Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21.541
Filtrar
1.
Chem Biol Interact ; 312: 108816, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505164

RESUMO

Indirubins E804 (indirubin-3'-(2,3 dihydroxypropyl)-oximether) and 7BIO (7-Bromoindirubin-3'-oxime) are synthetic derivatives of natural indirubin, the active compound in Danggui Longhui Wan, a traditional Chinese remedy for cancer and inflammation. Herein, we explore E804 and 7BIO for their potential to modulate key pro-inflammatory genes and cytokines in LN-18 and T98G glioblastoma cells. High grade gliomas typically secrete large amounts of inflammatory cytokines and growth factors that promote tumor growth in an autocrine fashion. Inflammation is emerging as a key concern in the success of new treatment modalities for glioblastomas. Studies indicate that select indirubin derivatives bind and activate signaling of the AHR pathway, as well as inhibit cyclin-dependent kinases and STAT3 signaling. AHR signaling is involved in hematopoiesis, immune function, cell cycling, and inflammation, and thus may be a possible target for glioma treatment. To determine the significance of the AHR pathway in LN-18 and T98G glioma inflammatory profiles, and on the effects of E804 and 7BIO on these profiles, we used 6,2',4'-trimethoxyflavone (TMF), a putative selective AHR antagonist. It was confirmed that E804 and 7BIO activates the AHR leading to cyp1b1 expression, and that TMF antagonizes expression. We then employed a commercial cancer inflammation and immunity crosstalk qRT-PCR array to screen for anti-inflammatory related properties. TMF alone inhibited expression of ifng, ptsg2, il12b, tnfa, il10, il13, the balance between pd1 and pdl1, and even expression of mhc1a/b. E804 was very potent in suppressing many pro-inflammatory genes, including il1a, il1b, il12a, ptgs2, tlr4, and others. E804 also affected expression of il6, vegfa, and stat3. Conversely, 7BIO induced cox2, but suppressed a different selection of pro-inflammatory genes including nos2, tnfa, and igf1. Secretion of IL-6 protein, an iconic inflammatory cytokine, was decreased by E804. VEGF (vascular endothelial growth factor) protein secretion was upregulated by 7BIO, yet downregulated by E804 and E804 plus TMF. Thus, E804 is both an AHR ligand and regulator of important pro-inflammatory cytokines such as IL-6 and oncogene STAT3, among others. Our results point to the use of E804 and TMF in combination as a promising new treatment for glioblastoma.


Assuntos
Indóis/farmacologia , Oximas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Citocinas/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Indóis/química , Oximas/química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Gene ; 717: 144047, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31421190

RESUMO

BACKGROUND: Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways play important roles in the formation of the blood vascular system and nervous system across animal phyla. We have earlier reported VEGF and FGF from Hydra vulgaris Ind-Pune, a cnidarian with a defined body axis, an organized nervous system and a remarkable ability of regeneration. We have now identified three more components of VEGF and FGF signaling pathways from hydra. These include FGF-1, FGF receptor 1 (FGFR-1) and VEGF receptor 2 (VEGFR-2) with a view to deciphering their possible roles in regeneration. METHODS: In silico analysis of proteins was performed using Clustal omega, Swiss model, MEGA 7.0, etc. Gene expression was studied by whole mount in situ hybridization. VEGF and FGF signaling was inhibited using specific pharmacological inhibitors and their effects on head regeneration were studied. RESULTS: Expression patterns of the genes indicate a possible interaction between FGF-1 and FGFR-1 and also VEGF and VEGFR-2. Upon treatment of decapitated hydra with pharmacological inhibitor of FGFR-1 or VEGFR-2 for 48 h, head regeneration was delayed in treated as compared to untreated, control regenerates. When we studied the expression of head specific genes HyBra1 and HyKs1 and tentacle specific gene HyAlx in control and treated regenerates using whole mount in situ hybridization, expression of all the three genes was found to be adversely affected in treated regenerates. CONCLUSIONS: The results suggest that VEGF and FGF signaling play important roles in regeneration of hypostome and tentacles in hydra.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Cabeça/fisiologia , Hydra/fisiologia , Regeneração/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Simulação por Computador , Fator 1 de Crescimento de Fibroblastos/química , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Hydra/efeitos dos fármacos , Indóis/farmacologia , Domínios Proteicos , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais , Homologia Estrutural de Proteína , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
Int J Nanomedicine ; 14: 4931-4947, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371941

RESUMO

Background: Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), is a promising noninvasive strategy in the treatment of cancers due to its highly localized specificity to tumors and minimal side effects to normal tissues. However, single phototherapy often causes tumor recurrence which hinders its clinical applications. Therefore, developing a NIR-guided dendritic nanoplatform for improving the phototherapy effect and reducing the recurrence of tumors by synergistic chemotherapy and phototherapy is essential. Methods: A fluorescent targeting ligand, insisting of ICG derivative cypate and a tumor penetration peptide iRGD (CRGDKGPDC), was covalently combined with PAMAM dendrimer to prepare a single agent-based dendritic theranostic nanoplatform iRGD-cypate-PAMAM-DTX (RCPD). Results: Compared with free cypate, the resulted RCPD could generate enhanced singlet oxygen species while maintaining its fluorescence intensity and heat generation ability when subjected to NIR irradiation. Furthermore, our in vitro and in vivo therapeutic studies demonstrated that compared with phototherapy or chemotherapy alone, the combinatorial chemo-photo treatment of RCPD with the local exposure of NIR light can significantly improve anti-tumor efficiency and reduce the risk of recurrence of tumors. Conclusion: The multifunctional theranostic platform (RCPD) could be used as a promising method for NIR fluorescence image-guided combinatorial treatment of tumor cancers.


Assuntos
Antineoplásicos/farmacologia , Dendrímeros/química , Raios Infravermelhos , Nanopartículas/química , Fototerapia , Animais , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Docetaxel/farmacologia , Endocitose/efeitos dos fármacos , Fluorescência , Células Hep G2 , Temperatura Alta , Humanos , Indóis/farmacologia , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oligopeptídeos/química , Fotoquimioterapia , Propionatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Nanomedicina Teranóstica
5.
Chem Commun (Camb) ; 55(67): 9919-9922, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31328197

RESUMO

Reported herein is a relebactam-derived fluorogenic reagent for covalent labeling of serine ß-lactamases (SBLs), which are the major causes of bacterial resistance to ß-lactam antibiotics. This highly selective imaging reagent generates over 300-fold stronger near-infrared fluorescence signals upon covalently bonding to SBLs, allowing wash-free visualization of live antimicrobial-resistant bacteria.


Assuntos
Marcadores de Afinidade/farmacologia , Compostos Azabicíclicos/farmacologia , Enterobacter cloacae/isolamento & purificação , Corantes Fluorescentes/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/química , Marcadores de Afinidade/síntese química , Marcadores de Afinidade/química , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Enterobacter cloacae/enzimologia , Fluoresceínas/síntese química , Fluoresceínas/química , Fluoresceínas/farmacologia , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/química
6.
J Photochem Photobiol B ; 197: 111554, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31326843

RESUMO

Bovine mastitis is an endemic disease of dairy cattle that is considered to be one of the most frequent and costly diseases in veterinary medicine. An increase in the incidence of disease results in the increased use of antibiotics, which in turn increases the potential of bacterial resistance. This study aimed to investigate the effectiveness of antimicrobial photodynamic therapy (aPDT) in the treatment of bovine mastitis, as an alternative to systemic antibiotics. To identify the key factors affecting photoinactivation efficacy, realistic experiments in view of the end-use were conducted in milk samples using two different photosensitizers: methylene blue (MB) and silicon (IV) phthalocyanine derivative (SiPc). We explored the effects of divalent ions and fat content on the aPDT outcome and determined influence of different proteins on aPDT efficacy. Levels of bacterial sensitivity to PSs varied depending on the type of bacteria (Gram-positive vs. Gram-negative) and light exposure time. Critical interrelated factors affecting aPDT in milk were identified and an efficient combination of treatment conditions that can lead to a full photodynamic inactivation of bacteria was determined.


Assuntos
Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Leite/microbiologia , Fármacos Fotossensibilizantes/farmacologia , Animais , Bovinos , Feminino , Indóis/química , Indóis/farmacologia , Indóis/uso terapêutico , Luz , Mastite Bovina/tratamento farmacológico , Mastite Bovina/microbiologia , Mastite Bovina/patologia , Azul de Metileno/farmacologia , Azul de Metileno/uso terapêutico , Proteínas do Leite/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Oxigênio Singlete/metabolismo
7.
Anticancer Res ; 39(7): 3615-3620, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262887

RESUMO

Heterocyclic rings are recognized as key components of many natural, semi-synthetic and synthetic molecules with a broad spectrum of biological activities. Among these molecules, the indole and imidazo[2,1-b][1,3,4]thiadiazole systems have recently been described as useful scaffolds for the design of anticancer agents. Herein the antitumor activity of a series of 3-(6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1H-indoles, designed as hybrid structures, was assessed. Seven out of 10 compounds (1a-g) were submitted to National Cancer Institute (NCI). Remarkably, compound 1g showed antiproliferative activity against the full panel of sixty human cancer lines, with half-maximal inhibitory concentration of between 1.67 and 10.3 µM. Further studies showed antiproliferative activity of 1a-g and of three additional compounds 1h, 1i and 1l, with different substituents on the indole nucleus and phenyl ring, against three pancreatic cancer cell lines. In particular, derivatives 1g and 1h inhibited both proliferation and migration of SUIT-2 cells at concentrations lower than 10 µM. In conclusion, new indole derivatives are characterized by in vitro antitumor activity, supporting future mechanistic studies.


Assuntos
Antineoplásicos/farmacologia , Indóis/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos
8.
Zhongguo Zhong Yao Za Zhi ; 44(12): 2532-2537, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359720

RESUMO

According to drug design flattening principle,a series of novel indole podophyllotoxin derivatives which were introduced different indole substituents in C-4 position on the basis of podophyllotoxin nucleus were synthesized with the starting material podophyllotoxin and 1 H-indole-5-carboxylic acid. Its anti-tumor activity in vitro was tested in order to screen for high-efficiency and low-toxic compounds. Six target compounds were synthesized,and were confirmed by~1 H-NMR,~(13)C-NMR,HR-ESI-MS and melting point determination analysis. All these target compounds were not reported by previous literature. Using etoposide as positive control drug,all the target compounds were screened for cytotoxicity against He La cells,K562 cells and K562/A02 cell in vitro by MTT method. The antitumor activity screening results showed that compounds 4 b,4 e,4 f exhibited higher inhibitory rate against He La cells and K562 cells than those of control drug VP-16. This route has the advantages on simple operation and reasonable design,provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.


Assuntos
Antineoplásicos/farmacologia , Indóis/farmacologia , Podofilotoxina/farmacologia , Antineoplásicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Indóis/síntese química , Células K562 , Podofilotoxina/síntese química , Relação Estrutura-Atividade
9.
Fitoterapia ; 137: 104257, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278976

RESUMO

Two new meroditerpene pyrones, chevalone F (1) and 11-hydroxychevalone E (2), a new tryptoquivaline analog, tryptoquivaline V (3) and a new brasiliamide analog, brasiliamide G (4), together with thirteen known compounds, chevalones A-C (5-7), chevalone E (8), 11-hydroxychevalone C (9), pyripyropene A (10), isochaetominine C (11), pyrrolobenzoxazine terpenoids CJ-12662 (12) and CJ-12663 (13), fischerindoline (14), eurochevalierine (15), 1,4-diacetyl-2,5-dibenzylpiperazine-3,7''-oxide (16) and lecanorin (17) were isolated from the fungus Neosartorya pseudofischeri. Their structures were established on the basis of spectroscopic evidence. Compound 2 showed weak antibacterial activity against Escherichia coli and Salmonella enterica serovar Typhimurium, whereas compounds 7, 12, 13 and 15 showed antibacterial activity against Bacillus cereus and Staphylococcus aureus. In addition, compounds 13 and 14 showed cytotoxicity against KB and MCF-7 cancer cell lines, as well as the Vero cell line.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Indóis/farmacologia , Neosartorya/química , Pironas/farmacologia , Animais , Antibacterianos/isolamento & purificação , Antineoplásicos/isolamento & purificação , Cercopithecus aethiops , Florestas , Humanos , Indóis/isolamento & purificação , Células KB , Células MCF-7 , Estrutura Molecular , Pironas/isolamento & purificação , Microbiologia do Solo , Tailândia , Células Vero
10.
J Enzyme Inhib Med Chem ; 34(1): 1152-1157, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31179771

RESUMO

Nine indole derivatives (9a-i) were tested as potential inhibitors of the Keap1-Nrf2 interaction. This class of compounds increases the intracellular levels of the transcription factor Nrf2 and the consequent expression of enzymes encoded by genes containing the antioxidant response element (ARE). In the ARE-luciferase reporter assay only 9e-g revealed to be remarkably more active than t-butylhydroxyquinone (t-BHQ), with 9g standing out as the best performing compound. While 9e and 9f are weak acids, 9g is an ampholyte prevailing as a zwitterion in neutral aqueous solutions. The ability of 9e-g to significantly increase levels of Nrf2, NADPH:quinone oxidoreductase 1, and transketolase (TKT) gave further support to the hypothesis that these compounds act as inhibitors of the Keap1-Nrf2 interaction. Docking simulations allowed us to elucidate the nature of the putative interactions between 9g and Keap1.


Assuntos
Indóis/química , Indóis/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
11.
Nat Commun ; 10(1): 2427, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160593

RESUMO

Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme's activity on intestinal immune responses during inflammatory bowel disease (IBD). Here we report that suppressing EZH2 activity ameliorates experimental intestinal inflammation and delayed the onset of colitis-associated cancer. In addition, we identified an increased number of functional MDSCs in the colons, which are essential for EZH2 inhibitor activity. Moreover, inhibition of EZH2 activity promotes the generation of MDSCs from hematopoietic progenitor cells in vitro, demonstrating a previously unappreciated role for EZH2 in the development of MDSCs. Together, these findings suggest the feasibility of EZH2 inhibitor clinical trials for the control of IBD. In addition, this study identifies MDSC-promoting effects of EZH2 inhibitors that may be undesirable in other therapeutic contexts and should be addressed in a clinical trial setting.


Assuntos
Colite/imunologia , Colo/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Doenças Inflamatórias Intestinais/imunologia , Células Supressoras Mieloides/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/etiologia , Sulfato de Dextrana/toxicidade , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Feminino , Células-Tronco Hematopoéticas/citologia , Código das Histonas , Histonas/metabolismo , Técnicas In Vitro , Indazóis/farmacologia , Indóis/farmacologia , Metilação , Camundongos , Células Supressoras Mieloides/citologia , Piridonas/farmacologia
12.
Expert Opin Ther Pat ; 29(7): 497-507, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31242055

RESUMO

INTRODUCTION: Positive allosteric modulation of mGlu2 has attracted much interest as an alternative approach to classical orthosteric receptor activation. Two mGlu2 PAMS have advanced into the clinic. The results obtained in schizophrenia and MDD phase 2 clinical trials have tempered the high expectations put on selective mGlu2 receptor activation for treating these conditions; nevertheless, the search for novel therapeutic indications and novel chemotypes continues to be an active field of research. AREAS COVERED: 2013-2018 patent literature on mGlu2 receptor PAMs. EXPERT OPINION: After a decade of intensive research, the mGlu2 PAM field has seen a deceleration in the last five years. Negative phase 2 schizophrenia clinical trials with JNJ-40411813 and AZD8529 seem to have tempered the high expectations of the scientific community on the utility of mGlu2 PAMs for the treatment of schizophrenia. Nevertheless, novel therapeutic indications continue to be explored and AZD8529 is currently in a phase 2 study for smoking cessation. The advances in medicinal chemistry and in pharmacology, with novel indications such as epilepsy, have set the stage in the field of mGlu2 receptor PAMs. Ongoing preclinical and clinical studies will contribute to define their optimal therapeutic indication and potential to become novel therapeutic agents.


Assuntos
Indóis/uso terapêutico , Oxidiazóis/uso terapêutico , Piperidinas/uso terapêutico , Piridonas/uso terapêutico , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Humanos , Indóis/farmacologia , Oxidiazóis/farmacologia , Patentes como Assunto , Piperidinas/farmacologia , Piridonas/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia
13.
Eur J Med Chem ; 177: 414-424, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158754

RESUMO

Due to the role of butyrylcholinesterase (BChE) in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE) have been recently envisaged, besides acetylcholinesterase (AChE) inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI) is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC50s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N2-(4-phenylbutyl) HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC50 0.17 µM) and selective (>100-fold) inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-ß (Aß) peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P < 0.001) cell viability when impaired by Aß1-42 and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD.


Assuntos
Azepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/metabolismo , Azepinas/síntese química , Azepinas/química , Azepinas/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Relação Dose-Resposta a Droga , Desenho de Drogas , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
15.
Comput Biol Chem ; 80: 512-523, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31185422

RESUMO

A new series of N'-(substituted phenyl)-5-chloro/iodo-3-phenyl-1H-indole-2-carbohydrazide (5, 6) and N-[2-(substituted phenyl)-4-oxo-1,3-thiazolidin-3-yl]-5-iodo/chloro-3-phenyl-1H-indole-2-carboxamide (7, 8) derivatives were synthesized and evaluated for their anticancer properties. Compounds 5a and 6b, selected as prototypes by the National Cancer Institute for screening against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions, demonstrated remarkable antiproliferative activity against leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, and breast cancer (MCF-7) cell lines with GI50 values < 0.4 µM. A subset of the compounds was then tested for their potential to inhibit tubulin polymerization. Compounds 6f and 6g showed significant cytotoxicity at the nM level on MCF-7 cells and exhibited significant inhibitory activity on tubulin assembly and colchicine binding at about the same level as combretastatin A-4. Finally, docking calculations were performed to identify the binding mode of these compounds. Group 5 and 6 compounds interacted with the colchicine binding site through hydrophobic interactions similar to those of colchicine. These compounds with antiproliferative activity at high nanomolar concentration can serve as scaffolds for the design of novel microtubule targeting agents.


Assuntos
Antineoplásicos/farmacologia , Hidrazinas/farmacologia , Indóis/farmacologia , Tiazolidinas/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Hidrazinas/metabolismo , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Células MCF-7 , Simulação de Acoplamento Molecular , Ligação Proteica , Tiazolidinas/síntese química , Tiazolidinas/química , Tiazolidinas/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo
16.
Eur J Med Chem ; 178: 571-588, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220675

RESUMO

In order to obtain novel pharmacological tools and to investigate a multitargeting analgesic strategy, the CB1 and CB2 cannabinoid receptor agonist JWH-018 was conjugated with the opiate analgesic oxycodone or with an enkephalin related tetrapeptide. The opioid and cannabinoid pharmacophores were coupled via spacers of different length and chemical structure. In vitro radioligand binding experiments confirmed that the resulting bivalent compounds bound both to the opioid and to the cannabinoid receptors with moderate to high affinity. The highest affinity bivalent derivatives 11 and 19 exhibited agonist properties in [35S]GTPγS binding assays. These compounds activated MOR and CB (11 mainly CB2, whereas 19 mainly CB1) receptor-mediated signaling, as it was revealed by experiments using receptor specific antagonists. In rats both 11 and 19 exhibited antiallodynic effect similar to the parent drugs in 20 µg dose at spinal level. These results support the strategy of multitargeting G-protein coupled receptors to develop lead compounds with antinociceptive properties.


Assuntos
Analgésicos Opioides/farmacologia , Encefalinas/farmacologia , Indóis/farmacologia , Naftalenos/farmacologia , Oxicodona/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , Encefalinas/química , Indóis/química , Camundongos , Estrutura Molecular , Naftalenos/química , Oxicodona/química , Ratos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 178: 433-445, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202991

RESUMO

Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as A-region and triazole as B-region. The SAR analysis indicated that 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole analogues displayed excellent antagonism of hTRPV1 activation by capsaicin and showed better potency compared to the corresponding dihydroindole analogues. Optimization of this design led to the eventual identification of 2-((1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (6g), a potent TRPV1 antagonist. In vitro, using cells expressing recombinant human TRPV1 channels, 6g displayed potent antagonism activated by capsaicin (IC50 = 0.075 µM) and only partially blocked acid activation of TRPV1. In vivo, 6g exhibited good efficacy in capsaicin-induced and heat-induced pain models and had almost no hyperthermia side-effect. Furthermore, pharmacokinetic studies revealed that compound 6g had a superior oral exposure after oral administration in rats. To understand its binding interactions with the receptor, the docking study of 6g was performed in rTRPV1 model and showed an excellent fit to the binding site. On the basis of its superior profiles, 6g could be considered as the lead candidate for the further development of antinociceptive drugs.


Assuntos
Desenho de Drogas , Indóis/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Triazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Indóis/administração & dosagem , Indóis/química , Masculino , Camundongos , Camundongos Endogâmicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo , Triazóis/administração & dosagem , Triazóis/química
18.
Toxicol Lett ; 313: 66-76, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31201936

RESUMO

Mono-methylindoles (MMI) were described as agonists and/or antagonists of the human aryl hydrocarbon receptor (AhR). Here, we investigated the effects of MMI on AhR-CYP1A pathway in human hepatocytes and HepaRG cells derived from human progenitor hepatic cells. All MMI, except of 2-methylindole, strongly induced CYP1A1 and CYP1A2 mRNAs in HepaRG cells. Induction of CYP1A genes was absent in AhR-knock-out HepaRG cells. Consistently, CYP1A1 and CYP1A2 mRNAs and proteins were induced by all MMIs (except 2-methylindole), in human hepatocytes. The enzyme activity of CYP1A1 was inhibited by MMIs in human hepatocytes and LS180 colon cancer cells in a concentration-dependent manner (IC50 values from 1.2 µM to 23.8 µM and from 3.4 µM to 11.4 µM, respectively). Inhibition of CYP1A1 activity by MMI in human liver microsomes was much weaker as compared to that in intact cells. Incubation of parental MMI with human hepatocytes either diminished (4-methylindole, 6-methylindole) or enhanced (7-methylindole) their agonist effects on AhR in AZ-AHR reporter cells. In conclusion, overall effects of MMI on AhR-CYP1A pathway in human cells comprise the induction of CYP1A genes through AhR, the inhibition of CYP1A catalytic activity and possibly the metabolic transformation causing loss or gain of AhR agonist activity of parental compounds.


Assuntos
Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/biossíntese , Indutores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Hepatócitos/efeitos dos fármacos , Indóis/farmacologia , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/enzimologia , Citocromo P-450 CYP1A1/genética , Relação Dose-Resposta a Droga , Indução Enzimática , Feminino , Hepatócitos/enzimologia , Humanos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Pessoa de Meia-Idade , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Adulto Jovem
19.
Gastroenterology ; 157(3): 793-806.e14, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31170413

RESUMO

BACKGROUND & AIMS: The role of aryl hydrocarbon receptor (AhR) in liver fibrosis is controversial because loss and gain of AhR activity both lead to liver fibrosis. The goal of this study was to investigate how the expression of AhR by different liver cell types, hepatic stellate cells (HSCs) in particular, affects liver fibrosis in mice. METHODS: We studied the effects of AhR on primary mouse and human HSCs, measuring their activation and stimulation of fibrogenesis using RNA-sequencing analysis. C57BL/6J mice were given the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE); were given carbon tetrachloride (CCl4); or underwent bile duct ligation. We also performed studies in mice with disruption of Ahr specifically in HSCs, hepatocytes, or Kupffer cells. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and immunoblotting. RESULTS: AhR was expressed at high levels in quiescent HSCs, but the expression decreased with HSC activation. Activation of HSCs from AhR-knockout mice was accelerated compared with HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor ß-induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis after administration of CCl4 or bile duct ligation. C57BL/6J mice given ITE did not develop CCl4-induced liver fibrosis, whereas mice without HSC AhR given ITE did develop CCl4-induced liver fibrosis. In studies of mouse and human HSCs, we found that AhR prevents transforming growth factor ß-induced fibrogenesis by disrupting the interaction of Smad3 with ß-catenin, which prevents the expression of genes that mediate fibrogenesis. CONCLUSIONS: In studies of human and mouse HSCs, we found that AhR prevents HSC activation and expression of genes required for liver fibrogenesis. Development of nontoxic AhR agonists or strategies to activate AhR signaling in HSCs might be developed to prevent or treat liver fibrosis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Senescência Celular , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Células Estreladas do Fígado/metabolismo , Cirrose Hepática Experimental/prevenção & controle , Fígado/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proliferação de Células , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Regulação da Expressão Gênica , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Indóis/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/deficiência , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais , Proteína Smad3/metabolismo , Tiazóis/farmacologia , beta Catenina/metabolismo
20.
Gynecol Oncol ; 154(1): 218-227, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31053403

RESUMO

OBJECTIVES: NR4A1 is overexpressed in many solid tumors, and the objectives of this study were to investigate the expression and functional role of this receptor in endometrial cancer cells and demonstrate that NR4A1 antagonist inhibit mTOR. METHODS: Ishikawa and Hec-1B endometrial cells were used as models to investigate the parallel effects of NR4A1 knockdown by RNA interference (siNR4A1) and treatment with bis-indole-derived NR4A1 ligands (antagonists) on cell growth and survival by determining cell numbers and effects on Annexin V staining. Western blot analysis of whole cell lysates was used to determine effects of these treatments on expression of growth promoting, survival and apoptotic genes and mTOR signaling. Effects of NR4A1 antagonists on tumor growth were determined in athymic nude mice bearing Hec-1B cells as xenografts. RESULTS: siNR4A1 or treatment with bis-indole-derived NR4A1 antagonists inhibited growth of endometrial cancer cells in vitro and endometrial tumors in vivo and this was accompanied by decreased expression of growth promoting and survival genes and mTOR inhibition. CONCLUSIONS: NR4A1 exhibited pro-oncogenic activity in endometrial cells due, in part, to regulation of cell growth, survival and mTOR signaling, and all of these pathways and their associated gene products were inhibited after treatment with bis-indole-derived NR4A1 antagonists. Moreover, these compounds also blocked endometrial tumor growth in vivo demonstrating that NR4A1 is a potential novel drug target for treatment of endometrial cancer.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Indóis/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Endométrio/patologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , Ligantes , Camundongos , Camundongos Nus , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA