Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 49
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Pharmaceuticals (Basel) ; 15(12)2022 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-36558913

RESUMEN

Metastasis, in which cancer cells migrate to other tissues and form new tumors, is a major cause of both cancer death and treatment failure. In a previous study, benproperine (Benp) was identified as a cancer cell migration inhibitor and an inhibitor of actin-related protein 2/3 complex subunit 2 (ARPC2). However, Benp is a racemic mixture, and which stereoisomer is the active isomer remains unclear. In this study, we found that S-Benp is an active isomer and inhibits the migration and invasion of cancer cells much more strongly than R-Benp, with no effect on normal cells. The metastasis inhibitory effect of S-Benp was also verified in an animal model. Validating that inhibitors bind to their targets in cells and tissues has been a very challenging task in drug discovery. The direct interactions between ARPC2 and S-Benp were verified by surface plasmon resonance analysis (SPR), a cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). In the mutant study with ARPC2F225A cells, S-Benp did not bind to ARPC2F225A according to CETSA and DARTS. Furthermore, we validated that S-Benp colocalized with ARPC2 in cancer cells and directly bound to ARPC2 in tumor tissues using Cy3-conjugated S-Benp according to CETSA. Finally, actin polymerization assays and immunocytochemistry showed that S-Benp suppressed actin remodeling such as lamellipodium formation. Taken together, our data suggest that S-Benp is an active stereoisomer of Benp and a potential metastasis inhibitor via ARPC2 binding.

2.
Sensors (Basel) ; 20(7)2020 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-32235673

RESUMEN

With the growth of the number of Internet of Things (IoT) devices, a wide range of wireless sensor networks (WSNs) will be deployed for various applications. In general, WSNs are constrained by limitations in spectrum and energy resources. In order to circumvent these technical challenges, we propose a novel cooperative phase-steering (CPS) technique with a simple on-off power control for generic spectrum sharing-based WSNs, which consists of a single secondary source (SS) node, multiple secondary relay (SR) nodes, a single secondary destination (SD) node, and multiple primary destination (PD) nodes. In the proposed technique, each SR node that succeeds in packet decoding from the SS and for which its interference power to the PD nodes is lower than a certain threshold is allowed to transmit the signal to the SD node. All SR nodes that are allowed to transmit signals to the SD node adjust the phase of their transmit signal such that the phase of received signals at the SD node from the SR nodes is aligned to a certain angle. Moreover, we mathematically analyze the outage probability of the proposed scheme. Our analytical and simulation results show that the proposed technique outperforms the conventional cooperative relaying schemes in terms of outage probability. Through extensive computer simulations, it is shown that the analytical results match well with the simulated outage probability as a lower bound.

3.
Cell Rep ; 30(5): 1447-1462.e5, 2020 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-32023461

RESUMEN

Primary cilium is an antenna-like microtubule-based cellular sensing structure. Abnormal regulation of the dynamic assembly and disassembly cycle of primary cilia is closely related to ciliopathy and cancer. The Wnt signaling pathway plays a major role in embryonic development and tissue homeostasis, and defects in Wnt signaling are associated with a variety of human diseases, including cancer. In this study, we provide direct evidence of Wnt3a-induced primary ciliogenesis, which includes a continuous pathway showing that the stimulation of Wnt3a, a canonical Wnt ligand, promotes the generation of ß-catenin p-S47 epitope by CK1δ, and these events lead to the reorganization of centriolar satellites resulting in primary ciliogenesis. We have also confirmed the application of our findings in MCF-7/ADR cells, a multidrug-resistant tumor cell model. Thus, our data provide a Wnt3a-induced primary ciliogenesis pathway and may provide a clue on how to overcome multidrug resistance in cancer treatment.


