RESUMEN
Picornaviruses are non-enveloped viruses that represent a large family of positive-sense single-stranded RNA viruses including a number of causative agents of many human and animal diseases such as coxsackievirus B3 (CVB3) and rhinoviruses (HRV). In this study, we performed a high-throughput screening of a compound library composed of â¼6000 small molecules in search of potential picornavirus 3C protease (3Cpro) inhibitors. As results, we identified quinone analogues that effectively inhibited both CVB3 3Cpro and HRV 3Cpro with IC50 values in low micromolar range. Together with predicted binding modes of these compounds to the active site of the viral protease, it is implied that structural features of these non-peptidic inhibitors may act as useful scaffold for further anti-picornavirus drug design and development.
Asunto(s)
Antivirales/farmacología , Benzoquinonas/farmacología , Inhibidores de Proteasas/farmacología , Rhinovirus/efectos de los fármacos , Proteínas Virales/antagonistas & inhibidores , Proteasas Virales 3C , Antivirales/síntesis química , Antivirales/química , Benzoquinonas/síntesis química , Benzoquinonas/química , Cisteína Endopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Rhinovirus/enzimología , Relación Estructura-Actividad , Proteínas Virales/metabolismoRESUMEN
Many cancer types are serious diseases causing mortality, and new therapeutics with improved efficacy and safety are required. Immuno-(cell)-therapy is considered as one of the promising therapeutic strategies for curing intractable cancer. In this study, we tested R2016, a newly developed heterocyclic quinone derivative, for induction of immunogenic tumor cell death and as a possible novel immunochemotherapeutic. We studied the anti-cancer effects of R2016 against LLC, a lung cancer cell line and B16F10, a melanoma cell line. LLC (non-immunogenic) and B16F10 (immunogenic) cells were killed by R2016 in dose-dependent manner. R2016 reduced the viability of both LLC and B16F10 tumor cells by inducing apoptosis and necrosis, while it demonstrated no cytotoxicity against normal splenocytes. Expression of immunogenic death markers on the cell surface of R2016 treated tumor cells including calreticulin (CRT) and heat shock proteins (HSPs) was increased along with the induction of their genes. Increased CRT expression correlated with dendritic cell (DC) uptake of dying tumor cells: the proportion of CRT+CD11c+cells was increased in the R2016-treated group. The gene transcription of Calr3, Hspb1, and Tnfaip6, which are related to immunogenicity induction of dead cells, was up-regulated in the R2016 treated tumor cells. On the other hand, ANGPT1, FGF7, and URGCP gene levels were down-regulated by R2016 treatment. This data suggests that R2016 induced immunogenic tumor cell death, and suggests R2016 as an effective anti-tumor immunochemotherapeutic modality.
Asunto(s)
Apoptosis/efectos de los fármacos , Carbazoles/toxicidad , Compuestos Heterocíclicos/toxicidad , Quinonas/toxicidad , Animales , Antígeno CD11c/metabolismo , Calreticulina/genética , Calreticulina/metabolismo , Carbazoles/síntesis química , Carbazoles/química , Carbazoles/uso terapéutico , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Técnicas de Cocultivo , Citocinas/análisis , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Femenino , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Necrosis , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Quinonas/síntesis química , Quinonas/química , Quinonas/uso terapéutico , Regulación hacia Arriba/efectos de los fármacosRESUMEN
We report the discovery of aurora kinase inhibitor using the fragment-based virtual screening by multi-docking strategy. Among a number of fragments collected from eMololecules, we found four fragment molecules showing potent activity (>50% at 100 µM) against aurora kinase. Based on the explored fragment scaffold, we selected two compounds in our synthesized library and validated the biological activity against Aurora kinase.
Asunto(s)
Aurora Quinasas/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/análisis , Inhibidores de Proteínas Quinasas/farmacología , Interfaz Usuario-Computador , Ligandos , Relación Estructura-ActividadRESUMEN
2H-[1,2,3]Triazolo[4,5-g]isoquinoline-4,9-diones and 2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-diones were synthesized and tested for in vitro antifungal activity against pathogenic fungi. Many of those synthesized showed potent antifungal activity. Compounds 3a, 3b, 3g, and 3h completely inhibited the growth of all fungal species tested at the MIC level of 0.8-12.5 µg/mL. The results suggest that 2H-[1,2,3]triazolo[4,5-g]isoquinoline-4,9-diones could be antifungal agents.
Asunto(s)
Antifúngicos/química , Antifúngicos/farmacología , Hongos/efectos de los fármacos , Isoquinolinas/química , Isoquinolinas/farmacología , Triazoles/química , Triazoles/farmacología , Antifúngicos/síntesis química , Diseño de Fármacos , Humanos , Isoquinolinas/síntesis química , Pruebas de Sensibilidad Microbiana , Micosis/tratamiento farmacológico , Relación Estructura-Actividad , Triazoles/síntesis químicaRESUMEN
Benzofuro[6,7-d]thiazoles, benzofuro[7,6-d]thiazoles and 6-arylaminobenzo[d]thiazole-4,7-diones were synthesized and tested for in vitro antifungal activity against Candida, Aspergillus species and Cryptococcus neoformans. Among them tested, many of synthesized compounds showed potent antifungal activity. The compounds 4d, 6e and 6h completely inhibited the growth of all Candida and Aspergillus species tested at the MIC level of 6.3 µg/mL. The results suggest that benzofuro[6,7-d]thiazoles and 6-arylaminobenzo[d]thiazole-4,7-diones would be promising antifungal agents.
Asunto(s)
Antifúngicos/síntesis química , Benzofuranos/química , Tiazoles/química , Antifúngicos/química , Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Candida/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Tiazoles/síntesis química , Tiazoles/farmacologíaRESUMEN
7-Arylamino-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylates were synthesized and tested for in vitro antifungal activity against two pathogenic strains of fungi. Most of tested compounds showed good antifungal activity. The results suggest that those 5,8-dioxo-5,8-dihydroisoquinolines would be potent antifungal agents.
Asunto(s)
Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Candida/efectos de los fármacos , Ácidos Carboxílicos/farmacología , Cryptococcus neoformans/efectos de los fármacos , Isoquinolinas/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Candida/clasificación , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Relación Dosis-Respuesta a Droga , Isoquinolinas/síntesis química , Isoquinolinas/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
1-Thia-4b-aza-cyclopenta[b]fluorene-4,10-diones were synthesized and tested for in vitro antifungal activity against two pathogenic strains of fungi. Among them tested, many compounds showed good antifungal activity. The results suggest that 1-thia-4b-aza-cyclopenta[b]fluorene-4,10-diones would be antifungal agents.
Asunto(s)
Antifúngicos/síntesis química , Antifúngicos/farmacología , Fluorenos/farmacología , Hongos/efectos de los fármacos , Antifúngicos/química , Relación Dosis-Respuesta a Droga , Fluorenos/síntesis química , Fluorenos/química , Hongos/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The immunological death induction by EY-6 on the human tumor cell lines was screened. Human colon carcinoma (HCT15, HCT116), gastric carcinoma (MKN74, SNU668), and myeloma (KMS20, KMS26, KMS34) cells were died by EY-6 treatment with dose-dependent manner. CRT expression, a typical marker for the immunological death, was increased on the EY-6-treated colorectal and gastric cancer cells. Interestingly, the effects on the myeloma cell lines were complicated showing cell line dependent differential modulation. Cytokine secretion from the EY-6 treated tumor cells were dose and cell-dependent. IFN-γ and IL-12 secretion was increased in the treated cells (200% to over 1000% of non-treated control), except HCT116, SNU668 and KMS26 cells which their secretion was declined by EY-6. Data suggest the potential of EY-6 as a new type of immuno-chemotherapeutics inducing tumor-specific cell death. Further studies are planned to confirm the efficacy of EY-6 including in vivo study.
RESUMEN
Pyrido[1,2-a]indole-1,4-diones and benzo[f]pyrido[1,2-a]indole-6,11-diones were synthesized and tested for in vitro antifungal activity against two pathogenic strains of fungi. Among them tested, many compounds showed good antifungal activity. The results suggest that pyrido[1,2-a]indole-1,4-diones and benzo[f]pyrido[1,2-a]indole-6,11-diones would be potent antifungal agents.
Asunto(s)
Antifúngicos/farmacología , Carbolinas/síntesis química , Química Farmacéutica/métodos , Aspergillus flavus/metabolismo , Aspergillus niger/metabolismo , Candida albicans/metabolismo , Carbolinas/farmacología , Diseño de Fármacos , Hongos/efectos de los fármacos , Indoles/química , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Saccharomyces cerevisiae/metabolismo , Factores de TiempoRESUMEN
6,7-Bis(arylthio)-quinazoline-5,8-dione and furo[2,3-f]quinazolin-5-ol derivatives were synthesized and tested for in vitro antifungal activity against Candida, Aspergillus species, and Cryptococcus neoformans. Among them tested, many of furo[2,3-f]quinazolin-5-ols and 6,7-bis(arylthio)-quinazoline-5,8-diones showed good antifungal activity. The compounds completely inhibited the growth of all against Candida and Aspergillus species tested at the MIC level of 12.5µg/mL. The results suggest that furo[2,3-f]quinazolin-5-ols and 6,7-bis(arylthio)-quinazoline-5,8-diones would be promising antifungal agents.
Asunto(s)
Antifúngicos/farmacología , Aspergillus/metabolismo , Candida/metabolismo , Química Farmacéutica/métodos , Cryptococcus neoformans/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Fluconazol/química , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Quinazolinas/química , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/químicaRESUMEN
Furo[2,3-f]quinolin-5-ol derivatives were synthesized and tested for in vitro antifungal activity against Candida,Aspergillus species, and Cryptococcus neoformans. Among them tested, many furo[2,3-f]quinolin-5-ols showed good antifungal activity. The results suggest that furo[2,3-f]quinolin-5-ols would be promising antifungal agents.
Asunto(s)
Antifúngicos/síntesis química , Hidroxiquinolinas/química , Antifúngicos/química , Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Candida/efectos de los fármacos , Hidroxiquinolinas/metabolismo , Hidroxiquinolinas/farmacocinética , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
6-Hydroxy-1H-carbazole-1,4(9H)-diones were synthesized and tested for in vitro antifungal activity against two pathogenic strains of fungi. Among them tested, many compounds showed good antifungal activity. The results suggest that 6-hydroxy-1H-carbazole-1,4(9H)-diones would be potent antifungal agents.
Asunto(s)
Antifúngicos/síntesis química , Carbazoles/química , Antifúngicos/química , Antifúngicos/farmacología , Carbazoles/síntesis química , Carbazoles/farmacología , Hongos/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
BACKGROUND: EY-6 is one of the newly synthesized indoledione derivatives to induce tumor cell-specific cell death. In this study, we investigated the mechanism of immunological death induced by EY-6 at mouse colon cancer cell as well as at the normal immune cell represented by dendritic cell. METHODS: C57BL/6 mouse syngeneic colon cancer cell MC38 was treated with EY-6, and analyzed by MTT for viability test, flow cytometry for confirming surface expressing molecules and ELISA for detection of cytokine secretion. Normal myeloid-dendritic cell (DC) was ex vivo cultured from bone marrow hematopoietic stem cells of C57BL/6 mice with GM-CSF and IL-4 to analyze the DC uptake of dead tumor cells and to observe the effect of EY-6 on the normal DC. RESULTS: EY-6 killed the MC38 tumor cells in a dose dependent manner (25, 50 and 100 µM) with carleticulin induction. And EY-6 induced the secretion of IFN-γ but not of TNF-α from the MC38 tumor cells. EY-6 did not kill the ex-vivo cultured DCs at the dose killing tumor cells and did slightly but not significantly induced the DC maturation. The OVA-specific cross-presentation ability of DC was not induced by chemical treatment (both MHC II and MHC I-restricted antigen presentation). CONCLUSION: Data indicate that the EY-6 induced tumor cell specific and immunological cell death by modulation of tumor cell phenotype and cytokine secretion favoring induction of specific immunity eliminating tumor cells.
RESUMEN
Benzofuran-5-ol derivatives were synthesized and tested for in vitro antifungal activity against Candida, Aspergillus species, and Cryptococcus neoformans. Among them tested, many benzofuran-5-ols showed good antifungal activity. The results suggest that benzofuran-5-ols would be promising antifungal agents.
Asunto(s)
Antifúngicos/síntesis química , Antifúngicos/farmacología , Benzofuranos/síntesis química , Benzofuranos/farmacología , Aspergillus/efectos de los fármacos , Candida/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Pruebas de Sensibilidad MicrobianaRESUMEN
Benzo[d]oxazole-4,7-diones were synthesized and tested for in vitro antifungal activity against fungi. Among them tested, many compounds showed good antifungal activity. The results suggest that benzo[d]oxazole-4,7-diones would be potent antifungal agents.
Asunto(s)
Antifúngicos/síntesis química , Oxazoles/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Hongos/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Oxazoles/química , Oxazoles/farmacología , Relación Estructura-ActividadRESUMEN
1H-Pyrrolo[3,2-g]quinoline-4,9-diones and 4,9-dioxo-4,9-dihydro-1H-benzo[f]indoles were synthesized and tested for in vitro antifungal activity against fungi. Among them tested, many compounds showed good antifungal activity. The results suggest that 1H-pyrrolo[3,2-g]quinoline-4,9-diones and 4,9-dioxo-4,9-dihydro-1H-benzo[f]indoles would be potent antifungal agents.
Asunto(s)
Antifúngicos/síntesis química , Indoles/síntesis química , Quinolinas/síntesis química , Animales , Antifúngicos/farmacología , Hongos/efectos de los fármacos , Indoles/farmacología , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
The abnormal proliferation and migration of vascular smooth muscle cells (SMCs) play an important role in the pathology of coronary artery atherosclerosis and restenosis following angioplasty. It was reported that some heterocyclic quinone derivatives such as 6-arylamino-quinoxaline-5,8-diones and 6-arylamino-1H-benzo[d]imidazole-4,7-diones have inhibitory activity on rat aortic smooth muscle cell (RAoSMC) proliferation. To understand the structural basis for antiproliferative activity to design more potent agents, we generated pharmacophore models of representative molecules with high activity using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD) and aligned a series of compounds to the selected pharmacophore model, then performed three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Good cross-validated correlations were obtained with CoMFA (resulting in q(2) of 0.734 and r(2) of 0.947) and CoMSIA (resulting in q(2) of 0.736 and r(2) of 0.913). The IC(50) values of the heterocyclic quinone derivatives on RAoSMC exhibited a strong correlation with steric and hydrophobic fields of the 3D structure of the molecules, resulting in the reliable prediction of inhibitory activity of the series of compounds.
Asunto(s)
Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Quinonas/química , Quinonas/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Simulación por Computador , Diseño de Fármacos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Músculo Liso Vascular/citología , Relación Estructura-Actividad Cuantitativa , Quinonas/síntesis química , RatasRESUMEN
A series of 2-phenyl-1H-benzo[d]imidazole-4,7-diones were synthesized and tested for their inhibitory activity on the PDGF-stimulated proliferation of rat aortic vascular smooth muscle cells. Among the tested compounds, 6-arylthio-5-chloro-2-phenyl-1H-benzo[d]imidazole-4,7-diones exhibited an potent antiproliferative activity.
Asunto(s)
Aorta/efectos de los fármacos , Bencimidazoles/farmacología , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Inhibidores de Crecimiento/farmacología , Músculo Liso Vascular/efectos de los fármacos , Animales , Aorta/citología , Bencimidazoles/síntesis química , Células Cultivadas , Inhibidores de Crecimiento/síntesis química , Concentración 50 Inhibidora , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Modelos Químicos , Músculo Liso Vascular/citología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Indoledione derivatives have pronounced biological effects, i.e., cytotoxic activities against cancer cell lines and antifungal and antibacterial activities. The present study was designed to investigate the effects of YSK2821, a newly synthesized indoledione derivative, on platelet-derived growth factor (PDGF-BB)-induced vascular smooth muscle cell (VSMC) proliferation, as well as the molecular mechanisms of the anti-proliferative effects of YSK2821 in VSMCs. We found that YSK2821 caused the accumulation of cells in the G1 phase of the cell cycle and inhibited [3H]-thymidine incorporation. We demonstrated that YSK2821 remarkably decreased Akt kinase phosphorylation as the mechanism by which YSK2821 suppressed cell signal transduction events in VSMC proliferation. Furthermore, in terms of the effects of YSK2821 on cell cycle-related proteins, YSK2821 enhanced the expression of the cyclin-dependent protein kinase (CDK) inhibitor p27 and down-regulated CDK2 and cyclin E expression, but did not affect CDK4 and cyclin D1 expression. YSK2821 also inhibited the phosphorylation of Rb, a key regulator in the cell cycle. These results indicate that YSK2821, a newly synthesized indoledione derivative, may inhibit VSMC proliferation via a phosphatidylinositol (PI)-3 kinase-dependent pathway, and thus shed light on a novel role for YSK2821 as a potential preventive regulator of cardiovascular disease.
Asunto(s)
Proteínas de Ciclo Celular/fisiología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Músculo Liso Vascular/enzimología , Fosfatidilinositol 3-Quinasas/metabolismo , Pirroles/farmacología , Quinolonas/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Recuento de Células , Muerte Celular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Necrosis/inducido químicamente , Factor de Crecimiento Derivado de Plaquetas/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Timidina/metabolismoRESUMEN
The increased potential for growth of vascular smooth muscle cells (VSMCs) is a key abnormality in the development of atherosclerosis and postangioplasty restenosis. Platelet-derived growth factor (PDGF)-BB is a potent mitogen for VSMCs that plays an important role in the intimal accumulation of VSMCs. This study examined the effect of JM91, a newly synthesized indoledione derivative, on the proliferation of PDGF-BB-stimulated rat aortic VSMCs. The antiproliferative effect of JM91 on rat aortic VSMCs was examined by cell counting and [(3)H]thymidine incorporation assay. The pre-incubation of JM91 (0.5-3.0 microM) significantly inhibited the proliferation and DNA synthesis of 25 ng/mL PDGF-BB-stimulated rat aortic VSMCs in a concentration-dependent manner. JM91 inhibited the PDGF-BB-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt kinase, while had no effect on PLCgamma1 and PDGF-Rbeta activation. In addition, treatment with JM91 (0.5-3.0 microM) induced cell-cycle arrest in the G(1) phase, which was associated with the down-regulation of cyclins and CDKs. These findings suggest that the inhibitory effects of JM91 against proliferation, DNA synthesis and cell cycle progression of PDGF-BB-stimulated rat aortic VSMCs are mediated by the suppression of the ERK1/2 and PI3K/Akt signaling pathways. Furthermore, JM91 may be a potential antiproliferative agent for the treatment of atherosclerosis and angioplasty restenosis.