovery of 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (23), which exhibited potent ACAT inhibitory activity (IC50=12 nM) and good pharmacokinetic profile in mice. Compound 23 also showed regressive effects on atherosclerotic plaques in apolipoprotein (apo)E knock out (KO) mice at a dose of 0.3 mg/kg per os (p.o.).