Asunto(s)
Centriolos/metabolismo , Cilios/metabolismo , Organogénesis , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo , Secuencia de Aminoácidos , Animales , Caseína Quinasas/metabolismo , Centrosoma/metabolismo , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Epítopos/metabolismo , Células HEK293 , Células HeLa , Humanos , Ligandos , Células MCF-7 , Ratones , Fosforilación , Fosfoserina/metabolismo , Proteína Wnt3A/química
4.
Bone ; 131: 115153, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31730830

RESUMEN

Bone homeostasis is regulated by a balance of bone formation and bone resorption; dysregulation of bone homeostasis may cause bone-related diseases (e.g., osteoporosis, osteopetrosis, bone fracture). Members of the nuclear factor of activated T cells (NFAT) family of transcription factors play crucial roles in the regulation of immune system, inflammatory responses, cardiac formation, skeletal muscle development, and bone homeostasis. Of these, NFATc1 is a key transcription factor mediating osteoclast differentiation, which is regulated by phosphorylation by distinct NFAT kinases including casein kinase 1 (CK1), glycogen synthase kinase 3 (GSK3), and dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs). In this study, we report that cell division control protein 2 homolog (cdc2) is a novel NFAT protein kinase that inhibits NFATc1 activation by direct phosphorylation of the NFATc1 S263 residue. Cdc2 inhibitors such as Roscovitine and BMI-1026 induce reduction of phosphorylation of NFATc1, and this process leads to the inhibition of NFATc1 translocation from the nucleus to the cytoplasm, consequently increasing the nuclear pool of NFATc1. Additionally, the inhibition of cdc2-mediated NFATc1 phosphorylation causes an elevation of osteoclast differentiation or TRAP-positive staining in zebrafish scales. Our results suggest that cdc2 is a novel NFAT protein kinase that negatively regulates osteoclast differentiation.


Asunto(s)
Resorción Ósea , Osteoclastos , Animales , Diferenciación Celular , Glucógeno Sintasa Quinasa 3 , Factores de Transcripción NFATC/metabolismo , Osteoclastos/metabolismo , Fosforilación , Ligando RANK , Pez Cebra/metabolismo
5.
Cell Death Dis ; 10(8): 570, 2019 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-31358734

RESUMEN

The initiation of centrosome duplication is regulated by the Plk4/STIL/hsSAS-6 axis; however, the involvement of other centrosomal proteins in this process remains unclear. In this study, we demonstrate that Cep131 physically interacts with Plk4 following phosphorylation of residues S21 and T205. Localizing at the centriole, phosphorylated Cep131 has an increased capability to interact with STIL, leading to further activation and stabilization of Plk4 for initiating centrosome duplication. Moreover, we found that Cep131 overexpression resulted in centrosome amplification by excessive recruitment of STIL to the centriole and subsequent stabilization of Plk4, contributing to centrosome amplification. The xenograft mouse model also showed that both centrosome amplification and colon cancer growth were significantly increased by Cep131 overexpression. These findings demonstrate that Cep131 is a novel substrate of Plk4, and that phosphorylation or dysregulated Cep131 overexpression promotes Plk4 stabilization and therefore centrosome amplification, establishing a perspective in understanding a relationship between centrosome amplification and cancer development.


Asunto(s)
Proteínas de Ciclo Celular/genética , Centrosoma/metabolismo , Neoplasias del Colon/genética , Proteínas del Citoesqueleto/genética , Proteínas Serina-Treonina Quinasas/genética , Animales , Línea Celular Tumoral , Neoplasias del Colon/patología , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Células HCT116 , Células HEK293 , Xenoinjertos , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Fosforilación/genética
6.
Bioorg Med Chem Lett ; 29(14): 1746-1748, 2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-31103445

RESUMEN

Structure based virtual screening attempts to discover DUSP1 inhibitors have yielded a scaffold featuring benzoxazole and acylthiourea pharmacophore. A series of its analogues were synthesized to explore structure activity relationship (SAR) of DUSP1 inhibition.


