RESUMEN
A library of new quinazoline pharmacophores bearing benzenesulfonamide moiety was designed and synthesized. Compounds 3a-n were screened for their in vitro antimicrobial activity against eight multidrug-resistant clinical isolates. Compounds 3d and 3n exhibited prominent antibacterial activity, specifically against MRSA. After exhibiting relative in vitro and in vivo safety, compound 3n was selected to assess its anti-inflammatory activity displaying promising COX-2 inhibitory activity compared to Ibuprofen. In vivo experimental MRSA pneumonia model was conducted on immunodeficient (irradiated) mice to reveal the antimicrobial and anti-inflammatory responses of compound 3n compared to azithromycin (AZ). Treatment with compound 3n (10 and 20 mg/kg) as well as AZ resulted in a significant decrease in bacterial counts in lung tissues, suppression of serum C-reactive protein (CRP), lung interleukin-6 (IL-6), myeloperoxidase activity (MPO) and transforming growth factor-ß (TGF-ß). Compound 3n showed a non-significant deviation of lung TGF-ß1 from normal values which in turn controlled the lung inflammatory status and impacted the histopathological results. Molecular docking of 3n showed promising interactions inside the active sites of TGF-ß and COX-2. Our findings present a new dual-target quinazoline benzenesulfonamide derivative 3n, which possesses significant potential for treating MRSA-induced pneumonia in an immunocompromised state.
Asunto(s)
Antibacterianos , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Quinazolinas , Sulfonamidas , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Animales , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Ratones , Quinazolinas/farmacología , Quinazolinas/química , Quinazolinas/síntesis química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Estructura Molecular , Relación Estructura-Actividad , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Neumonía Estafilocócica/tratamiento farmacológicoRESUMEN
In a search for new anticancer agents with better activity and selectivity, the present work described the synthesis of several new series of sulfachloropyridazine hybrids with thiocarbamates 3a-e, thioureids 4a-h, 5a-e and 4-substituted sulfachloropyridazines 6a, b, 7a, b and 8. The synthesized compounds were screened in vitro against a panel of 60 cancer cell lines in one dose assay. The most potent derivatives 3a, 3c, 4c, 4d, 5e, 7a and 7b were tested for their antiangiogenic activity by measuring their ability to inhibit VEGFR-2. The most potent compounds in VEGFR-2 inhibitory assay were further evaluated for their ability to inhibit PDGFR. In addition, the ability of 4c compound to inhibit cell migration on HUVEC cells and cell cycle effect on UO-31 cells has been studied. The pro-apoptotic effect of compound 4c was studied by the evaluation of caspase-3, Bax and BCl-2. Alternatively, the IC50 of compounds 3a, 3c, 4c, 5e, 7a and 7b against certain human cancer cell lines were determined. Re-evaluation in combination with γ-radiation was carried out for compounds 4c, 5e and 7b to study the possible synergistic effect on cytotoxicity. Docking studies of the most active compounds were performed to give insights into the binding mode within VEGFR-2 active site.
Asunto(s)
Inhibidores de la Angiogénesis , Antineoplásicos , Apoptosis , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Relación Estructura-Actividad , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Relación Dosis-Respuesta a Droga , Piridazinas/farmacología , Piridazinas/química , Piridazinas/síntesis química , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacosRESUMEN
A set of novel N-substituted-2-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)thio)acetamide 3-16 were designed and synthesized from 2-mercapto-3-phenylquinazolinone 2. The targeted compounds were screened for their cytotoxic activity against the hepatocellular carcinoma cell line HepG-2. Compounds 8, 9, 10, and 11 with IC50 values of 1.11, 4.28, 5.70, and 4.69 µM, respectively, showed 5.7- to 28-fold higher activities than the positive control doxorubicin (IC50 32.02 µM). Furthermore, compounds 8 and 9 were tested for EGFR inhibitory activity and demonstrated IC50 values of 73.23 and 58.26 µM, respectively, when compared to erlotinib's IC50 value of 9.79 µM. The most potent compounds, 8 and 9, were subjected to a single dose of 8 Gy of γ-radiation, and their cytotoxic efficacy was found to increase after irradiation, demonstrating the synergistic effect of γ-irradiation. Molecular docking was adopted for the most active compounds to confirm their mode of action.
Asunto(s)
Antineoplásicos , Carcinoma , Humanos , Quinazolinonas/farmacología , Simulación del Acoplamiento Molecular , Receptores ErbB , Modelos Moleculares , Antineoplásicos/farmacología , Estructura Molecular , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular , Línea Celular TumoralRESUMEN
Herein, we report the synthesis of a series of new quinazoline sulfonamide conjugates 2-16 and their evaluation as potential anticancer agents via dual targeting of EGFRT790M and VEGFR-2. The newly synthesized compounds were designed based on the structure requirements of the target receptors and were confirmed using spectral data. The compounds were evaluated for their cytotoxicity against four cancer cell lines (HepG2, MCF-7, HCT116 and A549) using MTT assay. The most active compounds were further evaluated for their inhibitory activity against EGFRT790M and VEGFR-2. Compound 15 showed the most significant cytotoxic activity with IC50 = 0.0977 µM against MCF-7 and the most potent inhibitory activity against both EGFR and VEGFR with IC50 = 0.0728 and 0.0523 µM, respectively. Compound 15 was able to induce apoptosis in MCF-7 cells and cell cycle arrest at the G2/M phase. The relative safety profile of 15 was assessed using HEK-293 normal cell line and an ADMET profile was carried out. Radiosensitizing evaluation of 15 proved its significant ability to sensitize the cancer cell to the effect of radiation after being subjected to a single dose of 8 Gy gamma irradiation. Molecular docking studies revealed that 15 could bind to the ATP-binding site of EGF and VEGF receptors, inhibiting their activity.
Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Humanos , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Receptores ErbB , Células HEK293 , Simulación del Acoplamiento Molecular , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/farmacología , SulfanilamidaRESUMEN
Novel series of aminopyrimidines bearing a biologically active cyclohexenone 3a-f and oxo-selaneylidene moiety 4, besides selenadiazolopyrimidines (5a-e and 7), were synthesised using 5,6-diaminouracils as starting materials. Compound 3a exhibited strong anti-proliferative activity against three cell lines: HepG-2 (IC50 14.31 ± 0.83 µM), A-549 (IC50 30.74 ± 0.76 µM), and MCF-7 (IC50 27.14 ± 1.91 µM). Also, it was four times more selectively cytotoxic against WI-38 cell lines than doxorubicin. Furthermore, Topoisomerase II (IC50 4.48 ± 0.65 µM) and HSP90 (IC50 1.78 ± 0.11 µM) were both strongly inhibited in vitro by 3a. The cell cycle was halted at the G1-S phase, and total apoptotic cells were 65 times more than control Hep-G2 cells. Besides, it increased caspase-3 gene expression, triggering mitochondrial cell death. Molecular docking study indicated that it could bind to Topoisomerase II and HSP90 binding sites in an inhibitory mode. Its geometric properties were investigated using the density functional theory (DFT). Furthermore, compound 3a demonstrated in silico good oral bioavailability.
Asunto(s)
Antineoplásicos , Proteínas HSP90 de Choque Térmico , Pirimidinas , Inhibidores de Topoisomerasa II , Pirimidinas/síntesis química , Pirimidinas/farmacología , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Células Hep G2 , Células A549 , Células MCF-7 , Humanos , Proliferación Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Simulación por Computador , Antineoplásicos/síntesis química , Antineoplásicos/farmacologíaRESUMEN
A new series of 4-((7-methoxyquinolin-4-yl) amino)-N-(substituted) benzenesulfonamide 3(a-s) was synthesized via the reaction of 4-chloro-7-methoxyquinoline 1 with various sulfa drugs. The structural elucidation was verified based on spectroscopic data analysis. All the target compounds were screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, and unicellular fungi. The results revealed that compound 3l has the highest effect on most tested bacterial and unicellular fungal strains. The highest effect of compound 3l was observed against E. coli and C. albicans with MIC = 7.812 and 31.125 µg/mL, respectively. Compounds 3c and 3d showed broad-spectrum antimicrobial activity, but the activity was lower than that of 3l. The antibiofilm activity of compound 3l was measured against different pathogenic microbes isolated from the urinary tract. Compound 3l could achieve biofilm extension at its adhesion strength. After adding 10.0 µg/mL of compound 3l, the highest percentage was 94.60% for E. coli, 91.74% for P. aeruginosa, and 98.03% for C. neoformans. Moreover, in the protein leakage assay, the quantity of cellular protein discharged from E. coli was 180.25 µg/mL after treatment with 1.0 mg/mL of compound 3l, which explains the creation of holes in the cell membrane of E. coli and proves compound 3l's antibacterial and antibiofilm properties. Additionally, in silico ADME prediction analyses of compounds 3c, 3d, and 3l revealed promising results, indicating the presence of drug-like properties.
Asunto(s)
Antiinfecciosos , Infecciones Urinarias , Escherichia coli , Relación Estructura-Actividad , Pruebas de Sensibilidad Microbiana , Antiinfecciosos/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Sulfanilamida/farmacología , Sulfonamidas/farmacología , Hongos , BiopelículasRESUMEN
We synthesised a new series of sulphonamide-bearing quinazolinone derivatives 5-18 and evaluated their in vitro cytotoxicity in various cancer cell lines (A549, HepG-2, LoVo and MCF-7) and in normal human cells (HUVEC). Compounds 6 and 10 exhibited the higher activity against all the cancer cell lines compared with 5-flourourcil as positive control. The ability of the most promising compounds 6 and 10 to induce cell cycle arrest and apoptosis in breast cancer (MCF-7) cells was evaluated by flow cytometry. Reverse transcriptase-polymerase chain reaction and western blotting were used to evaluate the expression of apoptosis-related markers. We found that the 2-tolylthioacetamide derivative 6 and the 3-ethyl phenyl thioacetamide derivative 10 exhibited cytotoxic activity comparable to that of 5-fluorouracil as reference drug in MCF-7 and LoVo colon cancer cells. Cell cycle analysis showed a concentration-dependent accumulation of cells in the sub-G1 phase upon treatment with both compounds. The Annexin V-fluorescein isothiocyanate/propidium iodide assay showed that the compounds 6 and 10 increased the early and late apoptosis cell death modes in a dose-dependent manner. These compounds downregulated the expression of B-cell lymphoma-2 (Bcl-2), while increasing that of p53, Bcl-2-like protein 4, and caspase-7, at the mRNA and protein levels. Molecular docking of compounds 6 and 10 with Bcl-2 predicted them to show moderate - high binding affinity (6: -7.5 kcal/mol, 10: -7.9 kcal/mol) and interactions with key central substrate cavity residues. Overall, compounds 6 and 10 were found to be promising anticancer and apoptosis-inducing agents.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Quinazolinonas/farmacología , Sulfonamidas/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 , Estructura Molecular , Quinazolinonas/síntesis química , Quinazolinonas/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
Many quinazoline derivatives with pharmacological properties, such as anticancer activity, have been synthesized. Fourteen quinazoline derivatives bearing a substituted sulfonamide moiety (4a-n) were previously synthesized and fully characterized. These compounds exerted antiproliferative activity against cell lines derived from solid tumors. Herein, the antileukemic activities of these compounds (4a-n) against two different leukemia cell lines (Jurkat acute T cell and THP-1 acute monocytic) were investigated. Our investigation included examining their activity in vivo in a zebrafish embryo model. Remarkably, compounds 4a and 4d were the most potent in suppressing cell proliferation, with an IC50 value range of 4-6.5 µM. Flow cytometry analysis indicated that both compounds halted cell progression at the G2/M phase and induced apoptosis in a dose-dependent manner. RT-PCR and Western blot analyses also showed that both compounds effectively induced apoptosis by upregulating the expression of proapoptotic factors while downregulating that of antiapoptotic factors. In vivo animal toxicity assays performed in zebrafish embryos indicated that compound 4d was more toxic than compound 4a, with compound 4d inducing multiple levels of teratogenic phenotypes in zebrafish embryos at a sublethal concentration. Moreover, both compounds perturbed the hematopoiesis process in developing zebrafish embryos. Collectively, our data suggest that compounds 4a and 4d have the potential to be used as antileukemic agents.
Asunto(s)
Antineoplásicos , Leucemia , Animales , Antineoplásicos/farmacología , Línea Celular , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Hematopoyesis , Humanos , Estructura Molecular , Quinazolinas/farmacología , Relación Estructura-Actividad , Sulfonamidas/farmacología , Pez CebraRESUMEN
In order to investigate for a new effective and safe anticancer drug, we synthesized a novel series of quinazoline containing biologically active substituted-sulfonamide moiety at 3- position 4a-n. The structure of the newly prepared compounds was proved by microanalysis, IR, 1H-NMR, 13C-NMR and mass spectral data. All the synthesized compounds were evaluated for their in vitro cytotoxic activity in numerous cancer cell lines including A549, HepG-2, LoVo and MCF-7 and normal HUVEC cell line. The two most active compounds 4d and 4f were then tested for their apoptosis induction using DNA content and Annexin V-FITC/PI staining. Moreover, apoptosis initiation was also confirmed using RT-PCR and Western blot. To further understand the binding preferences of quinazoline sulfonamides, docking simulations were used. Among the fourteen new synthesized compounds, we found that compounds 4d and 4f exerted the strongest cytotoxicity against MCF-7 cells with an IC50 value of 2.5 and 5 µM, respectively. Flow cytometry data revealed the ability of compounds 4d and 4f to mediate apoptosis and arrest cell cycle growth at G1 phase. Furthermore, RT-PCR and Western blot results suggested that both 4d and 4f activates apoptotic cell death pathway in MCF-7 cells. Molecular docking assessments indicated that compounds 4d and 4f fit perfectly into Bcl2's active site. Based on the biological properties, we conclude that both compounds 4d and 4f could be used as a new type of anticancer agent, which provides a scientific basis for further research into the treatment of cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quinazolinas/farmacología , Sulfonamidas/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Humanos , Técnicas In Vitro , Simulación del Acoplamiento Molecular , Quinazolinas/químicaRESUMEN
Twenty new quinazolinone derivatives bearing a piperonyl moiety were designed and synthesized. The structures of the target compounds were in agreement with the microanalytical and spectral data. Compounds 4-10, 13, 14 and 17-27 were screened for their cytotoxic activity against HepG-2 and MCF-7 cancer cell lines. The target compounds showed IC50 in the range of 2.46-36.85 µM and 3.87-88.93 µM for HepG-2 and MCF-7, respectively. The promising compounds 7, 19, 26 and 27 were selected to measure their EGFR inhibitory activity. The IC50 values of the promising compounds were in the range of 146.9-1032.7 nM for EGFR in reference to Erlotinib (IC50 = 96.6 nM). In further studies on compounds 7, 19, 26 and 27 using HepG-2 cell line, there was significant overexpression of p21 and downregulation of two members of IAPs protein family; Survivin and XIAP, relative to their controls. Annexin V-FITC and caspase-3 analyses have established a significant increase in early apoptosis. Moreover, the four selected compounds have impaired cell proliferation by cell cycle arrest at the G2/M phase compared to their respective control. Considering radiotherapy as the primary treatment for many types of solid tumors, the radiosensitizing abilities of compounds 7, 19, 26 and 27 were measured against HepG-2 and MCF-7 cell lines combined with a single dose of 8 Gy gamma radiation. Measurement of the IC50 of the promising compounds after irradiation revealed their ability to sensitize the cells to the lethal effect of gamma irradiation (IC50 = 1.56-4.32 µM and 3.06-5.93 µM for HepG-2 and MCF-7 cells, respectively). Molecular docking was performed to gain insights into the ligand-binding interactions of 7, 19, 26 and 27 inside the EGFR binding sites and revealed their essential interactions, explaining their good activity towards EGFR.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Quinazolinonas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Quinazolinonas/síntesis química , Quinazolinonas/metabolismo , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/metabolismo , Sulfonamidas/farmacología , Survivin/antagonistas & inhibidores , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidoresRESUMEN
Reactive oxygen species (ROS) play an integral role in the pathogenesis of most diseases. This work presents the design and synthesis of fourteen new diiodoquinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail and evaluation of their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) using its classical target NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The N-(2-chloropyridin-3-yl)-2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio) acetamide 17 was the most potent NQO1 inducer (CD = 25 µM) with free radical scavenging activity (IC50 = 28 µM) and in vivo median lethal dose (LD50) of 500 mg/Kg. The possible radioprotective activity of compound 17 was evaluated in (7 Gy) irradiated mice. Compound 17 showed a reduction in radiation induced oxidative stress as evidenced by the lower levels of ROS, malondialdehyde (MDA) and NQO1 in liver tissues. Moreover, compound 17 showed improvement in the complete blood count (CBC) of irradiated mice and decreased mortality over 30 days following irradiation. Additionally, docking studies inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, confirmed that 17 revealed the same interactions with the key amino acids as those of the co-crystallized ligand. This study identifies 17 as a novel antioxidant that protects against the harmful effect of radiation.
Asunto(s)
Antioxidantes/farmacología , Quinazolinonas/farmacología , Sulfonamidas/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Relación Dosis-Respuesta a Droga , Halogenación , Humanos , Estructura Molecular , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo/efectos de los fármacos , Quinazolinonas/síntesis química , Quinazolinonas/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
A library of iodoquinazolinones endowed with benzenesulfonamide moiety was designed and synthesized as human carbonic anhydrase (hCA) inhibitors. Compounds 4-17 showed generally poor activity against the cytosolic hCA I and hCA II isoforms. Contrarily they were more potent and showed a variable spectrum of selectivity against the tumor-specific isoforms hCA IX and hCA XII. The 4-iodophenyl derivative 12 and the 4-pyridinyl derivative 15 were the most active and selective in this series against hCA IX and hCA XII isoforms with KI of 18 and 9 nM, respectively. Compounds 12 and 15 were further screened for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines besides WI38 and MCF-10A normal cell lines to determine their selectivity towards cancer cells. Compound 12 was selective towards HepG-2 and HCT-116 cell lines but less selective towards MCF-7. While compound 15 showed higher selectivity towards HepG-2 than HCT-116 and MCF-7 cell lines. The ability of compounds 12 and 15 to sensitize the cells against gamma irradiation's effect proved their potential radiosensitizing activity. Molecular docking analysis was carried out to discover the possible binding mode of the compounds within the active site of isoform hCA IX and XII. Compounds 12 and 15 revealed the probable fundamental interactions explaining the good activity and selectivity towards the tumor-specific isoforms.
Asunto(s)
Anhidrasa Carbónica IX/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/química , Quinazolinas/química , Fármacos Sensibilizantes a Radiaciones/química , Antígenos de Neoplasias/metabolismo , Sitios de Unión , Anhidrasa Carbónica IX/metabolismo , Inhibidores de Anhidrasa Carbónica/metabolismo , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Dominio Catalítico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Rayos gamma , Halogenación , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Simulación del Acoplamiento Molecular , Fármacos Sensibilizantes a Radiaciones/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacología , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
A set of quinazolinones synthesized by the aid of L-norephedrine was assembled to generate novel analogues as potential anticancer and radiosensitizing agents. The new compounds were evaluated for their cytotoxic activity against MDA-MB-231, MCF-7, HepG-2, HCT-116 cancer cell lines and EGFR inhibitory activity. The most active compounds 5 and 6 were screened against MCF-10A normal cell line and displayed lower toxic effects. They proved their relative safety with high selectivity towards MDA-MB-231 breast cancer cell line. Measurement of the radiosensitizing activity for 5 and 6 revealed that they could sensitize the tumour cells after being exposed to a single dose of 8 Gy gamma radiation. Compound 5 was able to induce apoptosis and arrest the cell cycle at the G2-M phase. Molecular docking of 5 and 6 in the active site of EGFR was performed to gain insight into the binding interactions with the key amino acids.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Fenilpropanolamina/química , Quinazolinonas/síntesis química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Sitios de Unión , Línea Celular , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/efectos de la radiación , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/química , Receptores ErbB/metabolismo , Rayos gamma , Células HCT116 , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Simulación del Acoplamiento Molecular , Fenilpropanolamina/metabolismo , Fenilpropanolamina/farmacología , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Quinazolinonas/metabolismo , Quinazolinonas/farmacología , Fármacos Sensibilizantes a Radiaciones/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Multitargeted therapy is considered a successful approach to cancer treatment. The development of small molecule multikinase inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. A library of N-alkyl-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide derivatives 5-18 was designed and synthesized. The synthesized compounds were screened for cytotoxic activity against MDA-MB-231 breast cancer cell line and showed IC50 in the range of 0.34-149.10⯵M. The inhibition percentage of VEGFR-2 was measured for all the compounds and found to be in the range of 90.09-20.44%. The promising compounds 8, 12, 13, 16 and 17 were selected to measure their possible multikinase inhibitory activity against VEGFR-2 and EGFR. IC50 of the promising compounds were in the range of 247-793â¯nM for VEGFR-2 in reference to sunitinib (IC50 320â¯nM), and 369-725â¯nM for EGFR in reference to erlotinib (IC50 568â¯nM). Compounds 12 and 13 showed the most potent activity towards VEGFR-2 & EGFR, respectively. Measuring the cytotoxicity of 12 and 13 against MCF-10 normal breast cell line indicates their relative safety to normal breast cells (IC50 37 & 97⯵M, respectively). As radiotherapy is considered the primary treatment for some types of solid tumors, the radiosensitizing ability of 12 and 13 was measured by subjecting the MDA-MB-231 cells to a single dose of 8â¯Gy of gamma radiation. IC50 of 12 and 13 decreased from 1.91 & 0.51⯵M to 0.79 & 0.43⯵M, respectively. Molecular docking was performed to gain insights into the ligand-binding interactions of 12 inside VEGFR-2 and EGFR binding sites in comparison to their co-crystallized ligands.
Asunto(s)
Acetamidas/farmacología , Antineoplásicos/farmacología , Neoplasias de la Mama/terapia , Fármacos Sensibilizantes a Radiaciones/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Acetamidas/síntesis química , Acetamidas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Femenino , Rayos gamma , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
In this study, novel series of thioureido-benzenesulfonamide derivatives bearing an enaminone linker either meta or para oriented and having terminal linear or substituted aromatic or heteroaromatic ring system 5-16a,b were designed and synthesized based on the general pharmacophoric features of type II VEGFR2 inhibitors. Evaluation of the synthesized compounds against HEPG2 hepatocellular carcinoma cells in vitro identified compounds 5b, 6b and 10-13b as most active anticancer agents with IC50 equal to 0.12, 0.29, 0.58, 0.44, 0.42 and 0.66⯵M, respectively. These compounds were evaluated for their ability to in vitro inhibit VEGFR2 kinase enzyme. The results demonstrated highly potent dose-related VEGFR2 inhibition with IC50 values in nanomolar range (33, 57, 210, 37, 37 and 220â¯nM, respectively). The radiosensitizing ability of the most promising compounds was studied which showed an increase in the cell killing effect of radiation after combination with the synthesized compounds which revealed lowered IC50 by nearly 50%. Molecular docking for the most potent compounds was performed to predict their possible binding mode within VEGFR2 active site and they showed binding affinity in a similar way to sorafenib.
Asunto(s)
Aminas/farmacología , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Sulfonamidas/farmacología , Tiourea/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Aminas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Relación Estructura-Actividad , Sulfonamidas/química , Tiourea/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , BencenosulfonamidasRESUMEN
Dual targeting of EGFR and HER2 is a proven anticancer strategy for the treatment of solid tumors. An array of new N-substituted-2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio) acetamides 5-18 were designed and synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4. The targeted compounds were screened for their cytotoxic activity against MDA-MB-231 breast cancer cell line. The IC50 of all the compounds were in the range of 0.36-40.90⯵M. The percentage inhibition towards EGFR was measured and found to be in the range of 63.00-16.90 %. The most potent compounds 5, 9, 15, 17 and 18 were further screened for their activity against both EGFR and HER2 receptors. The compounds showed IC50 in the range of 0.64-1.81⯵M for EGFR and 1.13-2.21⯵M for HER2, in comparison to erlotinib, the reference drug. Compound 17, the most potent towards EGFR in this series, undergoes cell cycle analysis and was found to arrest the cycle at the G2/M phase. Measurement of the cytotoxicity of compound 17 against normal breast cell line showed mild cytotoxic activity. The most potent compounds were subjected to a single dose of 8â¯Gy of γ-radiation and the cytotoxicity of the tested compounds was found to increase after irradiation, thus proving the synergistic effect of γ-irradiation. Molecular docking was adopted for all the synthesized compounds to confirm their mechanism of action.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Quinazolinas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Sulfonamidas/farmacología , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Femenino , Humanos , Modelos Moleculares , Quinazolinas/química , Fármacos Sensibilizantes a Radiaciones/química , Receptor ErbB-2/metabolismo , Sulfonamidas/química , BencenosulfonamidasRESUMEN
Two series of 2-aminopyridine derivatives 6-17 and tyrphostin AG17 analogs 18-22 bearing 4-methylbenzenesulfonamide moiety were designed and synthesized as anticancer compounds. The synthesized compounds were biologically evaluated for their cytotoxic activity against human breast cancer cell line MCF-7. From 2-aminopyridine and tyrphostin AG17 series, compounds 14, 16 and 20 showed the best activities with IC50 values of 20.4, 18.3 and 26.3⯵M, respectively compared to E7070 IC50 36.3⯵M. Further biological evaluation of 14, 16 and 20 against cyclin dependent kinase-2 (CDK2) revealed good inhibitory activity with IC50 of 2.53, 1.79 and 2.92⯵M, respectively compared to roscovitine IC50 0.43⯵M. Additionally, capability of γ-radiation to augment the cytotoxic activity of 14, 16 and 20 was studied and showed a dramatic increase in the cell killing effect at lower concentrations after irradiation. Docking was used to investigate the possible binding modes of compounds 14, 16 and 20 inside the active site of CDK2 enzyme.
Asunto(s)
Antineoplásicos/síntesis química , Quinasa 2 Dependiente de la Ciclina/metabolismo , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Sulfonamidas/química , Tolueno/análogos & derivados , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Ensayos de Selección de Medicamentos Antitumorales , Rayos gamma , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/farmacología , Tolueno/química , Tolueno/metabolismo , Tolueno/farmacologíaRESUMEN
Targeting EGFR has proven to be beneficial in the treatment of several types of solid tumours. So, a series of novel 2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio)-N-substituted acetamide 5-19 were synthesised from the starting material 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4, to be evaluated as dual EGFR/HER2 inhibitors. The target compounds 5-19, were screened for their cytotoxic activity against A549 lung cancer cell line. The percentage inhibition of EGFR enzyme was measured and compared with erlotinib as the reference drug. Compounds 6, 8, 10, and 16 showed excellent EGFR inhibitory activity and were further selected for screening as dual EGFR/HER2 inhibitors. The four selected compounds showed IC50 ranging from 0.009 to 0.026 µM for EGFR and 0.021 to 0.069 µM for the HER2 enzyme. Compound 8 was found to be the most potent in this study with IC50 0.009 and 0.021 µM for EGFR and HER2, respectively.
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Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/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 , Receptores ErbB/metabolismo , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Quinazolinas/síntesis química , Quinazolinas/química , Relación Estructura-ActividadRESUMEN
We report the synthesis and characterisation of a novel series of triazole benzenesulfonamide derivatives, which incorporate the general pharmacophore associated with carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The synthesised compounds were tested in vitro against four human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I, hCA II, hCA IV and hCA IX. The obtained results showed that the tumour-associated hCA IX was the most sensitive to inhibition with the synthesised derivatives, with the triazolo-pyridine benzenesulfonamides 14, 16 and 17 being the most effective inhibitors. Some selected compounds were chosen for a single dose anti-proliferative activity testing against a panel of 57 human tumour cell lines and show some anti-proliferative activity ex vivo.
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Inhibidores de Anhidrasa Carbónica/farmacología , Sulfonamidas/farmacología , Triazoles/farmacología , Anhidrasas Carbónicas/efectos de los fármacos , Anhidrasas Carbónicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Isoenzimas/efectos de los fármacos , Isoenzimas/metabolismo , Análisis Espectral/métodos , Sulfonamidas/química , Triazoles/química , BencenosulfonamidasRESUMEN
Fourteen novel 4-aminoquinazoline derivatives 2-15 were designed and synthesized. The structure of the newly synthesized compounds was established on the basis of elemental analyses, IR, (1)H-NMR, (13)C-NMR, and mass spectral data. The compounds were evaluated for their potential cytoprotective activity in murine Hepa1c1c7 cells. All of the synthesized compounds showed concentration-dependent ability to induce the cytoprotective enzyme NAD(P)H: quinone oxidoreductase (NQO1) with potencies in the low- to sub-micromolar range. This approach offers an encouraging framework which may lead to the discovery of potent cytoprotective agents.