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1.
Med Chem ; 16(1): 69-77, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30520382

RESUMO

BACKGROUND: Norcantharimides are known as norcantharidine derivatives and contain an isoindole skeleton structure. Isoindole derivatives have positive effect on inflammatory pathologies including cancers. OBJECTIVE: Considering this information, firstly, isoindole derivatives containing different functional groups 4-13 have been synthesized from 2-alkyl/aryl-3a, 4,7,7a-tetrahydro-1H-isoindole-1, 3(2H)-dione. METHODS: For the synthesis of all compounds, 2-alkyl/aryl-3a, 4,7,7a-tetrahydro-1H-isoindole- 1,3(2H)-dione was used as the starting compound. The syntheses were based on two main reactions: Ene-reaction of singlet oxygen and epoxidation. Secondly, their anticancer activities were evaluated against HeLa, C6 and A549 cancer cell lines by the BrdU assay. RESULTS: Anticancer activities of synthesized compounds (4-13) and 5-FU (5-Florouracil) against HeLa, C6 and A549 cells were investigated at four concentrations (100, 50, 25 and 5 µM). IC50 values of compounds 4-13 were calculated for all cancer cell lines. The investigated compounds showed anticancer activity against the cancer cell lines depending on doses. Compound 7 containing azide and silyl ether exhibited higher inhibitory activity than the other compounds and 5-FU against A549 cancer cell lines (IC50 =19.41± 0.01 µM). Compounds 9 and 11 were determined to exhibit cell-selective activity against HeLa cancer cell lines. Compound 11 had higher activity than the positive control at 100 µM concentrations against C6 cancer cell lines. CONCLUSION: According to the results observed, isoindole derivatives 7, 9, and 11 might be good potential anticancer agents for the treatment of cervical and glioma cancer due to their antiproliferative properties, having less cytotoxic effects on healthy cells. In addition, compound 7 could be used in in vivo studies of all three-cancer cell lines (C6, HeLa, and A549).


Assuntos
Antineoplásicos/farmacologia , Isoindóis/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Isoindóis/síntese química , Isoindóis/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
2.
J Agric Food Chem ; 67(39): 10844-10852, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31525997

RESUMO

The discovery of 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 µM to over 1 µM. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4- carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a Ki value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (Ki = 44 nM) and slightly more potent than mesotrione (Ki = 4.56 nM). In addition, the cocrystal structure of the AtHPPD-4ae complex was successfully resolved at a resolution of 1.8 Å. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π-π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Isoindóis/farmacologia , Proteínas de Plantas/antagonistas & inibidores , Pirazóis/farmacologia , 4-Hidroxifenilpiruvato Dioxigenase/química , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Arabidopsis/efeitos dos fármacos , Arabidopsis/crescimento & desenvolvimento , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Herbicidas/síntese química , Herbicidas/química , Isoindóis/química , Cinética , Estrutura Molecular , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/crescimento & desenvolvimento , Pirazóis/química , Relação Estrutura-Atividade
3.
Biomed Res ; 40(4): 169-178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413238

RESUMO

Migration of osteoblasts to the sites resorbed by osteoclasts is an essential step in bone remodeling. However, the exact mechanism of osteoblast migration is still not known. We have shown that platelet-derived growth factor (PDGF)-BB induces the migration of osteoblast-like MC3T3-E1 cells through the activation of p38 mitogen-activated protein (MAP) kinase, c-Jun N-terminal kinase (JNK) and p44/p42 MAP kinase. Evidence is accumulating that heat shock protein 90 (HSP90) acts as a central regulator of proteostasis under stress conditions and physiological cell functions. In the present study, using transwell cell migration assay and wound-healing assay, we investigated the involvement of HSP90 in the PDGF-BB-stimulated migration of MC3T3-E1 cells, and the underlying signaling mechanism estimated by Western blot analyses. Onalespib, an HSP90 inhibitor, significantly reduced the PDGF-BB-stimulated migration evaluated by the two types of migration assays. The cell migration was also suppressed by geldanamycin, another type of HSP90 inhibitor. Onalespib markedly attenuated the PDGF-BB-elicited phosphorylation of p44/p42 MAP kinase without affecting that of p38 MAP kinase or JNK. In addition, the phosphorylation of p44/p42 MAP kinase by PDGF-BB was reduced by geldanamycin. Taken together, these results strongly suggest that HSP90 inhibitors suppress the PDGF-BB-induced osteoblast migration through the attenuation of p44/p42 MAP kinase activity.


Assuntos
Becaplermina/farmacologia , Benzamidas/farmacologia , Benzoquinonas/farmacologia , Movimento Celular/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoindóis/farmacologia , Lactamas Macrocíclicas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Osteoblastos/metabolismo , Animais , Linhagem Celular , Proteínas de Choque Térmico HSP90/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos
4.
Expert Opin Investig Drugs ; 28(8): 659-666, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31272246

RESUMO

Introduction: Pruritus is a common symptom associated with several potential underlying causes, including both dermatologic and systemic diseases; it can also occur without an identifiable cause. Current treatment options are limited and most patients experience impaired quality of life. Serlopitant is a neurokinin 1 (NK1) receptor antagonist under development for the treatment of pruritus associated with various dermatologic conditions and chronic pruritus of unknown origin. Areas covered: This review describes the epidemiology and unmet needs of patients with chronic pruritus, focusing specifically on patients with prurigo nodularis, psoriatic itch, and chronic pruritus of unknown origin; the rationale for targeting the NK1 receptor for treatment of chronic pruritus; and the clinical development of serlopitant, including efficacy and safety data from completed phase II studies. Expert opinion: There is an unmet need for novel, safe, and effective therapies to treat chronic pruritus. Serlopitant has shown promising efficacy, safety, and tolerability across different patient populations, including adolescents and elderly patients. In contrast to less convenient administration options, serlopitant is a once-daily oral tablet, which is expected to facilitate compliance.


Assuntos
Isoindóis/administração & dosagem , Antagonistas do Receptor de Neuroquinina-1/administração & dosagem , Prurido/tratamento farmacológico , Animais , Antipruriginosos/administração & dosagem , Antipruriginosos/efeitos adversos , Antipruriginosos/farmacologia , Doença Crônica , Humanos , Isoindóis/efeitos adversos , Isoindóis/farmacologia , Antagonistas do Receptor de Neuroquinina-1/efeitos adversos , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Prurido/fisiopatologia , Qualidade de Vida , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-1/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-31081456

RESUMO

Three new Ru(II) polypyridyl complexes [Ru(phen)2CIIP]2+ (1) {CIIP = 2-(5-Chloro-3a H-Isoindol-3-yl)-1H-Imidazo[4,5-f][1, 10]phenantholine} (phen = 1, 10 phenanthroline), [Ru(bpy)2CIIP]2+ (2) (bpy = 2, 2' bipyridine) and [Ru(dmb)2CIIP]2+ (3) (dmb = 4, 4'-dimethyl 2, 2' bipyridine) were synthesized and characterized by different spectral methods. The DNA-binding behavior of these complexes was investigated by absorption, emission spectroscopic titration and viscosity measurements, indicating that these three complexes bind to CT-DNA in an intercalative mode, but binding affinities of these complexes were different. The DNA-binding constants Kb of complexes 1, 2 and 3 were calculated in the order of 106. All three complexes cleave pBR322 DNA in photoactivated cleavage studies and exhibit good antimicrobial activity. Anticancer activity of these Ru(II) complexes was evaluated in MCF7 cells. Cytotoxicity by MTT assay showed growth inhibition in a dose dependent manner. Cell cycle analysis by flow cytometry data showed an increase in Sub G1 population. Annexin V FITC/PI staining confirms that these complexes cause cell death by the induction of apoptosis.


Assuntos
Antibacterianos/química , Antineoplásicos/química , Complexos de Coordenação/química , Substâncias Intercalantes/química , Isoindóis/química , Fenantrolinas/química , Piridinas/química , Rutênio/química , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , DNA/metabolismo , Clivagem do DNA , Escherichia coli/efeitos dos fármacos , Humanos , Substâncias Intercalantes/farmacologia , Isoindóis/farmacologia , Células MCF-7 , Fenantrolinas/farmacologia , Processos Fotoquímicos , Piridinas/farmacologia , Termodinâmica
6.
Biomater Sci ; 7(7): 2749-2758, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-30997445

RESUMO

Combining chemotherapy and immunotherapy has been considered as an attractive approach to improve cancer therapy. Here we prepared folated PVA-based nanogels for the simultaneous delivery of docetaxel (DTX) and the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG919 (N9) for enhancing cancer chemo-immunotherapy. FDA-approved poly(vinyl alcohol) (PVA) with good biocompatibility was modified with vinyl ether acrylate (VEA) groups for UV-crosslinking and acidic degradation. Carboxyl groups were introduced via modification with succinic anhydride for improved drug loading and folic acid (FA) ligands were incorporated for tumor targeting. UV-crosslinked folated PVA nanogels were efficiently taken up by tumor cells followed by endo/lysosomal pH-triggered intracellular drug release, which induced significant cytotoxicity towards 4T1 breast cancer cells in vitro. DTX and N9 co-loaded PVA nanogels exhibited a much higher antitumor efficiency in 4T1 mouse breast cancer models in vivo as compared to the free drug controls. The drug-laden nanogels not only directly killed the tumor cells by DTX, but also induced immunogenic cell death (ICD) promoting intratumoral accumulation of cytotoxic T lymphocytes, and further combining with N9 elevated the intratumoral infiltration of CD8+ T cells and NK cells and inhibited the infiltration of MDSCs, downregulating IDO1-mediated immunosuppression.


Assuntos
Docetaxel/química , Inibidores Enzimáticos/química , Ácido Fólico/química , Imidazóis/química , Imunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Isoindóis/química , Nanopartículas/química , Animais , Transporte Biológico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Docetaxel/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Inibidores Enzimáticos/farmacologia , Ácido Fólico/metabolismo , Concentração de Íons de Hidrogênio , Imidazóis/farmacologia , Isoindóis/farmacologia , Camundongos , Álcool de Polivinil/química
7.
Prostaglandins Other Lipid Mediat ; 143: 106327, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30946899

RESUMO

Heat shock protein (HSP) 90 that is ubiquitously expressed in various tissues is a major molecular chaperone. We have previously demonstrated that prostaglandin D2 (PGD2), a bone remodeling factor, elicits the expression of HSP27, a small HSP, through stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 mitogen-activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the involvement of HSP90 in the PGD2-stimulated HSP27 induction and the underlying mechanism in MC3T3-E1 cells. Onalespib, an inhibitor of HSP90, significantly enhanced the PGD2-stimulated HSP27 induction. In addition, geldanamycin, another HSP90 inhibitor, potentiated the HSP27 induction. Both onalespib and geldanamycin markedly amplified the PGD2-induced phosphorylation of SAPK/JNK and p38 MAP kinase. SP600125, an inhibitor of SAPK/JNK, and SB203580, an inhibitor of p38 MAP kinase, suppressed the amplification by onalespib of the PGD2-stimulated HSP27 induction. These results strongly suggest that HSP90 plays a negative role in the HSP27 induction stimulated by PGD2 in osteoblasts, and that the inhibitory effect of HSP90 is mediated through the regulation of SAPK/JNK and p38 MAP kinase.


Assuntos
Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Prostaglandina D2/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Células 3T3 , Animais , Antracenos/farmacologia , Benzamidas/farmacologia , Sinergismo Farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Isoindóis/farmacologia , Camundongos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia
8.
Molecules ; 24(5)2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30862068

RESUMO

Enterovirus 71 (EV-A71) is the main causative pathogen of childhood hand, foot and mouth disease. Effective medicine is currently unavailable for the treatment of this viral disease. Using the fragment-hopping strategy, a series of 2-aryl-isoindolin-1-one compounds were designed, synthesized and investigated for their in vitro antiviral activity towards multiple EV-A71 clinical isolates (H, BrCr, Shenzhen98, Jiangsu52) in Vero cell culture in this study. The structure⁻activity relationship (SAR) studies identified 2-phenyl-isoindolin-1-ones as a new potent chemotype with potent antiviral activity against EV-A71. Ten out of the 24 tested compounds showed significant antiviral activity (EC50 < 10 µM) towards four EV-A71 strains. Compounds A3 and A4 exhibited broad and potent antiviral activity with the 50% effective concentration (EC50) values in the range of 1.23⁻1.76 µM. Moreover, the selectivity indices of A3 and A4 were significantly higher than those of the reference compound, pirodavir. The western blotting experiment indicated that the viral VP1 was significantly decreased at both the protein and RNA level in a dose-dependent manner following treatment with compound A3. Moreover, compound A3 inhibited the viral replication by acting on the virus entry stage. In summary, this study led to the discovery of 2-aryl-isoindolin-1-ones as a promising scaffold with potent anti-EV-A71 activities, which deserves further in-depth studies.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Enterovirus Humano A/efeitos dos fármacos , Isoindóis/síntese química , Isoindóis/farmacologia , Animais , Antivirais/química , Linhagem Celular , Enterovirus Humano A/isolamento & purificação , Enterovirus Humano A/fisiologia , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Isoindóis/química , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Células Vero , Replicação Viral/efeitos dos fármacos
9.
J Antibiot (Tokyo) ; 72(5): 311-315, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30816348

RESUMO

Heterologous expression of the fluostatin biosynthetic gene cluster from the marine-derived Micromonospora rosaria SCSIO N160 in Streptomyces albus J1074 led to the isolation of a novel isoindolequinone albumycin (1) and a known isoquinolinequinone mansouramycin A (2). The structure of 1 was elucidated on the basis of detailed 1D and 2D NMR spectroscopic analysis. Mansouramycin A (2) is active against methicillin-resistant Staphylococcus aureus ATCC 43300, with a MIC of 8 µg ml-1, while albumycin (1) displayed negligible antibacterial activities. This study represents another example of activation of secondary metabolites that are non-relevant to the heterologously introduced biosynthetic gene cluster in a bacterial host.


Assuntos
Antibacterianos/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Isoindóis/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Streptomyces/metabolismo , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Vias Biossintéticas/genética , Isoindóis/metabolismo , Isoindóis/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Streptomyces/genética
10.
Inflamm Res ; 68(5): 369-377, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30852628

RESUMO

Tristetraprolin (TTP) is an anti-inflammatory molecule known to post-transcriptionally regulate cytokine production and is, therefore, an attractive drug target for chronic respiratory diseases driven by inflammation, such as asthma and chronic obstructive pulmonary disease. Our recent in vitro studies in primary human airway smooth (ASM) cells have confirmed the essential anti-inflammatory role played by TTP as a critical partner in a cytokine regulatory network. However, several unanswered questions remain. While prior in vitro studies have suggested that TTP is regulated in a cAMP-mediated manner, raising the possibility that this may be one of the ways in which ß2-agonists achieve beneficial effects beyond bronchodilation, the impact of ß2-agonists on ASM cells is unknown. Furthermore, the effect of prostaglandin E2 (PGE2) on TTP expression in ASM cells has not been reported. We address this herein and reveal, for the first time, that TTP is not regulated by cAMP-activating agents nor following treatment with long-acting ß2-agonists. However, PGE2 does induce TTP mRNA expression and protein upregulation in ASM cells. Although the underlying mechanism of action remains undefined, we can confirm that PGE2-induced TTP upregulation is not mediated via cAMP, or EP2/EP4 receptor activation, and occurred in a manner independent of the p38 MAPK-mediated pathway. Taken together, these data confirm that ß2-agonists do not upregulate TTP in human ASM cells and indicate that another way in which PGE2 may achieve beneficial effects in asthma and COPD may be via upregulation of the master controller of inflammation-TTP.


Assuntos
Dinoprostona/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Tristetraprolina/biossíntese , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Azetidinas/farmacologia , Brônquios/citologia , Células Cultivadas , AMP Cíclico/metabolismo , Fosfatase 1 de Especificidade Dupla/genética , Fumarato de Formoterol/farmacologia , Humanos , Isoindóis/farmacologia , Miócitos de Músculo Liso/metabolismo , RNA Mensageiro/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Xinafoato de Salmeterol/farmacologia , Sulfonamidas/farmacologia , Tristetraprolina/genética , Regulação para Cima/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
J Asian Nat Prod Res ; 21(8): 735-741, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30014709

RESUMO

Two new compounds herialpins A-B (1-2), along with eleven known compounds, were isolated from the culture of fungus Hericium alpestre. The structures were elucidated by 1D and 2D NMR data, ESI-MS and X-ray crystallographic analysis. Compounds 1-2 were assayed for their cytotoxicity against three tumor cell lines compared with the known compound 3. Compounds 1 and 2 were found with modest activity, while compound 3 exhibits stronger selective inhibitory activity against A549 and HT-29 cells with IC50 values of 15.1 and 20.1 µmol/L, respectively. The pyrano[3,4-g]chromene-4,6-dione moiety in compound 3 should be responsible for the stronger selective inhibitory activity.


Assuntos
Agaricales/química , Furanos/isolamento & purificação , Isoindóis/isolamento & purificação , Células A549 , Agaricales/crescimento & desenvolvimento , Fermentação , Furanos/farmacologia , Células HT29 , Humanos , Isoindóis/farmacologia
12.
Int J Neurosci ; 129(5): 492-500, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30431374

RESUMO

BACKGROUND: Learning and memory are among the most important cognitive functions of the brain. Melatonin receptor type 2 (MT2R) is located in the hippocampus and participates in learning and memory processes. In the present study, we examined the role of hippocampal MT2R activation in the acquisition, consolidation, and retrieval of learning and memory in novel object recognition (NOR) and passive avoidance (PA) tasks. METHODS: IIK7 (0.03, 0.3, and 3 µg/µl/side), as a selective MT2R agonist, or vehicle was injected bilaterally into the dentate gyrus (DG) region of the hippocampus in rats five minutes before training, immediately after training, and five minutes before the retrieval-behavioral tasks, respectively. The discrimination index (DI) was measured in the NOR task, while step-through latency in acquisition (STLa), number of trials to acquisition (NOT), step-through latency in the retention trial (STLr), and time spent in the dark compartment (TDC) were determined in the PA task. RESULTS: The pretraining intrahippocampal injection of IIK7 at all doses significantly improved acquisition in the PA task. On the other hand, the posttraining intrahippocampal administration of IIK7 had no significant effects on consolidation. The preretrieval intrahippocampal injection of IIK7 at different doses attenuated the retrieval of memory. However, the NOR data showed that the intrahippocampal injection of IIK7 at different doses had no significant effects on the acquisition, consolidation, or retrieval in this task. DISCUSSION: Based on the findings, stimulation of MT2R could improve acquisition, whereas it had no effects on consolidation. It could impair retrieval in the PA task, while it had no effects on object recognition in rats.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Isoindóis/farmacologia , Memória/efeitos dos fármacos , Receptor MT2 de Melatonina/efeitos dos fármacos , /efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Isoindóis/administração & dosagem , Masculino , Consolidação da Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Ratos , Ratos Wistar , Receptor MT2 de Melatonina/agonistas , Fatores de Tempo
13.
Pharmacopsychiatry ; 52(2): 63-69, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29486512

RESUMO

INTRODUCTION: Accumulating evidence suggests the importance of epigenetic changes in the brain induced by antipsychotic drugs. However, due to the lack of systematic investigation, their effects on epigenetic status remain largely unclear. During the course of examining the epigenetic effects of antipsychotics, we here focused on perospirone, an atypical antipsychotic drug mainly used in Japan. METHODS: Genomic DNA was obtained from human neuroblastoma cells exposed to 2 different doses of perospirone. Comprehensive DNA methylation analysis was performed using the Infinium HumanMethylation450 BeadChip. RESULTS: Of about 470,000 probes, perospirone exposure changed DNA methylation at 4098 probes. These probes were enriched to genes for neural development. Probes showing hypermethylation were mainly found at gene body and intergenic regions, whereas those that showed hypomethylation were located near promoter regions. Additionally, DNA methylation changes were found in the probes for dopamine receptor 2 and serotonin receptor (HTR) 2A and HTR1A, which are the pharmacological targets of atypical antipsychotics. DISCUSSION: Our comprehensive DNA methylation analyses will contribute to a better understanding of detailed pharmacological actions of perospirone.


Assuntos
Antipsicóticos/farmacologia , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Isoindóis/farmacologia , Tiazóis/farmacologia , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Humanos , Japão , Neuroblastoma/patologia , Análise de Sequência com Séries de Oligonucleotídeos
14.
Sci Rep ; 8(1): 17239, 2018 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-30467317

RESUMO

The development of new treatments for castrate resistant prostate cancer (CRPC) must address such challenges as intrinsic tumor heterogeneity and phenotypic plasticity. Combined PTEN/TP53 alterations represent a major genotype of CRPC (25-30%) and are associated with poor outcomes. Using tumor-derived, castration-resistant Pten/Tp53 null luminal prostate cells for comprehensive, high-throughput, mechanism-based screening, we identified several vulnerabilities among >1900 compounds, including inhibitors of: PI3K/AKT/mTOR, the proteasome, the cell cycle, heat shock proteins, DNA repair, NFκB, MAPK, and epigenetic modifiers. HSP90 inhibitors were one of the most active compound classes in the screen and have clinical potential for use in drug combinations to enhance efficacy and delay the development of resistance. To inform future design of rational drug combinations, we tested ganetespib, a potent second-generation HSP90 inhibitor, as a single agent in multiple CRPC genotypes and phenotypes. Ganetespib decreased growth of endogenous Pten/Tp53 null tumors, confirming therapeutic activity in situ. Fifteen human CRPC LuCaP PDX-derived organoid models were assayed for responses to 110 drugs, and HSP90 inhibitors (ganetespib and onalespib) were among the select group of drugs (<10%) that demonstrated broad activity (>75% of models) at high potency (IC50 <1 µM). Ganetespib inhibits multiple targets, including AR and PI3K pathways, which regulate mutually compensatory growth and survival signals in some forms of CRPC. Combined with castration, ganetespib displayed deeper PDX tumor regressions and delayed castration resistance relative to either monotherapy. In all, comprehensive data from near-patient models presents novel contexts for HSP90 inhibition in multiple CRPC genotypes and phenotypes, expands upon HSP90 inhibitors as simultaneous inhibitors of oncogenic signaling and resistance mechanisms, and suggests utility for combined HSP90/AR inhibition in CRPC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Benzamidas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Genótipo , Ensaios de Triagem em Larga Escala/métodos , Humanos , Isoindóis/farmacologia , Masculino , Camundongos , PTEN Fosfo-Hidrolase/metabolismo , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Próstata/efeitos dos fármacos , Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Triazóis/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
15.
J Pharmacol Sci ; 138(3): 192-197, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30360947

RESUMO

We examined whether combination treatment with doxorubicin and cyclophosphamide, a traditional chemotherapy for breast cancer, induced anxiety-like behavior in rats. Furthermore, we evaluated the role of the serotonin (5-HT)2A receptor subtype in the anxiety-like behavior induced by such chemotherapy. Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. This caused the rats to display anxiety-like behavior during the light-dark test. In addition, we examined the rats' 5-HT2A receptor-mediated behavioral responses. Combination treatment with doxorubicin and cyclophosphamide significantly increased (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (a 5-HT2A receptor agonist)-induced wet-dog shake activity. This anxiety-like behavior was significantly inhibited by mirtazapine, a 5-HT2A receptor antagonist/5-HT1A receptor agonist, and tandospirone, a partial 5-HT1A receptor agonist, but not by fluoxetine, a selective serotonin reuptake inhibitor. The anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment is mediated by hyperfunctioning of the 5-HT2A receptor. Thus, 5-HT2A receptor antagonists or 5-HT1A receptor agonists might be useful for treating chemotherapy-induced anxiety disorders.


Assuntos
Ansiedade/prevenção & controle , Ciclofosfamida/farmacologia , Doxorrubicina/farmacologia , Anfetaminas/farmacologia , Animais , Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Ciclofosfamida/antagonistas & inibidores , Doxorrubicina/antagonistas & inibidores , Sinergismo Farmacológico , Fluoxetina/farmacologia , Isoindóis/farmacologia , Masculino , Mirtazapina/farmacologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Ratos
16.
Bioorg Med Chem Lett ; 28(23-24): 3761-3765, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30340900

RESUMO

A novel series of aminopyrimidinylisoindoline derivatives 1a-w having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC50 values of submicromolar range. Especially, compound 1u possessing (4-acetylpiperazin-1-yl)phenyl moiety exhibited extremely excellent efficacy (IC50 = <0.00050 µM). Their in vitro antiproliferative activities were tested over five cancer cell lines. Most compounds showed good antiproliferative activities against HeLa cell line. The kinase panel profiling of 50 different kinases and the selected inhibitory activities for the representative compound 1u were carried out. The compound 1u exhibited excellent inhibitory activities (IC50 = <0.00050, 0.025, and 0.050 µM for AXL, MER, and TYRO3, respectively) against TAM family, together with potent antiproliferative activity against MV4-11 cell line (GI50 = 0.10 µM) related to acute myeloid leukemia (AML).


Assuntos
Desenho de Drogas , Isoindóis/química , Isoindóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Aminação , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Isoindóis/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo
17.
Biomed Pharmacother ; 108: 263-270, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30223097

RESUMO

INTRODUCTION: The biological action of Substance P (SP) is mediated mainly by NK-1 receptors (NK1R) followed by NK2 receptors (NK2R). Aberrant expression of NK1R and NK2R has been identified in various carcinomas. The role of Substance P and its receptors, especially NK2R in cancer progression is not entirely known and there are conflicting results in the literature demonstrating the need for further investigation. In the current study, we examined the effects of SP and antagonists selective for the NK1R and NK2R in breast carcinoma cells metastasize to vital organs. METHODS: The effects of highly potent and selective non-peptide mouse NK1R and NK2R antagonists RP 67,580 and GR 159897, respectively, as well as SP and SP methyl ester, on both metastatic (4THM, 4TBM, 4TLM, 4T1) and non-metastatic (67NR) breast cancer cells were determined. RESULTS: NK1R and NK2R were over expressed in metastatic breast cells compared to non-metastatic cells. The NK1R antagonist at a 30 µM dose inhibited cell growth and induced cell death in metastatic cells while enhancing phosphorylation of Akt, the latter response not observed in the non-metastatic 67NR cells. Blocking the action of SP at the NK2R (30 µM antagonist) suppressed cellular proliferation in all the cell lines examined, with a response less prominent than that of the NK1R antagonist. Differently, the NK2R antagonist increased phosphorylation of p38 and enhanced MIP-2 secretion. SP and the SP methyl ester neither altered cell proliferation nor the effects of NK1R and NK2R antagonists in the metastatic cell lines. CONCLUSIONS: Increased sensitivity of metastatic breast carcinoma cells to NK1R and NK2R antagonists suggest potential therapeutic value of antagonists in metastatic disease. NK1R and NK2R in metastatic breast carcinoma cells react differently to agonists and antagonists. These findings together with previously published data demonstrate that differential consequences of receptor antagonists and SP may inhibit breast cancer growth and metastasis.


Assuntos
Neoplasias da Mama/patologia , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-2/metabolismo , Substância P/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL2/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Isoindóis/farmacologia , Camundongos , Metástase Neoplásica , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Substância P/análogos & derivados , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Bioorg Chem ; 80: 706-713, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30064081

RESUMO

The synthesis, characterization and biological evaluation of a library of isoindoline-1,3-dione-based oximes and benzenesulfonamide hydrazones is disclosed. The set of hydroxyiminoethyl aromatic derivatives 10-18 was designed to assess the potentiality as zinc-binder for a feebly studied functional group in the field of carbonic anhydrase (CA, EC 4.2.1.1) inhibition. Analogue phenylphthalimmides were linked to benzenesulfonamide scaffold by hydrazone spacers in the second subset of derivatives 20-28 to further investigate the application of the "tail approach" as tool to afford CA selective inhibition profiles. The compounds were assayed for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1), the cytosolic CA I and II, and the membrane-bound CA IV and tumor-associated CA IX. The new zinc-binders, both of the oxime and sulfonamide types, showed a striking selective activity against the target hCA IX over ubiquitous hCA I and II, with diverse inhibitory ranges and ratio differing the two subsets. With CA IX being a strongly current antitumor/antimetastatic drug target, these series of compounds may be of interest for the development of new, both conventional and unconventional anticancer drugs targeting hypoxia-induced CA isoforms such as CA IX with minimum ubiquitous CAs-related side effects.


Assuntos
Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Hidrazonas/farmacologia , Isoindóis/farmacologia , Oximas/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Isoindóis/síntese química , Isoindóis/química , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Oximas/síntese química , Oximas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
19.
Bioorg Med Chem Lett ; 28(18): 3050-3056, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30097366

RESUMO

A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different ß-substituted phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation (30, EC50 = 1.2 µM, cLogP = 1.3; TAK-875: EC50 = 5.1 µM, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice.


Assuntos
Desenho de Drogas , Isoindóis/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Tetra-Hidroisoquinolinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Isoindóis/química , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química
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