Asunto(s)
Fosfatasa 1 de Especificidad Dual/antagonistas & inhibidores , Humanos , Relación Estructura-Actividad
7.
Biochem Pharmacol ; 163: 46-59, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30710516

RESUMEN

Metastasis is the leading cause of cancer mortality and cancer cell migration is an essential stage of metastasis. We identified benproperine (Benp, a clinically used antitussive drug) as an inhibitor of cancer cell migration and an anti-metastatic agent. Benp selectively inhibited cancer cell migration and invasion, which also suppressed metastasis of cancer cells in animal models. Actin-related protein 2/3 complex subunit 2 (ARPC2) was identified as a molecular target of Benp by affinity column chromatography with Benp-tagged Sepharose beads. Benp bound directly to ARPC2 in cells, which was validated by pull-down assay using Benp-biotin and label-free biochemical methods such as the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA). Benp inhibited Arp2/3 function, showing disruption of lamellipodial structure and inhibition of actin polymerization. Unlike Arp2/3 inhibitors, Benp selectively inhibited the migration of cancer cells but not normal cells. ARPC2-knockdown cancer cells showed defective cell migration and suppressed metastasis in an animal model. Therefore, ARPC2 is a potential target for anti-metastatic therapy, and Benp has the clinical potential to block metastasis. Furthermore, Benp is a useful agent for studying the functions of the Arp2/3 complex in cancer cell migration and metastasis.


Asunto(s)
Complejo 2-3 Proteico Relacionado con la Actina/antagonistas & inhibidores , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Antineoplásicos/farmacología , Compuestos de Bencidrilo/farmacología , Movimiento Celular/efectos de los fármacos , Piperidinas/farmacología , Complejo 2-3 Proteico Relacionado con la Actina/química , Animales , Antineoplásicos/uso terapéutico , Compuestos de Bencidrilo/uso terapéutico , Movimiento Celular/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Células HeLa , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia/prevención & control , Piperidinas/uso terapéutico , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
8.
Stem Cells Dev ; 28(7): 438-453, 2019 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-30667343

RESUMEN

Spinal muscular atrophy (SMA) is caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene. Only ∼10% of the products of SMN2, a paralogue of SMN1, are functional full-length SMN (SMN-FL) proteins, whereas SMN2 primarily produces alternatively spliced transcripts lacking exon 7. Reduced SMN protein levels in SMA patients lead to progressive degeneration of spinal motor neurons (MNs). In this study, we report an advanced platform based on an SMN2 splicing-targeting approach for SMA drug screening and validation using an SMN2 splicing reporter cell line and an in vitro human SMA model through induced pluripotent stem cell (iPSC) technology. Through drug screening using a robust cell-based luciferase assay to quantitatively measure SMN2 splicing, the small-molecule candidate compound rigosertib was identified as an SMN2 splicing modulator that led to enhanced SMN protein expression. The therapeutic potential of the candidate compound was validated in MN progenitors differentiated from SMA patient-derived iPSCs (SMA iPSC-pMNs) as an in vitro human SMA model, which recapitulated the biochemical and molecular phenotypes of SMA, including lower levels of SMN-FL transcripts and protein, enhanced cell death, and reduced neurite length. The candidate compound exerted strong splicing correction activity for SMN2 and potently alleviated the disease-related phenotypes of SMA iPSC-pMNs by modulating various cellular and molecular abnormalities. Our combined screening platform representing a pMN model of human SMA provides an efficient and reliable drug screening system and is a promising resource for drug evaluation and the exploration of drug modes of action.


Asunto(s)
Empalme Alternativo/efectos de los fármacos , Glicina/análogos & derivados , Modelos Neurológicos , Atrofia Muscular Espinal , Sulfonas/farmacología , Animales , Línea Celular , Glicina/farmacología , Humanos , Ratones , Ratones Transgénicos , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patología , Proteína 2 para la Supervivencia de la Neurona Motora/biosíntesis , Proteína 2 para la Supervivencia de la Neurona Motora/genética
9.
Exp Dermatol ; 27(11): 1304-1308, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30092122

RESUMEN

Atopic dermatitis (AD) is a chronic inflammatory skin disease whose prevalence is increasing worldwide. Filaggrin (FLG) is essential for the development of the skin barrier, and its genetic mutations are major predisposing factors for AD. In this study, we developed a convenient and practical method to detect FLG mutations in AD patients using peptide nucleic acid (PNA) probes labelled with fluorescent markers for rapid analysis. Fluorescence melting curve analysis (FMCA) precisely identified FLG mutations based on the distinct difference in the melting temperatures of the wild-type and mutant allele. Moreover, PNA probe-based FMCA easily and accurately verified patient samples with both heterozygote and homozygote FLG mutations, providing a high-throughput method to reliable screen AD patients. Our method provides a convenient, rapid and accurate diagnostic tool to identify potential AD patients allowing for early preventive treatment, leading to lower incidence rates of AD, and reducing total healthcare expenses.


