Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 19 de 19
Filtrar
1.
Bioorg Chem ; 130: 106234, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36375353

RESUMO

Ras protein has been considered a fascinating target for anticancer therapy because its malfunction is closely related to cancer. However, Ras has been considered undruggable because of the failure to regulate its malfunction by controlling the Ras activation mechanism. Recently, Lumakras targeting the G12C mutation was approved, and therapeutic interest in Ras for anticancer therapy has been rejuvenated. Here, we present a series of compounds that inhibit Ras via a unique mechanism of action that exploits the relationship between the Wnt/ß-catenin pathway and Ras. KYA1797K (1) binds to axin to stabilize the ß-catenin destruction complex that causes the phosphorylation and subsequent degradation of Ras, similar to canonical ß-catenin regulation. Based on the chemical structure of 1, we performed a structural optimization and identified 3-(2-hydroxyethyl)-5-((6-(4-nitrophenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (13d) as the most potent compound. 13d displayed antitumor effects in a colorectal cancer model with enhanced inhibition activity on Ras. The results of this study suggest that the further development of 13d could contribute to the development of Ras inhibitors with novel mechanisms of action.


Assuntos
Neoplasias Colorretais , beta Catenina , Proteínas ras , Humanos , Proteína Axina/química , Proteína Axina/genética , Proteína Axina/metabolismo , beta Catenina/química , beta Catenina/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Proteínas ras/efeitos dos fármacos , Proteínas ras/metabolismo , Via de Sinalização Wnt
2.
Bioorg Chem ; 121: 105664, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35176556

RESUMO

Glycogen synthase kinase-3ß (GSK-3ß) appears to be ordinarily expressed, and functionally redundant in Wnt/ß-catenin signaling. The Wnt proteins induce transduction of a cytoplasmic protein, Dishevelled (Dvl) which negatively modulates GSK-3ß activity. CXXC5 is a negative modulator of the Wnt/ß-catenin signaling through the interaction with Dvl in the cytosol. This indicates that Wnt/ß-catenin signaling could be efficiently modulated by controlling GSK-3ß and the CXXC5-Dvl interaction. In this study, we designed a series of indirubin-3'-oxime and indirubin-3'-alkoxime derivatives containing various functional groups at the 5- or 6-position (R1) alongside alkyl or benzylic moieties at the 3'-oxime position (R2). These activate Wnt signaling through inhibitions of both GSK-3ß and the CXXC5-Dvl protein-protein interaction, in addition, the improvement of pharmacological properties. The potent activity profiles of the synthesized compounds suggested that dual inhibition of GSK-3ß and the CXXC5-Dvl interaction could be an appropriate approach towards safely and efficientlyactivating Wntsignaling. Thus, dual-targeting inhibitors are potentially better candidates for efficient activation ofWntsignaling compared to GSK-3ß inhibitors.


Assuntos
Via de Sinalização Wnt , beta Catenina , Proteínas Desgrenhadas/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Indóis , Oximas/farmacologia , Regulação para Cima , beta Catenina/metabolismo
3.
Bioorg Chem ; 112: 104907, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33979735

RESUMO

The enzyme leucyl-tRNA synthetase (LRS) and the amino acid leucine regulate the mechanistic target of rapamycin (mTOR) signaling pathway. Leucine-dependent mTORC1 activation depends on GTPase activating protein events mediated by LRS. In a prior study, compound BC-LI-0186 was discovered and shown to interfere with the mTORC1 signaling pathway by inhibiting the LRS-RagD interaction. However, BC-LI-0186 exhibited poor solubility and was metabolized by human liver microsomes. In this study, in silico physicochemical properties and metabolite analysis of BC-LI-0186 are used to investigate the addition of functional groups to improve solubility and microsomal stability. In vitro experiments demonstrated that 7b and 8a had improved chemical properties while still maintaining inhibitory activity against mTORC1. The results suggest a new strategy for the discovery of novel drug candidates and the treatment of diverse mTORC1-related diseases.


Assuntos
Inibidores Enzimáticos/farmacologia , Leucina-tRNA Ligase/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Proteínas Monoméricas de Ligação ao GTP/antagonistas & inibidores , Pirazolonas/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Leucina-tRNA Ligase/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Estrutura Molecular , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Pirazolonas/síntese química , Pirazolonas/química , Relação Estrutura-Atividade
5.
Pharmaceuticals (Basel) ; 17(2)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38399447

RESUMO

The epidermal growth factor receptor (EGFR), also known as ErbB1 and HER1, belongs to the receptor tyrosine kinase family. EGFR serves as the primary driver in non-small-cell lung cancer (NSCLC) and is a promising therapeutic target for NSCLC. In this study, we synthesized a novel chemical library based on a benzofuran-indole hybrid scaffold and identified 8aa as a potent and selective EGFR inhibitor. Interestingly, 8aa not only showed selective anticancer effects against NSCLC cell lines, PC9, and A549, but it also showed significant inhibitory effects against the double mutant L858R/T790M EGFR, which frequently occurs in NSCLC. In addition, in PC9 and A549 cells, 8aa potently blocked the EGFR signaling pathway, cell viability, and cell migration. These findings suggest that 8aa, a benzofuran-indole hybrid derivative, is a novel EGFR inhibitor that may be a potential candidate for the treatment of NSCLC patients with EGFR mutations.

6.
J Med Chem ; 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39405365

RESUMO

This study explored novel immunomodulatory approaches for cancer treatment, with a specific focus on lung cancer, the leading cause of cancer-related deaths worldwide. We synthesized indole-based phospholipase D (PLD) inhibitors with various substituents to improve anticancer efficacy. Through structure-activity relationship studies, the key compound was identified that significantly inhibiting PLD, suppressing cell growth, viability, and migration in vitro, while inducing apoptosis of lung cancer cells. In silico docking studies confirmed its binding to the PLD1 active site, highlighting the role of specific residues in inhibiting PLD1 activity. The inhibitor modulated oncogenic pathways and immune evasion in lung cancer cells, showing potential for immunotherapy. In vivo experiments in a mouse model showed tumor reduction and immune response alteration. Combining these inhibitors with gemcitabine, an anticancer drug, synergistically enhanced inhibition of lung cancer cell apoptosis and proliferation. This research offers new insights into PLD inhibitor as potential cancer therapeutics.

7.
Bioorg Med Chem ; 21(3): 788-94, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23266181

RESUMO

RhoB, one of the upstream signaling proteins of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway, is frequently mutated in human cancer. Based on a piperazine alkyl derivative that induced apoptosis via up-regulation of RhoB, we synthesized novel aliphatic amido/sulfonamido-quaternary ammonium salts and evaluated their biological activities using an in vitro growth inhibition assay and RhoB promoter assay in human cancer cells. Compound 3a was the most promising anticancer agent in the series, based upon its potent growth inhibition via RhoB-mediated signaling. These novel aliphatic amido/sulfonamido-quaternary ammonium salts may be useful as a platform for development of anticancer chemotherapeutic agents.


Assuntos
Amidas/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Compostos de Amônio Quaternário/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Sais/síntese química , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade
8.
Biomed Pharmacother ; 167: 115445, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37690388

RESUMO

Variants in SLC26A4 (pendrin) are the most common reasons for genetic hearing loss and vestibular dysfunction in East Asians. In patients with Pendred syndrome and DFNB4 (autosomal recessive type of genetic hearing loss 4), caused by variants in SLC26A4, the hearing function is residual at birth and deteriorates over several years, with no curative treatment for these disorders. In the present study, we revealed that a novel small molecule restores the expression and function of mutant pendrin. High-throughput screening of 54,000 small molecules was performed. We observed that pendrin corrector (PC2-1) increased the surface expression and anion exchange activity of p.H723R pendrin (H723R-PDS), the most prevalent genetic variant that causes Pendred syndrome and DFNB4. Furthermore, in endogenous H723R-PDS-expressing human nasal epithelial cells, PC2-1 significantly increased the surface expression of pendrin. PC2-1 exhibited high membrane permeability in vitro and high micromolar concentrations in the cochlear perilymph in vivo. In addition, neither inhibition of Kv11.1 activity in the human ether-a-go-go-related gene assay nor cell toxicity in the cell proliferation assay was observed at a high PC2-1 concentration (30 µM). These preclinical data support the hypothesis of the druggability of mutant pendrin using the novel corrector molecule PC2-1. In conclusion, PC2-1 may be a new therapeutic molecule for ameliorating hearing loss and treating vestibular disorders in patients with Pendred syndrome or DFNB4.

9.
Immunol Lett ; 263: 87-96, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37722567

RESUMO

Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid and choline, plays multiple roles in inflammation. We investigated the therapeutic effects of the newly developed PLD1 inhibitors A2998, A3000, and A3773 in vitro and in vivo rheumatoid arthritis (RA) model. A3373 reduced the levels of LPS-induced TNF-α, IL-6, and IgG in murine splenocytes in vitro. A3373 also decreased the levels of IFN-γ and IL-17 and the frequencies of Th1, Th17 cells and germinal-center B cells, in splenocytes in vitro. A3373 ameliorated the severity of collagen-induced arthritis (CIA) and suppressed infiltration of inflammatory cells into the joint tissues of mice with CIA compared with vehicle-treated mice. Moreover, A3373 prevented systemic bone demineralization in mice with CIA and suppressed osteoclast differentiation and the mRNA levels of osteoclastogenesis markers in vitro. These results suggest that A3373 has therapeutic potential for RA.


Assuntos
Artrite Experimental , Artrite Reumatoide , Fosfolipase D , Camundongos , Animais , Osteoclastos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Fosfolipase D/genética , Fosfolipase D/farmacologia , Fosfolipase D/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Diferenciação Celular , Citocinas/genética , Células Th17/patologia
10.
Exp Mol Med ; 54(9): 1563-1576, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36131027

RESUMO

Phospholipase D (PLD) is a potential therapeutic target against cancer. However, the contribution of PLD inhibition to the antitumor response remains unknown. We developed a potent and selective PLD1 inhibitor based on computer-aided drug design. The inhibitor enhanced apoptosis in colorectal cancer (CRC) cells but not in normal colonic cells, and in vitro cardiotoxicity was not observed. The inhibitor downregulated the Wnt/ß-catenin signaling pathway and reduced the migration, invasion, and self-renewal capacity of CRC cells. In cancer, therapeutic engagement of immunogenic cell death (ICD) leads to more effective responses by eliciting the antitumor immunity of T cells. The CRC cells treated with the inhibitor showed hallmarks of ICD, including downregulation of "do not eat-me" signals (CD24, CD47, programmed cell death ligand 1 [PD-L1]), upregulation of "eat-me" signal (calreticulin), release of high-mobility group Box 1, and ATP. PLD1 inhibition subsequently enhanced the phagocytosis of cancer cells by macrophages through the surface expression of costimulatory molecules; as a result, the cancer cells were more susceptible to cytotoxic T-cell-mediated killing. Moreover, PLD1 inhibition attenuated colitis-associated CRC and orthotopically injected tumors, probably by controlling multiple pathways, including Wnt signaling, phagocytosis checkpoints, and immune signaling. Furthermore, combination therapy with a PLD1 inhibitor and an anti-PD-L1 antibody further enhanced tumor regression via immune activation in the tumor environment. Collectively, in this study, PLD1 was identified as a critical regulator of the tumor microenvironment in colorectal cancer, suggesting the potential of PLD1 inhibitors for cancer immunotherapy based on ICD and immune activation. PLD1 inhibitors may act as promising immune modulators in antitumor treatment via ICD.


Assuntos
Neoplasias Colorretais , Fosfolipase D , Trifosfato de Adenosina , Antígeno CD47/metabolismo , Calreticulina , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Humanos , Morte Celular Imunogênica , Imunoterapia , Ligantes , Fosfolipase D/metabolismo , Microambiente Tumoral , Via de Sinalização Wnt
11.
Bioorg Med Chem ; 18(24): 8618-29, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21078557

RESUMO

A series of coumarin based TACE inhibitors were designed to bind in S1' pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1' pocket and the TACE inhibitory activity well.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Cumarínicos , Relação Quantitativa Estrutura-Atividade , Proteína ADAM17 , Animais , Benzopiranos , Sítios de Ligação , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Ligação Proteica , Ratos , Eletricidade Estática
12.
Commun Biol ; 3(1): 428, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32759981

RESUMO

PRMT5 participates in various cellular processes, including transcription regulation, signal transduction, mRNA splicing, and DNA repair; however, its mechanism of regulation is poorly understood. Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity. Either phosphorylation or substitution of the Y324 residue suppresses PRMT5 activity by preventing its binding with the methyl donor S-adenosyl-L-methionine. Additionally, we show that PRMT5 activity is associated with non-homologous end joining (NHEJ) repair by methylating and stabilizing p53-binding protein 1 (53BP1), which promotes cellular survival after DNA damage. Src-mediated phosphorylation of PRMT5 and the subsequent inhibition of its activity during the DNA damage process blocks NHEJ repair, leading to apoptotic cell death. Altogether, our findings suggest that PRMT5 regulates DNA repair through Src-mediated Y324 phosphorylation in response to DNA damage.


Assuntos
Neoplasias/genética , Proteína-Arginina N-Metiltransferases/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Quinases da Família src/genética , Células A549 , Quebras de DNA de Cadeia Dupla , Dano ao DNA/genética , Reparo do DNA por Junção de Extremidades/genética , Metilação de DNA/genética , Células HeLa , Histonas/genética , Humanos , Células MCF-7 , Neoplasias/patologia , Fosforilação , Ligação Proteica , Processamento de Proteína Pós-Traducional/genética
13.
Theranostics ; 10(22): 9913-9922, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32929324

RESUMO

Rationale: Pendrin is encoded by SLC26A4 and its mutation leads to congenital hearing loss. Additionally, pendrin is up-regulated in inflammatory airway diseases such as chronic obstructive pulmonary disease, allergic rhinitis, and asthma. In this study, the effects of a novel pendrin inhibitor, YS-01, were investigated in an LPS-induced acute lung injury (ALI) mice model, and the mechanism underlying the effect of YS-01 was examined. Methods: Lipopolysaccharide (LPS, 10 mg/kg) was intranasally instilled in wild type (WT) and pendrin-null mice. YS-01 (10 mg/kg) was administered intra-peritoneally before or after LPS inhalation. Lung injury parameters were assessed in the lung tissue and bronchoalveolar lavage fluid (BALF). Pendrin levels in the BALF of 41 patients with acute respiratory distress syndrome (ARDS) due to pneumonia and 25 control (solitary pulmonary nodule) patients were also measured. Results: LPS instillation induced lung injury in WT mice but not in pendrin-null mice. Pendrin expression was increased by LPS stimulation both in vitro and in vivo. YS-01 treatment dramatically attenuated lung injury and reduced BALF cell counts and protein concentration after LPS instillation in WT mice. Proinflammatory cytokines and NF-κB activation were suppressed by YS-01 treatment in LPS-induced ALI mice. In BALF of patients whose ARDS was caused by pneumonia, pendrin expression was up-regulated compared to that in controls (mean, 24.86 vs. 6.83 ng/mL, P < 0.001). Conclusions: A novel pendrin inhibitor, YS-01, suppressed lung injury in LPS-induced ALI mice and our data provide a new strategy for the treatment of inflammatory airway diseases including sepsis-induced ALI.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Transportadores de Sulfato/antagonistas & inibidores , Lesão Pulmonar Aguda/metabolismo , Idoso , Animais , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Oxazóis/farmacologia , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
14.
Biomolecules ; 10(4)2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32230857

RESUMO

Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Ibogaína/análogos & derivados , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Antígenos CD13/metabolismo , Curcumina/farmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Ibogaína/química , Ibogaína/farmacocinética , Ibogaína/farmacologia , Espectrometria de Massas , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Distribuição Tecidual , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Eur J Med Chem ; 126: 997-1010, 2017 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-28011426

RESUMO

RUNX3, a tumor suppressor, is suppressed in various cancers by abnormal epigenetic changes. Histone deacetylases (HDACs) can deacetylate the lysine residues of RUNX3, followed by degradation via a ubiquitin-mediated pathway. Inhibition of HDAC leads to functional restoration of the RUNX3 protein by epigenetic expression and RUNX3 protein stabilization. We previously reported a series of HDAC inhibitors that restored RUNX3 function. In the present study, we introduced an alkenyl linker group to pyridine-based HDAC inhibitors to improve their potencies and chemical properties. This alkenyl linker made the compounds more rigid, facilitating a better fit than alkyl moieties to the active site of HDAC proteins. Most compounds in this series exhibited potent RUNX activities, HDAC inhibitory activities, and inhibitory activities towards the growth of human cancer cell lines. Notably, one of these derivatives, (E)-3-(1-cinnamyl-2-oxo-1,2-dihydropyridin-3-yl)-N-hydroxyacrylamide (7k), showed excellent properties in a microsomal stability study, in a xenograft study, and in an in vivo pharmacokinetic evaluation. Modulation of RUNX3 therefore results in highly potent and orally available anticancer chemotherapeutic agents.


Assuntos
Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Piridinas/metabolismo , Piridinas/farmacologia , Acetilação , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Subunidade alfa 3 de Fator de Ligação ao Core/química , Estabilidade de Medicamentos , Feminino , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Camundongos , Microssomos/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Piridinas/química , Piridinas/farmacocinética , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Tissue Eng Regen Med ; 9(4): 435-46, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23166016

RESUMO

In this study we showed that 2-(trimethylammonium)ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate [(R)-TEMOSPho], a derivative of an organic chemical identified from a natural product library, promotes highly efficient differentiation of megakaryocytes. Specifically, (R)-TEMOSPho induces cell cycle arrest, cell size increase and polyploidization from K562 and HEL cells, which are used extensively to model megakaryocytic differentiation. In addition, megakaryocyte-specific cell surface markers showed a dramatic increase in expression in response to (R)-TEMOSPho treatment. Importantly, we demonstrated that such megakaryocytic differentiation can also be induced from primary human CD34(+) haematopoietic stem cells. Activation of the PI3K-AKT pathway and, to a lesser extent, the MEK-ERK pathway appears to be required for this process, as blocking with specific inhibitors interferes with the differentiation of K562 cells. A subset of (R)-TEMOSPho-treated K562 cells undergoes spontaneous apoptosis and produces platelets that are apparently functional, as they bind to fibrinogen, express P-selectin and aggregate in response to SFLLRN and AYPGFK, the activating peptides for the PAR1 and PAR4 receptors, respectively. Taken together, these results indicate that (R)-TEMOSPho will be useful for dissecting the molecular mechanisms of megakaryocytic differentiation, and that this class of compounds represents potential therapeutic reagents for thrombocytopenia.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Megacariócitos/metabolismo , Organofosfatos/farmacologia , Humanos , Células K562 , Selectina-P/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor PAR-1/metabolismo , Receptores de Trombina/metabolismo
17.
Eur J Med Chem ; 69: 670-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24095759

RESUMO

RhoB is expressed during tumor cell proliferation, survival, invasion, and metastasis. In malignant progression, the expression levels of RhoB are commonly attenuated. RhoB is known to be linked to the regulation of the PI3K/Akt survival pathways. Based on aliphatic amido-quaternary ammonium salts that induce apoptosis via up-regulation of RhoB, we synthesized novel aliphatic sulfonamido-quaternary ammonium salts. These new synthetic compounds were evaluated for their biological activities using an in vitro RhoB promoter assay in HeLa cells, and in a growth inhibition assay using human cancer cell lines including PC-3, NUGC-3, MDA-MB-231, ACHN, HCT-15, and NCI-H23. Compound 5b (ethyl-dimethyl-{3-[methyl-(tetradecane-1-sulfonyl)-amino]-propyl}-ammonium; iodide) was the most promising anticancer agent in the series, based upon the potency of growth inhibition and RhoB promotion. These new aliphatic sulfonamido-quaternary ammonium salts could be a valuable series for development of new anticancer chemotherapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Compostos de Amônio Quaternário/farmacologia , Sulfonamidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Sais/síntese química , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade , Proteína rhoB de Ligação ao GTP/antagonistas & inibidores , Proteína rhoB de Ligação ao GTP/biossíntese , Proteína rhoB de Ligação ao GTP/metabolismo
18.
Eur J Med Chem ; 63: 621-8, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23567950

RESUMO

A series of novel aliphatic amido-quaternary ammonium salts were synthesized and evaluated for their anticancer effects involving induction of RhoB. Most of these compounds, featuring open-ring forms of aliphatic amido-quaternary ammonium salts, exhibited potent anti-proliferative activities in human cancer cell lines, including PC-3, NUGC-3, MDA-MB-231, ACHN, HCT-15, and NCI-H23. In further evaluation, the representative compound N,N-diethyl-N-(2-(N-methyltetradecanamido)ethyl)prop-2-en-1-aminium bromide (3b) exhibited potent pro-apoptotic activity, through RhoB activation, in HeLa cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Compostos de Amônio Quaternário/química , Relação Estrutura-Atividade
19.
Eur J Med Chem ; 46(7): 2861-6, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21543141

RESUMO

We synthesized novel aliphatic amido-quaternary ammonium salts in an effort to discover anticancer agents that increase Ras homolog gene family, member B, (RhoB) levels. These compounds exert anti-proliferative activities against several human cancer cell types. Seventeen compounds, varying in aliphatic carbon chain length and N-substituents, were synthesized and their biological activities were evaluated. Of these 17 compounds, compound 3i emerged as the most promising anticancer compound by promoting apoptosis through the RhoB mediated pathway. Potent biological activities observed for these novel aliphatic amido-quaternary ammonium salt analogues support their potential as anticancer, chemotherapeutic agents.


Assuntos
Amidas/química , Antineoplásicos/síntese química , Regulação Neoplásica da Expressão Gênica , Compostos de Amônio Quaternário/síntese química , Proteína rhoB de Ligação ao GTP/agonistas , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Piperazinas/química , Compostos de Amônio Quaternário/farmacologia , Sais/química , Transdução de Sinais , Relação Estrutura-Atividade , Proteína rhoB de Ligação ao GTP/genética , Proteína rhoB de Ligação ao GTP/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA