RESUMEN
A series of novel 1,3,4-oxadiazole-artemisinin hybrids have been designed and synthesized. An MTT assay revealed that most of tested hybrids showed more enhanced anti-proliferative activities than artemisinin, among which A8 had the superior potency with IC50 values ranging from 4.07 µM to 9.71 µM against five tested cancer cell lines. Cell colony formation assays showed that A8 could inhibit significantly more cell proliferation than artemisinin and 5-fluorouracil. Further mechanism studies reveal that A8 induces apoptosis and ferroptosis in MCF-7 cells in a dose-dependent manner, and CYPs inhibition assays reveal that A8 has a moderate inhibitory effect on CYP1A2 and CYP3A4 in the human body at 10 µM. The present work indicates that hybrid A8 may merit further investigation as a potential therapeutic agent.
Asunto(s)
Antineoplásicos , Artemisininas , Ferroptosis , Humanos , Células MCF-7 , Estructura Molecular , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Apoptosis , Artemisininas/farmacología , Proliferación Celular , Relación Estructura-Actividad , Línea Celular TumoralRESUMEN
A series of sulfonamides containing glucosamine moieties had been prepared and investigated for the inhibition of the zinc enzyme carbonic anhydrases (CAs, EC 4.2.1.1). Compared to their parent compound p-sulfamoylbenzoic acid, target compounds showed two order of magnitude improvement in their binding affinities against hCA II in vitro. Moreover, they also showed great selectivity toward hCA II enzyme with the ratios for inhibiting hCA II over hCA I in the range 20-96 and for inhibiting hCA II over hCA IX in the range 4.3-9. Due to the introduction of glucosamine moieties, all of compounds displayed good water solubility (in the range of 2.0-2.5%) and the pH values of the obtained solutions is neutral (7.0-7.2). Compared to the clinically available and relatively highly acidic dorzolamide (pH 5.5), target compounds are more likely to be less irritating to the eye when applied to topical glaucomatous drugs. Then, cytotoxicity evaluation suggested that all target compounds did not display any appreciable toxicity against human cornea epithelial cell. In addition, molecular docking studies elucidated the binding modes of those compounds toward hCA II. Collectively, these results suggest that target compounds represented a promising scaffold to treat glaucoma without major topical side effects.
Asunto(s)
Carbohidratos/farmacología , Anhidrasa Carbónica II/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/farmacología , Simulación del Acoplamiento Molecular , Sulfonamidas/farmacología , Carbohidratos/síntesis química , Carbohidratos/química , Anhidrasa Carbónica II/metabolismo , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
A series of saccharide-modified thiadiazole sulfonamide derivatives has been designed and synthesized by the "tail approach" and evaluated for inhibitory activity against carbonic anhydrases II, IX, and XII. Most of the compounds showed high topological polar surface area (TPSA) values and excellent enzyme inhibitory activity. The impacts of some compounds on the viability of HT-29, MDA-MB-231, and MG-63 human cancer cell lines were examined under both normoxic and hypoxic conditions, and they showed certain inhibitory effects on cell viability. Moreover, it was found that the series of compounds had the ability to raise the pH of the tumor cell microenvironment. All the results proved that saccharide-modified thiadiazole sulfonamides have important research prospects for the development of CA IX inhibitors.
Asunto(s)
Carbohidratos/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Tiadiazoles/síntesis química , Tiadiazoles/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células HT29 , Humanos , Simulación del Acoplamiento Molecular , Microambiente Tumoral/efectos de los fármacosRESUMEN
p21 activated kinase 4 (PAK4), which belongs to the serine/threonine (Ser/Thr) protein kinase family, is a representative member of the PAK family and plays a significant role in multiple processes associated with cancer development. In this study, structure-based virtual screening was performed to discover novel and selective small molecule scaffolds, and a 6-hydroxy-2-mercapto-3-phenylpyrimidin-4(3H)-one-based compound (SPU-106, 14#) was identified as an effective PAK4 inhibitor. By combining both a molecular docking study and molecular dynamics (MD) simulation strategies, the binding mode was determined in the PAK4 site. The SPU-106 compound could efficiently and selectively bind to the PAK4 kinase domain at an IC50 of 21.36⯵M according to the kinase analysis. The designed molecular probe demonstrated that SPU-106 binds to the kinase domain in the C-terminus of PAK4. Further investigation revealed that the SPU-106 had a strong inhibitory effect on the invasion of SGC7901 cells but without any cytotoxicity. The western blot analysis indicated that the compound potently inhibited the PAK4/LIMK1/cofilin and PAK4/SCG10 signaling pathways. Thus, our work shows the successful application of computational strategies for the discovery of selective hits, and SPU-106 may be an effective PAK4 inhibitor for further development as an antitumor agent.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinonas/química , Pirimidinonas/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Quinasas p21 Activadas/antagonistas & inhibidores , Movimiento Celular , Proliferación Celular , Ensayos Analíticos de Alto Rendimiento , Humanos , Isoenzimas , Estructura Molecular , Transducción de Señal , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/patología , Relación Estructura-Actividad , Células Tumorales Cultivadas , Quinasas p21 Activadas/química , Quinasas p21 Activadas/metabolismoRESUMEN
Selective estrogen receptor modulators (SERMs) act as either agonist or antagonist of estrogen receptor (ER) in a tissue selective manner and have been used in several diseases such as breast cancer, postmenopausal syndrome, osteoporosis, and cardiovascular diseases. However, current SERMs may also increase the risk of serious side effects and trigger drug resistance. Herein, a screening program, that was designed to search for novel SERMs, resulted in the identification of a series of 2-arylbenzofuran-containing compounds that are ligands for ERα, when applying the Gaussia-luciferase reporter assay. One of these compounds, 10-dehydrooxyglycyuralin E (T9) was chemically synthesized. T9 showed anti-estrogenic/proliferative activity in ERα-positive breast cancer cells. Pretreatment of T9 prevented the mRNA expression of GREB1, which is an estrogen response gene. Furthermore, by an in silico docking simulation study we demonstrated that T9 showed interactions directly to ERα. Taken together, these results demonstrated that T9 is a candidate of SERMs and a useful seed compound for the foundation of the selective activity of SERMs.
Asunto(s)
Benzofuranos/farmacología , Receptor alfa de Estrógeno/agonistas , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Benzofuranos/síntesis química , Benzofuranos/química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/química , Relación Estructura-ActividadRESUMEN
ß-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). ß-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the ß-arrestin-dependent signals downstream of a single GPCR have emerged, which can be used to selectively modulate GPCR signal transduction in such a way that desirable signals are enhanced to produce therapeutic effects while undesirable signals of the same GPCR are suppressed to avoid side effects. In the present study, we evaluated agonist bias for compounds developed along a drug discovery project of ß2-adrenoceptor agonists. About 150 compounds, including derivatives of fenoterol, 2-amino-1-phenylethanol and 2-amino-2-phenylethanol, were obtained or synthesized, and initially screened for their ß-adrenoceptor-mediated activities in the guinea pig tracheal smooth muscle relaxation assay or the cardiomyocyte contractility assay. Nineteen bioactive compounds were further assessed using both the HTRF cAMP assay and the PathHunter ß-arrestin assay. Their concentration-response data in stimulating cAMP synthesis and ß-arrestin recruitment were applied to the Black-Leff operational model for ligand bias quantitation. As a result, three compounds (L-2, L-4, and L-12) with the core structure of 5-(1-amino-2-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one were identified as a new series of ß-arrestin-biased ß2-adrenoceptor agonists, whereas salmeterol was found to be Gs-biased. These findings would facilitate the development of novel drugs for the treatment of both heart failure and asthma.
Asunto(s)
Agonistas Adrenérgicos beta/uso terapéutico , Etanolaminas/uso terapéutico , beta-Arrestinas/metabolismo , Agonistas Adrenérgicos beta/síntesis química , Animales , Broncodilatadores/síntesis química , Broncodilatadores/uso terapéutico , Células CHO , Cricetulus , Descubrimiento de Drogas , Etanolaminas/síntesis química , Cobayas , Células HEK293 , Humanos , Ligandos , Masculino , Tráquea/efectos de los fármacosRESUMEN
To find novel human carbonic anhydrase (hCA) inhibitors, we synthesized thirteen compounds by combining thiazolidinone with benzenesulfonamide. The result of the X-ray single-crystal diffraction experiment confirmed the configuration of this class of compounds. The enzyme inhibition assays against hCA II and IX showed desirable potency profiles, as effective as the positive controls. The docking studies revealed that compounds (2) and (7) efficiently bound in the active site cavity of hCA IX by forming sufficient interactions with active site residues. The fragment of thiazolidinone played an important role in the binding of the molecules to the active site.
Asunto(s)
Antígenos de Neoplasias , Anhidrasa Carbónica II , Anhidrasa Carbónica IX , Inhibidores de Anhidrasa Carbónica , Simulación del Acoplamiento Molecular , Sulfonamidas , Antígenos de Neoplasias/química , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/química , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasa Carbónica IX/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Dominio Catalítico , Humanos , Sulfonamidas/síntesis química , Sulfonamidas/química , BencenosulfonamidasRESUMEN
Based on the structural scaffolds of natural products, two series of flavonoid derivatives, for a total of twelve compounds, were designed and synthesized as potential human telomerase inhibitors. Using a modified TRAP-PCR assay, compound 5c exhibited the most potent inhibitory activity against human telomerase with an IC50 value of less than 50 µM. In vitro, the results demonstrated that compound 5c had potent anticancer activity against five classes of tumor cell lines. The molecular docking and molecular dynamics analyses binding to the human telomerase holoenzyme were performed to elucidate the binding mode of active compound 5c. This finding helps the rational design of more potent telomerase inhibitors based on the structural scaffolds of natural products.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Flavonoides/síntesis química , Flavonoides/farmacología , Simulación del Acoplamiento Molecular , Telomerasa/antagonistas & inhibidores , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Flavonoides/química , Humanos , Concentración 50 Inhibidora , Ligandos , Telomerasa/metabolismoRESUMEN
In an attempt to arrive at a more potent antitumor agent than the parent natural saponin hederacolchiside A1, 23 hederacolchiside A1 derivatives (4a-4w) were synthesized via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition and screened in vitro for cytotoxicity against six human cancer cell lines. The structure-activity relationship of these compounds was elucidated, and the biological screening results showed that most of the compounds exhibited moderate to high levels of antitumor activities against the tested cell lines and some of them displayed more potent inhibitory activities compared with hederacolchiside A1. Compound 4f showed a 2- to 7-fold more potent activity than hederacolchiside A1. The mechanistic study of 4f revealed that this compound can induce cell apoptosis in HepG2 cells via mitochondrial-mediated intrinsic pathways.
Asunto(s)
Antineoplásicos/farmacología , Saponinas/farmacología , Triazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estructura Molecular , Saponinas/síntesis química , Saponinas/química , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
A series of novel N-substituted-ß-d-glucosamine derivatives that incorporate benzenesulfonamides were designed using a fragment-based drug design strategy. Each derivative was synthesized and evaluated in vitro for its inhibitory activity against human carbonic anhydrase (hCA) IX; several derivatives displayed desirable potency profiles against this enzyme. The molecular docking studies provided the design rationale and predicted potential binding modes for carbonic anhydrase (CA) IX and three target compounds, including the most potent inhibitor, compound 7f (IC50 = 10.01 nM). Moreover, the calculated Log P (cLog P) values showed that all the compounds tended to be hydrophilic. In addition, topological polar surface area (TPSA) value-based predictions highlighted the selectivity of these carbohydrate-based inhibitors for membrane-associated CA IX.
Asunto(s)
Anhidrasa Carbónica IX/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/farmacología , Galactosamina/análogos & derivados , Glucosamina/análogos & derivados , Sulfonamidas/síntesis química , Antígenos de Neoplasias/metabolismo , Anhidrasa Carbónica IX/metabolismo , Diseño de Fármacos , Galactosamina/síntesis química , Galactosamina/química , Galactosamina/farmacología , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , BencenosulfonamidasRESUMEN
AIM: Aberrant c-Met activation plays a critical role in cancer formation, progression and dissemination, as well as in development of resistance to anticancer drugs. Therefore, c-Met has emerged as an attractive target for cancer therapy. The aim of this study was to develop new c-Met inhibitors and elaborate the structure-activity relationships of identified inhibitors. METHODS: Based on the predicted binding modes of Compounds 5 and 14 in docking studies, a new series of c-Met inhibitor-harboring 3-((1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)imidazo[1,2-a]pyridine scaffolds was discovered. Potent inhibitors were identified through extensive optimizations combined with enzymatic and cellular assays. A promising compound was further investigated in regard to its selectivity, its effects on c-Met signaling, cell proliferation and cell scattering in vitro. RESULTS: The most potent Compound 31 inhibited c-Met kinase activity with an IC50 value of 12.8 nmol/L, which was >78-fold higher than those of a panel of 16 different tyrosine kinases. Compound 31 (8, 40, 200 nmol/L) dose-dependently inhibited the phosphorylation of c-Met and its key downstream Akt and ERK signaling cascades in c-Met aberrant human EBC-1 cancer cells. In 12 human cancer cell lines harboring different background levels of c-Met expression/activation, Compound 31 potently inhibited c-Met-driven cell proliferation. Furthermore, Compound 31 dose-dependently impaired c-Met-mediated cell scattering of MDCK cells. CONCLUSION: This series of c-Met inhibitors is a promising lead for development of novel anticancer drugs.
Asunto(s)
Antineoplásicos/química , Imidazoles/química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridinas/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Perros , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Enlace de Hidrógeno , Imidazoles/síntesis química , Imidazoles/farmacología , Células de Riñón Canino Madin Darby , Simulación del Acoplamiento Molecular , Piridinas/síntesis química , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
Gastric cancer, which is the most common malignant gastrointestinal tumor, has jumped to the third leading cause of cancer-related mortality worldwide. It is of great importance to identify novel and potent drugs for gastric cancer treatment. P21-activated kinase 4 (PAK4) has emerged as an attractive target for the development of anticancer drugs in consideration of its vital functions in tumorigenesis and progression. In this paper, we reported that GL-1196, as a small molecular compound, effectively suppressed the proliferation of human gastric cancer cells through downregulation of PAK4/c-Src/EGFR/cyclinD1 pathway and CDK4/6 expression. Moreover, GL-1196 prominently inhibited the invasion of human gastric cancer cells in parallel with blockage of the PAK4/LIMK1/cofilin pathway. Interestingly, GL-1196 also inhibited the formation of filopodia and induced cell elongation in SGC7901 and BGC823 cells. Taken together, these results provided novel insights into the potential therapeutic strategy for gastric cancer.
Asunto(s)
Antineoplásicos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Neoplasias Gástricas/metabolismo , Quinasas p21 Activadas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Invasividad Neoplásica , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/tratamiento farmacológicoRESUMEN
ß2-Adrenoceptor agonists are highly effective bronchodilators and are widely used in the treatment of both chronic obstructive pulmonary disease (COPD) and asthma. In the last 15 years, there has been great interest within the pharmaceutical industry in the discovery of a long ß2-adrenoceptor agonist for a mono-therapy or combination therapy. The search for new long-acting ß2-adrenoreceptor agonists (LABA's), for the treatment of asthma and COPD, has become a very active area of drug discovery. This article reviews the mechanisms, potential candidates and research advances of long ß2-adrenoceptor agonists.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/farmacología , Broncodilatadores/farmacología , Asma/tratamiento farmacológico , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores AdrenérgicosRESUMEN
All-trans-retinoic acid (ATRA) as a physiological metabolite of vitamin A is widely applied in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. CYP26A1 enzyme, induced by ATRA in liver and target tissues, metabolizes ATRA into 4-hydroxyl-RA. Inhibition of CYP26A1 metabolic enzyme represents a promising strategy for discovery of new specific anticancer agents. Herein, we describe the design, synthesis and biological evaluation of a series of new amide imidazole derivatives as retinoic acid metabolism blocking agents (RAMBAs) toward CYP26A1 enzyme. First, based on the recent theoretical models (Sun et al., J. Mol. Graph. Model., 2015, 56, 10-19) a series of RAMBAs with novel scaffolds were designed using fragment-based drug discovery approach. Subsequently, the new RAMBAs were synthesized and evaluated for their biological activities. All the compounds demonstrated appropriate enzyme activities and cell activities. The promising inhibitors 20 and 23 with IC50 value of 0.22 µM and 0.46 µM toward CYP26A1, respectively, were further evaluated for CYP selectivity and the metabolic profile of ATRA. Both compounds 20 and 23 showed higher selectivity for CYP26A1 over other CYPs (CYP2D6, CYP3A4) when compared to liarozole. They also showed better inhibitory activities for the metabolism of ATRA when also compared to liarozole. These studies further validated the pharmacophore and structure-activity relationship models obtained about CYP26A1 inhibitors and highlighted the promising activities of the new series of CYP26A1 inhibitors designed from such models. They also paved the way for future development of those candidates as potential drugs.
Asunto(s)
Amidas/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Diseño de Fármacos , Imidazoles/farmacología , Amidas/síntesis química , Amidas/química , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450/síntesis química , Inhibidores Enzimáticos del Citocromo P-450/química , Relación Dosis-Respuesta a Droga , Células HL-60 , Humanos , Imidazoles/síntesis química , Imidazoles/química , Modelos Moleculares , Estructura Molecular , Ácido Retinoico 4-Hidroxilasa , Relación Estructura-ActividadRESUMEN
AIM: To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors. METHODS: Based on the prototype model inhibitor 1, four ligands with subtle differences in the fused aromatic rings were synthesized. Quantum chemistry was employed to calculate the binding free energy for each ligand. Symmetry-adapted perturbation theory (SAPT) was used to decompose the binding energy into several fundamental forces to elucidate the determinant factors. RESULTS: Binding free energies calculated from quantum chemistry were correlated well with experimental data. SAPT calculations showed that the predominant driving force for binding was derived from a sandwich π-π interaction with Tyr-1230. Arg-1208 was the differentiating factor, interacting with the 6-position of the fused aromatic ring system through the backbone carbonyl with a force pattern similar to hydrogen bonding. Therefore, a hydrogen atom must be attached at the 6-position, and changing the carbon atom to nitrogen caused unfavorable electrostatic interactions. CONCLUSION: The theoretical studies have elucidated the determinant factors involved in the binding of type I inhibitors to c-Met.
Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Teoría Cuántica , Enlace de Hidrógeno , Ligandos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/metabolismo , Electricidad EstáticaRESUMEN
The first chemical synthesis of the natural triterpenoid saponin Patrinia-glycoside B-II, namely oleanolic acid 3-O-α-L-rhamnopyranosyl-(1â2)-[ß-D-gluco-pyranosyl-(1â3)]-α-L-arabinopyranoside, has been accomplished in a linear 11-step sequence 11 with 9.4% overall yield. The abnormal 1C4 conformation of the arabinose residue was found to occur via conformational fluctuation during preparation of the intermediates. Molecular mechanism and quantum chemistry calculations showed that Patrinia-glycoside B-II and its conformer 1 cannot interconvert under normal conditions. Preliminary structure-activity relationships studies indicated that the 4C1 chair conformation of the arabinose residue in the unique α-L-rhamnopyranosyl-(1â2)-α-L-arabinopyranosyl disaccharide moiety is one of the chief positive factors responsible for its cytotoxic activity against tumors.
Asunto(s)
Glicósidos/síntesis química , Patrinia/química , Saponinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas Químicas Combinatorias , Glicósidos/toxicidad , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Ácido Oleanólico/química , Triterpenos/químicaRESUMEN
Carbonic anhydrase IX (CA IX) is a tumor associated protein which is able to be a potent anticancer target, since it is highly expressed in a multitude of carcinomas, while it is present in a limited number of normal tissues. This review focuses on its role in tumor physiology, the most recent three dimensional structure features of this enzyme which has recently been elucidated. In addition, we present recent advances in the development of small inhibitors able to target CA IX for therapeutic applications.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Antineoplásicos/uso terapéutico , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Anhidrasas Carbónicas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Antineoplásicos/química , Anhidrasa Carbónica IX , Inhibidores de Anhidrasa Carbónica/química , HumanosRESUMEN
A series of phthalazine ketone compounds were synthesized and the structures were confirmed by H NMR and HR-MS spectrum. All target compounds were obtained through 7 steps, including selective reduction, nitration, bromination, ring enlargement, reduction, Knoevenagel and acylated reaction. The compounds were evaluated for their immunosuppressive effects of T-cell proliferation and inhibitory activity of IMPDH type II in vitro, as well as their structure-activity relationship were assessed. Several compounds exhibited strong immunosuppressive properties, especially compounds 7f and 7h, with IC50 values of 0.093 micromol x L(-1) and 0.14 micromol x L(-1) respectively, which were superior to mycophenolic acid. The information obtained from the studies may be useful for further research on the immunosuppressive agents.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Inmunosupresores/síntesis química , Ftalazinas/síntesis química , Animales , Femenino , IMP Deshidrogenasa/metabolismo , Inmunosupresores/química , Inmunosupresores/farmacología , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Ftalazinas/química , Ftalazinas/farmacología , Bazo/citología , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacosRESUMEN
Twenty-four diosgenyl saponins bearing cinnamoyl, carbamido and thiosemicarbazone groups were synthesized concisely. The cytotoxicities of the synthetic compounds on six human caner cell lines were evaluated employing MTT method. Structure-activity relationship could be observed, and two of the synthesized compounds (5c and 5f) exhibited selective inhibition on HeLa and MCF-7 cells, while three of them (5d, 5f and 5h) showed strong inhibition against HT1080.
Asunto(s)
Saponinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Saponinas/síntesis química , Saponinas/toxicidad , Relación Estructura-Actividad , Tiosemicarbazonas/química , Urea/químicaRESUMEN
In this study, a new series of bis-benzimidazole derivatives were designed and synthesized. Most of these new compounds showed significant anti-tumor activity in vitro compared to Hoechst 33258. Among them, the most potent compound 8 had the IC(50) values of 0.56µM for HL60 (Human promyelocytic leukemia cells) tumor cell line and 0.58µM for U937 (Human leukemic monocyte lymphoma cells) tumor cell line. Subsequent toxicity study on human peripheral blood mononuclear cells (PBMC) showed that compound 8 exhibited less toxicity than 5-FU. We also found that apoptosis and autophagy were simultaneously induced by compound 8 in HL60 cells, and inhibition of autophagy by 3-MA decreased compound 8-induced apoptosis, indicating that they acted in synergy to exert tumor cell death.