Asunto(s)
Análisis Mutacional de ADN/métodos , Sondas de ADN , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/genética , Proteínas de Filamentos Intermediarios/genética , Alelos , Estudios de Casos y Controles , Proteínas Filagrina , Fluorescencia , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Homocigoto , Humanos , Mutación , Ácidos Nucleicos de Péptidos/genética , Temperatura de Transición
10.
Bioorg Med Chem Lett ; 28(14): 2566-2572, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29807795

RESUMEN

Piperlongumine (PL), isolated from Piper longum L., is receiving intense interest due to its selectively ability to kill cancer cells but not normal cells. We synthesized a number of analogues by replacing the cyclic amide of PL with aliphatic amides to explore structural diversity. Compound CG-06 had the strongest cytotoxic profile of this series, showing potent effects in human prostate cancer DU-145 cells, in which signal transducer and activator of transcription 3 (STAT3) is constitutively active. CG-06 inhibited STAT3 phosphorylation at tyrosine 705 in a dose- and time dependent manner in DU-145 cells and suppressed IL-6-induced STAT3 phosphorylation at Tyr-705 in DU-145 and LNCaP cell lines. CG-06 decreased the expression levels of STAT3 target genes, such as cyclin A, Bcl-2, and survivin. Notably, we used drug affinity responsive target stability (DARTS) to show that CG-06 binds directly to STAT3, and the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) rescued the CG-06-induced suppression p-STAT3. Our results suggest that CG-06 is a novel inhibitor of STAT3 and may be a useful lead molecule for the development of a therapeutic STAT3 inhibitor.


Asunto(s)
Antineoplásicos/farmacología , Dioxolanos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dioxolanos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Interleucina-6/antagonistas & inhibidores , Interleucina-6/metabolismo , Masculino , Estructura Molecular , Fosforilación/efectos de los fármacos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Factor de Transcripción STAT3/metabolismo , Relación Estructura-Actividad
11.
Sci China Life Sci ; 61(10): 1243-1253, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29524123

RESUMEN

The compound (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI) is known as an inhibitor of dual specific phosphatase 1/6 and mitogen-activated protein kinase. However, its precise anti-lung cancer mechanism remains unknown. In this study, the effects of BCI on the viability of non-small cell lung cancer cell lines NCI-H1299, A549, and NCI-H460 were evaluated. We confirmed that BCI significantly inhibited the viability of p53(-) NCI-H1299 cells as compared to NCI-H460 and A549 cells, which express wild-type p53. Furthermore, BCI treatment increased the level of cellular reactive oxygen species and pre-treatment of cells with N-acetylcysteine markedly attenuated BCI-mediated apoptosis of NCI-H1299 cells. BCI induced cellular morphological changes, inhibited viability, and produced reactive oxygen species in NCI-H1299 cells in a dose-dependent manner. BCI induced processing of caspase-9, caspase-3, and poly ADP-ribose polymerase as well as the release of cytochrome c from the mitochondria into the cytosol. In addition, BCI downregulated Bcl-2 expression and enhanced Bax expression in a dose-dependent manner in NCI-H1299 cells. However, BCI failed to modulate the expression of the death receptor and extrinsic factor caspase-8 and Bid, a linker between the intrinsic and extrinsic apoptotic pathways in NCI-H1299 cells. Thus, BCI induces apoptosis via generation of reactive oxygen species and activation of the intrinsic pathway in NCI-H1299 cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Mitocondrias/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células A549 , Caspasas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocromos c/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mitocondrias/genética , Mitocondrias/metabolismo , Estructura Molecular , Poli(ADP-Ribosa) Polimerasas/metabolismo
12.
Mol Cells ; 39(12): 855-861, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27927007

