RESUMO
Cancer is a common disease threatening human health, chemotherapy is widely used in clinical treatment of cancer, but chemotherapy-induced peripheral neuropathy (CIPN) has a relevant impact on life quality of cancer patients. Administration of gastrodin can relieve chronic pain to cancer patients with CIPN and attenuated the inflammatory response by reducing the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). However, its exact molecular mechanisms remain unclear. In this study, we established an animal model of CIPN using Walker-256 breast cancer cell and vincristine. We found that the mechanical and thermal pain threshold of rats was decreased with treatment of vincristine. Using gastrodin could restore the mechanical and thermal threshold without interfering anti-tumor effect of vincristine. Gastrodin relieved CIPN by inhibiting activation of spinal microglia through Fractalkine (CX3CL1) and its receptor CX3CR1, then inhibited P38/mitogen-activated protein kinase (MAPK) signaling pathway and reduced the expression of inflammatory factor TNF-α and interleukin-1ß (IL-1ß). Taking together, our study demonstrated that gastrodin is a potential drug for the treatment of CIPN and likely to improve cancer patient's life quality.
Assuntos
Analgésicos/farmacologia , Antineoplásicos Fitogênicos/toxicidade , Álcoois Benzílicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Glucosídeos/farmacologia , Neuralgia/prevenção & controle , Doenças do Sistema Nervoso Periférico/prevenção & controle , Coluna Vertebral/efeitos dos fármacos , Vincristina/toxicidade , Animais , Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Feminino , Interleucina-1beta , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/fisiopatologia , Ratos Sprague-Dawley , Transdução de Sinais , Coluna Vertebral/metabolismo , Coluna Vertebral/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) has a adverse impact to the living quality of cancer patients. This side effect of CIPN limit the dose of drug used in many chemotherapies, such as vincristine (VCR). The activation of microglia in the spinal dorsal horn is involved in the occurrence and development of neuropathic pain induced by VCR. Recent study has demonstrated that hypoxia induced microglia activation depends on Notch signaling, and it is involved in the release of many inflammatory related factors in microglia. In this work, we aimed to study that the role of Notch signaling pathway in microglia activation on a VCR-induced neuropathy rat model. Our results showed that the mechanical, thermal and cold pain threshold of rats was decreased by treatment of VCR, but N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor, relieved the hyperalgesia. Molecular analysis showed that activation of Notch signaling pathway increased after nerve injury and that DAPT could significantly inhibit the upregulation of Notch signaling pathway, the activation of microglia, and the release of pro-inï¬ammatory cytokines in the spinal. Taking together, Notch signaling pathway could be a potential therapeutic target to alleviate neuropathic pain.
Assuntos
Receptor 1 de Quimiocina CX3C/metabolismo , Microglia/metabolismo , Neuralgia/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Dipeptídeos/farmacologia , Feminino , Neuralgia/induzido quimicamente , Neuralgia/complicações , Neuralgia/prevenção & controle , Doenças do Sistema Nervoso Periférico/complicações , Ratos , Fatores de Transcrição HES-1/metabolismo , Regulação para Cima/efeitos dos fármacos , VincristinaRESUMO
Thirteen new N-aryl 1,2,3,4-tetrahydroquinoline compounds (4a-f, 6a-c, and 8a-d) were synthesized and evaluated for antitumor activity and drug-like properties. Compound 4a exhibited high inhibitory potency with low nanomolar GI50 values of 16-20 nM in cellular assays, including excellent activity against the P-glycoprotein overexpressing cell line KBvin. Compound 4a inhibited colchicine binding to tubulin and tubulin assembly with an IC50 value of 0.85 µM, superior to the reference compound CA4 (1.2 µM) in the same assay. In addition, 4a also exhibited highly improved water solubility (75 µg/mL) and a suitable logP value (3.43) at pH 7.4. With a good balance between antitumor potency and drug-like properties, compound 4a could be a new potential drug candidate for further development. Current results on SAR studies and molecular modeling provided more insight about this class of compounds as tubulin polymerization inhibitors targeting the colchicine site.
Assuntos
Quinolinas/química , Quinolinas/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino-3-nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI(50) values ranging from 0.33 to 3.45µM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta-chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC(50) values of 2.2-3.0µM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase.
Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Éteres/farmacologia , Aminas/síntese química , Aminas/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 , Éteres/síntese química , Éteres/química , Humanos , Estrutura Molecular , Proto-Oncogene Mas , Relação Estrutura-AtividadeRESUMO
Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC(50) values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC(50) values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC(50) < 10 nM) have better aqueous solubility (>1-90 µg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.
Assuntos
Compostos de Anilina/síntese química , Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Desenho de Fármacos , Farmacorresistência Viral , HIV-1/genética , Humanos , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Mutação , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Replicação ViralRESUMO
The current optimization of 2,4-diarylaniline analogs (DAANs) on the central phenyl ring provided a series of new active DAAN derivatives 9a-9e, indicating an accessible modification approach that could improve anti-HIV potency against wild-type and resistant strains, aqueous solubility, and metabolic stability. A new compound 9e not only exhibited extremely high potency against wild-type virus (EC(50) 0.53 nM) and several resistant viral strains (EC(50) 0.36-3.9 nM), but also showed desirable aqueous solubility and metabolic stability, which were comparable or better than those of the anti-HIV-1 drug TMC278 (2). Thus, new compound 9e might be a potential drug candidate for further development of novel next-generation NNRTIs.
Assuntos
Compostos de Anilina/síntese química , Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/síntese química , Compostos de Anilina/farmacologia , Animais , Fármacos Anti-HIV/farmacologia , Linhagem Celular Tumoral , Farmacorresistência Viral , Estabilidade de Medicamentos , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Nitrilas/farmacologia , Pirimidinas/farmacologia , Ratos , Inibidores da Transcriptase Reversa/farmacologia , Rilpivirina , SolubilidadeRESUMO
The computer-assisted surgery system is a complex system. All of the errors can be attributed to the loss of correspondence between the world coordinate system in the operation room and the virtual world coordinate system obtained from the multi-model medical images. The system's accuracy is composed of the accuracy of the localizer and that of registration. In order to improve the system accuracy, we analyse most of the possible error sources. The accuracy of the localizer affects deeply the registration between the intra-operation and pre-operation data. The localizer is the most basic and important part for a computer-assisted surgery system. We give a comprehensive possible error source at the end of the paper.