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J Med Chem ; 58(3): 1556-62, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25584393


The prominent role of IAPs in controlling cell death and their overexpression in a variety of cancers has prompted the development of IAP antagonists as potential antitumor therapies. We describe the identification of a series of heterodimeric antagonists with highly potent antiproliferative activities in cIAP- and XIAP-dependent cell lines. Compounds 15 and 17 further demonstrate curative efficacy in human melanoma and lung cancer xenograft models and are promising candidates for advanced studies.

Antineoplásicos/farmacologia , Descoberta de Drogas , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Prolina/farmacologia , Animais , 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 , Camundongos , Estrutura Molecular , Neoplasias Experimentais/patologia , Prolina/síntese química , Prolina/química , Relação Estrutura-Atividade
Rheumatology (Oxford) ; 51(3): 443-50, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22123992


OBJECTIVES: To further understand the expression regulation of MMP-1 and MMP-13 under physiological and pathological conditions, we investigated the combined effects of hypoxia and pro-inflammatory stimuli on the expression of MMP-1 and MMP-13 in rheumatoid synovial fibroblasts. METHODS: Synovial fibroblasts were cultured under either hypoxic or normoxic conditions in the presence of IL-1ß stimulation. The culture supernatant was analysed for secreted levels of VEGF, MMP-1 and MMP-13. Their gene expression was quantified with real-time and semi-quantitative PCR. Another group of cells was transfected with small-interfering RNA (siRNA) specific for hypoxia-inducible factor-1 α (HIF-1α). The protein levels of HIF-1α were detected by western blot analysis. RESULTS: In response to 10 ng/ml of IL-1ß under normoxia, the levels of MMP-1 and MMP-13 increased compared with the levels observed under hypoxia. IL-1ß stimulation under hypoxia induced a 2-fold increase in the level of MMP-1 and a 2-fold decrease in the level of MMP-13 compared with cells cultured under normoxia. A similar pattern of differential expression for MMP-1 and MMP-13 was observed with 1 and 5 ng/ml IL-1ß, but not at 0.1 ng/ml. The differential expression of MMPs under the combined effect of IL-1ß and hypoxia was significantly attenuated by silencing HIF-1α with siRNA. CONCLUSIONS: Hypoxia in arthritic joints may differentially affect the IL-1ß-stimulated expression of MMP-1 and MMP-13 in rheumatoid synovial fibroblasts. This effect is dependent on HIF-1α expression. This hypoxia-mediated differential effect should be taken into consideration when testing the efficiency of therapies that target HIF-1α.

Artrite Reumatoide/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Interleucina-1beta/farmacologia , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Membrana Sinovial/efeitos dos fármacos , Artrite Reumatoide/complicações , Western Blotting , Células Cultivadas , Primers do DNA/química , Ensaio de Imunoadsorção Enzimática , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Regulação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 13 da Matriz/genética , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Membrana Sinovial/enzimologia , Transfecção , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
Int J Rheum Dis ; 14(4): 320-4, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22004227


AIM: Thymosin (Tß4) may have various biological effects that are relevant to the pathogenesis of rheumatoid arthritis (RA). This study was performed to gain insight into the relevance of Tß4 in the pathogenesis of inflammatory arthritis. METHOD: The level of Tß4 in synovial fluid from patients with osteoarthritis (OA) or RA was measured by enzyme-linked immunosorbent assay. An association between Tß4 and matrix metalloproteinase (MMP)-1 and MMP-13 (collagenases), MMP-2 and MMP-9 (gelatinases), MMP-7, adiponectin, lactoferrin, vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (uPA), interleukin (IL)-6, IL-8 and prostaglandin E2 (PGE(2) ) in synovial joint fluids from OA and RA patients were investigated. RESULTS: The level of Tß4 in the synovial joint fluid of patients with OA and RA was (mean ± SD) 145 ± 88 and 1359 ± 1685 ng/mL, respectively. The level of Tß4 in the synovial joint fluid of RA patients was significantly associated with the levels of MMP-9, MMP-13, VEGF, uPA, IL-6 and IL-8, but not with MMP-1, MMP-2, MMP-7, adiponectin and lactoferrin. In contrast, the level of Tß4 in the synovial joint fluid of patients with OA was not associated with any of these molecules. CONCLUSIONS: The results suggest that Tß4 may play an important role in bone degradation and inflammation in RA but not OA, although nothing is known about the molecular mechanisms mediating Tß4 in arthritic joints. The role of Tß4 in arthritis should be studied to understand its relevance to the pathogenic processes in arthritis.

Artrite Reumatoide/metabolismo , Inflamação/metabolismo , Articulações/metabolismo , Osteoartrite/metabolismo , Líquido Sinovial/metabolismo , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Biomarcadores/metabolismo , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Articulações/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Osteoartrite/fisiopatologia , Líquido Sinovial/química , Timosina
J Immunol ; 177(10): 7211-24, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17082639


Tissue hypoxemia is common in several pathological diseases, including vaso-occlusion in sickle cell disease and myocardial infarction. One finds increased presence of leukocytes during lung injury and at sites of inflammation in vascular endothelium. In this study, we used human pulmonary microvascular endothelial cells and human dermal microvascular endothelial immortalized cell line to delineate the cellular signaling mechanism of hypoxia- and CoCl2 (a mimetic of hypoxia)-induced IL-8 expression, and the latter's role in chemotaxis of polmorphonuclear neutrophils. We show that hypoxia- and CoCl2-induced IL-8 mRNA and protein expression involved activation of PI3K/Akt and p38 MAPK, but not MEK kinase. Analysis of some transcription factors associated with IL-8 promoter revealed that hypoxia and CoCl2 increased DNA-binding activity of hypoxia-inducible factor-1alpha (HIF-1alpha), NF-kappaB, and AP-1. In addition, we show that hypoxia- and CoCl2-induced IL-8 expression requires activation of HIF as demonstrated by the following: 1) EMSA; 2) transfection studies with IL-8 promoter reporter constructs with mutation in HIF-1alpha binding site; 3) attenuation of IL-8 expression by both HIF-1alpha small interfering RNA and R59949; 4) augmentation of IL-8 expression by either transfection with HIF-prolyl hydroxylase-2 small interfering RNA or overexpression of HIF-1alpha; and 5) chromatin immunoprecipitation analysis. Moreover, conditioned medium from hypoxia-treated endothelial cells augmented chemotaxis of neutrophils, due to release of IL-8. These data indicate that hypoxia-induced signaling in vascular endothelium for transcriptional activation of IL-8 involves PI3K/Akt, p38 MAPK, and HIF-1alpha. Pharmacological agents, which inhibit HIF-1alpha, may possibly ameliorate inflammation associated with hypoxia in pathological diseases.

Cobalto/fisiologia , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Fator 1 Induzível por Hipóxia/fisiologia , Hipóxia/metabolismo , Interleucina-8/biossíntese , Sequência de Bases , Linhagem Celular Transformada , Células Cultivadas , Quimiocina CCL2/biossíntese , Quimiotaxia de Leucócito/imunologia , Cromonas/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Flavonoides/farmacologia , Humanos , Imidazóis/farmacologia , Interleucina-8/antagonistas & inibidores , Interleucina-8/genética , Dados de Sequência Molecular , Morfolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Artéria Pulmonar/citologia , Artéria Pulmonar/imunologia , Artéria Pulmonar/metabolismo , Piridinas/farmacologia , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese
Bioorg Med Chem Lett ; 14(11): 2973-7, 2004 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-15125971


N-Aryl aminothiazoles 6-9 were prepared from 2-bromothiazole 5 and found to be CDK inhibitors. In cells they act as potent cytotoxic agents. Selectivity for CDK1, CDK2, and CDK4 was dependent of the nature of the N-aryl group and distinct from the CDK2 selective N-acyl analogues. The N-2-pyridyl analogues 7 and 19 showed pan CDK inhibitory activity. Elaborated analogues 19 and 23 exhibited anticancer activity in mice against P388 murine leukemia. The solid-state structure of 7 bound to CDK2 shows a similar binding mode to the N-acyl analogues.

Antineoplásicos/síntese química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Leucemia/tratamento farmacológico , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Ligação Proteica , Relação Estrutura-Atividade , Tiazóis/síntese química , Resultado do Tratamento
J Med Chem ; 47(7): 1719-28, 2004 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-15027863


N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.

Antineoplásicos/síntese química , CDC2-CDC28 Quinases/antagonistas & inibidores , Oxazóis/síntese química , Tiazóis/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , CDC2-CDC28 Quinases/metabolismo , Linhagem Celular Tumoral , Sistema Livre de Células , Cristalografia por Raios X , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Transplante de Neoplasias , Oxazóis/farmacocinética , Oxazóis/farmacologia , Fosforilação , Ratos , Proteína do Retinoblastoma/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Transplante Heterólogo