RESUMEN

Ginsenosides, which are the active materials of ginseng, have biological functions that include anti-osteoporotic effects. Aqueous ginseng extract inhibits osteoclast differentiation induced by receptor activator of NF-κB ligand (RANKL). Aqueous ginseng extract produces chromatography peaks characteristic of ginsenosides. Among these peaks, ginsenoside Re is a major component. However, the preventive effects of ginsenoside Re against osteoclast differentiation are not known. We studied the effect of ginsenoside Re on osteoclast differentiation, RANKL-induced tartrate-resistant acid phosphatase (TRAP) activity, and formation of multinucleated osteoclasts in vitro. Ginsenoside Re hampered osteoclast differentiation in a dose-dependent manner. In an in vivo zebrafish model, aqueous ginseng extract and ginsenoside Re had anti-osteoclastogenesis effects. These findings suggest that both aqueous ginseng extract and ginsenoside Re prevent bone resorption by inhibiting osteoclast differentiation. Ginsenoside Re could be important for promoting bone health.


Asunto(s)
Células de la Médula Ósea/efectos de los fármacos , Ginsenósidos/farmacología , Macrófagos/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Animales , Células de la Médula Ósea/citología , Diferenciación Celular/efectos de los fármacos , Macrófagos/citología , Ratones , Osteoclastos/citología , Pez Cebra
13.
Eur J Pharmacol ; 771: 1-9, 2016 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-26683635

RESUMEN

GPR43/Free Fatty Acid Receptor 2 (FFAR2) is known to be activated by short-chain fatty acids and be coupled to Gi and Gq family of heterotrimeric G proteins. GPR43 is mainly expressed in neutrophils, adipocytes and enteroendocrine cells, implicated to be involved in inflammation, obesity and type 2 diabetes. However, several groups have reported the contradictory data about the physiological functions of GPR43, so that its roles in vivo remain unclear. Here, we demonstrate that a novel compound of pyrimidinecarboxamide class named as BTI-A-404 is a selective and potent competitive inverse agonist of human GPR43, but not the murine ortholog. Through structure-activity relationship (SAR), we also found active compound named as BTI-A-292. These regulators increased the cyclic AMP level and reduced acetate-induced cytoplasmic Ca(2+) level. Furthermore, we show that they modulated the downstream signaling pathways of GPR43, such as ERK, p38 MAPK, and NF-κB. It was surprising that two compounds augmented the secretion of glucagon-like peptide 1 (GLP-1) in NCI-H716 cell line. Collectively, these novel and specific competitive inhibitors regulate all aspects of GPR43 signaling and the results underscore the therapeutic potential of them.


Asunto(s)
Compuestos de Anilina/farmacología , Péptido 1 Similar al Glucagón/metabolismo , Pirimidinonas/farmacología , Receptores de Superficie Celular/agonistas , Animales , Calcio/metabolismo , Línea Celular , AMP Cíclico/metabolismo , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Receptores de Superficie Celular/genética , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad
14.
J Microbiol Biotechnol ; 25(7): 1047-55, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25907062

RESUMEN

For the search of a potent first-in-class compound to inactivate macrophages responsible for inflammatory responses, in the present study, we investigated the anti-inflammatory effects of YH-1118, a novel synthetic compound, in a lipopolysaccharide (LPS)-stimulated mouse macrophage cell line, Raw 264.7. YH-1118 inhibited LPS-induced nitric oxide (NO) production and inducible NO synthase (iNOS) expression at both the protein and mRNA levels. The suppression of LPS-induced iNOS expression by YH-1118 was mediated via nuclear factor kappa B (NF-κB), but not activator protein-1 (AP-1) transcription factor. This was supported by the finding that YH-1118 attenuated the phosphorylation of inhibitor of κBα (IκBα) and nuclear translocation and DNA binding activity of NF-kappaB. Through the mechanisms that YH- 1118 inhibited the activation of IkappaB kinases (IKKs), upstream activators of NF-κB, or p38 MAPK, YH-1118 significantly suppressed LPS-induced production of pro-inflammatory cytokines, tumor necrosis factor-α, interleukin-1ß (IL-1ß), and IL-6 (p < 0.05). In conclusion, our results suggest that YH-1118 inhibits LPS-induced inflammatory responses by blocking IKK and NF-κB activation in macrophages, and may be a therapeutic candidate for the treatment of various inflammatory diseases.


Asunto(s)
Inmunosupresores/farmacología , Inflamación/inducido químicamente , Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Animales , Perfilación de la Expresión Génica , Inmunosupresores/síntesis química , Ratones , Óxido Nítrico/análisis , Óxido Nítrico Sintasa de Tipo II/análisis , Células RAW 264.7
15.
Chem Biol Drug Des ; 85(5): 638-44, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25323822

RESUMEN

In this study, we have synthesized novel water soluble derivatives of natural compound aloe emodin 4(a-j) by coupling with various amino acid esters and substituted aromatic amines, in an attempt to improve the anticancer activity and to explore the structure-activity relationships. The structures of the compounds were determined by (1) H NMR and mass spectroscopy. Cell growth inhibition assays revealed that the aloe emodin derivatives 4d, 4f, and 4i effectively decreased the growth of HepG2 (human liver cancer cells) and NCI-H460 (human lung cancer cells) and some of the derivatives exhibited comparable antitumor activity against HeLa (Human epithelial carcinoma cells) and PC3 (prostate cancer cells) cell lines compared to that of the parent aloe emodin at low micromolar concentrations.


Asunto(s)
Antraquinonas/química , Antraquinonas/farmacología , Antineoplásicos/síntesis química , Antraquinonas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células HeLa , Células Hep G2 , Humanos , Relación Estructura-Actividad
16.
Biol Pharm Bull ; 37(10): 1655-60, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25099343

RESUMEN

Diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step in triacylglycerol (TG) synthesis, is a key enzyme associated with hepatic steatosis and insulin resistance. Here, using an in vitro screen of 20000 molecules, we identified a class of compounds with a substituted 1H-pyrrolo[2,3-b]pyridine core which proved to be potent and selective inhibitors of human DGAT2. Of these compounds, H2-003 and -005 exhibited a considerable reduction in TG biosynthesis in HepG2 hepatic cells and 3T3-L1 preadipose cells. These compounds exert DGAT2-specific-inhibitory activity, which was further confirmed in DGAT2- or DGAT1-overexpressing HEK293 cells. In addition, these compounds almost completely abolished lipid droplet formation in 3T3-L1 cells when co-treated with a DGAT1 inhibitor, which was not attained using either a DGAT2 or DGAT1 inhibitor alone. Collectively, we identified two DGAT2 inhibitors, H2-003 and -005. These compounds will aid in DGAT2-related lipid metabolism research as well as in therapeutic development for the treatment of metabolic diseases associated with excessive TG.


Asunto(s)
Acetatos/química , Acetatos/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Descubrimiento de Drogas/métodos , Piridinas/química , Piridinas/farmacología , Células 3T3-L1 , Animales , Diacilglicerol O-Acetiltransferasa/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Ratones
17.
PLoS One ; 8(11): e78922, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24312171

RESUMEN

Bacterial enoyl-acyl carrier protein reductase (FabI) is a promising novel antibacterial target. We isolated a new class of FabI inhibitor from Penicillium chrysogenum, which produces various antibiotics, the mechanisms of some of them are unknown. The isolated FabI inhibitor was determined to be meleagrin by mass spectroscopy and nuclear magnetic resonance spectral analyses, and its more active and inactive derivatives were chemically prepared. Consistent with their selective inhibition of Staphylococcus aureus FabI, meleagrin and its more active derivatives directly bound to S. aureus FabI in a fluorescence quenching assay, inhibited intracellular fatty acid biosynthesis and growth of S. aureus, and increased the minimum inhibitory concentration for fabI-overexpressing S. aureus. The compounds that were not effective against the FabK isoform, however, inhibited the growth of Streptococcus pneumoniae that contained only the FabK isoform. Additionally no resistant mutant to the compounds was obtained. Importantly, fabK-overexpressing Escherichia coli was not resistant to these compounds, but was resistant to triclosan. These results demonstrate that the compounds inhibited another target in addition to FabI. Thus, meleagrin is a new class of FabI inhibitor with at least one additional mode of action that could have potential for treating multidrug-resistant bacteria.


Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Enoil-ACP Reductasa (NADH)/antagonistas & inhibidores , Ovomucina/farmacología , Penicillium chrysogenum/metabolismo , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Vías Biosintéticas/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana/genética , Enoil-ACP Reductasa (NADH)/genética , Enoil-ACP Reductasa (NADH)/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Escherichia coli/genética , Ácidos Grasos/biosíntesis , Expresión Génica , Pruebas de Sensibilidad Microbiana , Mutación , Ovomucina/química , Ovomucina/aislamiento & purificación , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Staphylococcus aureus/genética
18.
Biol Pharm Bull ; 36(11): 1754-9, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23985900

RESUMEN

G-protein coupled receptor 43 (GPR43) serves as a receptor for short-chain fatty acids (SCFAs), implicated in neutrophil migration and inflammatory cytokine production. However, the intracellular signaling pathway mediating GPR43 signaling remains unclear. Here, we show that ß-arrestin 2 mediates the internalization of GPR43 by agonist. Agonism of GPR43 reduced the phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB), which was relieved by short interfering RNA (siRNA) of ß-arrestin 2. Subsequently, mRNA expression of proinflammatory cytokines, interleukin (IL)-6 and IL-1ß, was downregulated by activation of GPR43 and knockdown of ß-arrestin 2 recovered the expression of the cytokines. Taken together, these results suggest that GPR43 may be a plausible target for a variety of inflammatory diseases.


Asunto(s)
Arrestinas/metabolismo , FN-kappa B/metabolismo , Receptores de Superficie Celular/metabolismo , Células HEK293 , Células HeLa , Humanos , Arrestina beta 2 , beta-Arrestinas
19.
Biol Pharm Bull ; 36(7): 1167-73, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23585481

RESUMEN

Diacylglycerol acyltransferase 2 (DGAT2) is one of two distinct DGAT enzymes that catalyze the last step in triacylglycerol (TG) synthesis. Findings from previous studies suggest that inhibition of DGAT2 is a promising strategy for the treatment of hepatic steatosis and insulin resistance. Here, we identified compound 122 as a potent and selective inhibitor of human DGAT2, which appeared to act competitively against oleoyl-CoA in vitro. The selective inhibition of DGAT2 was also confirmed by the reductions in enzymatic activity and de novo TG synthesis in DGAT2-overexpressing HEK293 cells and hepatic cells HepG2. Compound 122, as a newly identified inhibitor of DGAT2, will be useful for the research on DGAT2-related lipid metabolism as well as the development of therapeutic drug for several metabolic diseases.


Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Diacilglicerol O-Acetiltransferasa/genética , Inhibidores Enzimáticos/química , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Estructura Molecular , Células Sf9 , Bibliotecas de Moléculas Pequeñas/química , Spodoptera , Relación Estructura-Actividad , Transfección
20.
Bioorg Med Chem Lett ; 21(3): 977-9, 2011 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-21215627

RESUMEN

A series of KRIBB3 analogs were synthesized by modifying substituents at aryl moieties of KRIBB3 for examining structure-activity relationships, and their inhibitory activities on microtubule polymerization were evaluated. The presence of free phenolic hydrogens in aryl moieties of KRIBB3 analogs plays an important role in inhibition of microtubule polymerization.


Asunto(s)
Anisoles/química , Isoxazoles/química , Moduladores de Tubulina/química , Tubulina (Proteína)/química , Anisoles/síntesis química , Anisoles/farmacología , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacología , Polimerizacion , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/farmacología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA