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1.
N Engl J Med ; 384(6): 512-520, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33567191

RESUMO

BACKGROUND: The tubulin polymerization and Src kinase signaling inhibitor tirbanibulin is being investigated as a topical treatment for actinic keratosis, a precursor of squamous-cell carcinoma. METHODS: In two identically designed double-blind trials, we randomly assigned, in a 1:1 ratio, adults with actinic keratoses on the face or scalp to receive either topical tirbanibulin or vehicle (placebo) ointment. The ointment was applied by the patients to a 25-cm2 contiguous area containing four to eight lesions once daily for 5 consecutive days. The primary outcome was the percentage of patients with a complete (100%) reduction in the number of lesions in the application area at day 57. The secondary outcome was the percentage of patients with a partial (≥75%) reduction in the number of lesions within the application area at day 57. The incidence of recurrence was evaluated at 1 year. Local reactions were scored with the use of 4-point scale (ranging from 0 [absent] to 3 [severe]). RESULTS: A total of 702 patients were enrolled in the two trials (351 patients per trial). Complete clearance in trial 1 occurred in 44% of the patients (77 of 175) in the tirbanibulin group and in 5% of those (8 of 176) in the vehicle group (difference, 40 percentage points; 95% confidence interval [CI], 32 to 47; P<0.001); in trial 2, the percentages were 54% (97 of 178 patients) and 13% (22 of 173), respectively (difference, 42 percentage points; 95% CI, 33 to 51; P<0.001). The percentages of patients with partial clearance were significantly higher in the tirbanibulin groups than in the vehicle groups. At 1 year, the estimated percentage of patients with recurrent lesions was 47% among patients who had had a complete response to tirbanibulin. The most common local reactions to tirbanibulin were erythema in 91% of the patients and flaking or scaling in 82%. Adverse events with tirbanibulin were application-site pain in 10% of the patients and pruritus in 9%, all of which resolved. CONCLUSIONS: In two identically designed trials, tirbanibulin 1% ointment applied once daily for 5 days was superior to vehicle for the treatment of actinic keratosis at 2 months but was associated with transient local reactions and recurrence of lesions at 1 year. Trials comparing tirbanibulin with conventional treatments and that have longer follow-up are needed to determine the effects of tirbanibulin therapy on actinic keratosis. (Funded by Athenex; ClinicalTrials.gov numbers, NCT03285477 and NCT03285490.).


Assuntos
Acetamidas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Morfolinas/uso terapêutico , Piridinas/uso terapêutico , Acetamidas/efeitos adversos , Administração Tópica , Idoso , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Face/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Pomadas/uso terapêutico , Polimerização/efeitos dos fármacos , Piridinas/efeitos adversos , Couro Cabeludo/patologia , Pele/patologia , Tubulina (Proteína)/metabolismo
2.
Nat Commun ; 11(1): 3765, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724196

RESUMO

Microtubules are dynamic tubulin polymers responsible for many cellular processes, including the capture and segregation of chromosomes during mitosis. In contrast to textbook models of tubulin self-assembly, we have recently demonstrated that microtubules elongate by addition of bent guanosine triphosphate tubulin to the tips of curving protofilaments. Here we explore this mechanism of microtubule growth using Brownian dynamics modeling and electron cryotomography. The previously described flaring shapes of growing microtubule tips are remarkably consistent under various assembly conditions, including different tubulin concentrations, the presence or absence of a polymerization catalyst or tubulin-binding drugs. Simulations indicate that development of substantial forces during microtubule growth and shortening requires a high activation energy barrier in lateral tubulin-tubulin interactions. Modeling offers a mechanism to explain kinetochore coupling to growing microtubule tips under assisting force, and it predicts a load-dependent acceleration of microtubule assembly, providing a role for the flared morphology of growing microtubule ends.


Assuntos
Microtúbulos/metabolismo , Modelos Biológicos , Tubulina (Proteína)/metabolismo , Animais , Microscopia Crioeletrônica , Tomografia com Microscopia Eletrônica , Microtúbulos/efeitos dos fármacos , Microtúbulos/ultraestrutura , Simulação de Dinâmica Molecular , Polimerização/efeitos dos fármacos , Suínos , Tubulina (Proteína)/isolamento & purificação , Tubulina (Proteína)/ultraestrutura , Moduladores de Tubulina/farmacologia
3.
Cell ; 180(5): 819, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142671

RESUMO

Sickle cell disease (SCD) is caused by a point mutation in the ß-globin gene that creates hemoglobin S (HbS). Upon deoxygenation, HbS forms long polymers that distort the shape of red blood cells, causing hemolysis and vaso-occlusion. Voxelotor inhibits HbS polymerization, the root cause of SCD complications. To view this Bench to Bedside, open or download the PDF.


Assuntos
Anemia Falciforme/genética , Benzaldeídos/uso terapêutico , Hemoglobina Falciforme/antagonistas & inibidores , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Globinas beta/genética , Anemia Falciforme/epidemiologia , Hemoglobina Falciforme/genética , Humanos , Mutação Puntual/genética , Polimerização/efeitos dos fármacos
4.
Eur J Med Chem ; 192: 112176, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32120327

RESUMO

We have synthesized a series of 2-phenyl-3-hydroxy-4(1H)-quinolinone derivatives substituted with one or more fluorine atoms on the quinolone backbone as well as on phenyl ring. The derivatives bearing more fluorine atoms were subjected to modification by nucleophilic substitutions by thiophenol, morpholine, and piperazine derivative. We have tested the prepared compounds in cytotoxic activity assay against cancer cell lines. Four derivatives exhibited micromolar values of IC50 against some of the cancer cell lines, and we have subjected them to cell cycle analysis on CCRF-CEM. Moreover, most active 7-fluoro-3-hydroxy-2-phenyl-6-(phenylthio)quinolin-4(1H)-one inhibits mitosis progression. Cell cycle analysis, in vitro tubulin polymerization assay, and tubulin imaging in cells indicated that the anticancer activity of thiophenol derivative is associated with its ability to inhibit microtubule formation.


Assuntos
Quinolonas/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Relação Dose-Resposta a Droga , Células HCT116 , Halogenação , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
5.
Int J Mol Sci ; 21(6)2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32183170

RESUMO

Amyloidosis refers to aggregates of protein that accumulate and are deposited as amyloid fibrils into plaques. When these are detected in organs, they are the main hallmark of Alzheimer's disease, Parkinson's disease, and other related diseases. Recent medical advances have shown that many precursors and proteins can induce amyloidosis even though the mechanism of amyloid aggregation and the relationship of these proteins to amyloidosis remains mostly unclear. In this study, we report the real-time 3D-imaging and inhibition analysis of amyloid ß (Aß), tau, and α-synuclein aggregation utilizing the affinity between quantum dots (QD) and amyloid aggregates. We successfully visualized these amyloid aggregations in real-time using fluorescence microscopy and confocal microscopy simply by adding commercially available QD. The observation by transmission electron microscopy (TEM) showed that QD particles bound to all amyloid fibrils. The 3D-imaging with QD revealed differences between amyloid aggregates composed of different amyloid peptides that could not be detected by TEM. We were also able to quantify the inhibition activities of these proteins by rosmarinic acid, which has high activity for Aß aggregation, from fluorescence micrographs as half-maximal effective concentrations. These imaging techniques with QD serve as quick, easy, and powerful tools to understand amyloidosis and to discover drugs for therapies.


Assuntos
Peptídeos beta-Amiloides/química , Imageamento Tridimensional/métodos , Microscopia Eletrônica de Transmissão/métodos , Pontos Quânticos , Cinamatos/farmacologia , Depsídeos/farmacologia , Humanos , Polimerização/efeitos dos fármacos , Ligação Proteica
6.
Biochem Biophys Res Commun ; 525(2): 303-307, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32089263

RESUMO

Microtubules are involved in celluar processes of movement, intracellular trafficking and mitosis, thus microtubule-targeting agents have been widely used in cancer therapy. Herein, we report isopenicin A, a novel meroterpenoid isolated from the plant endophytic fungus of Penicillium sp. sh18, as a novel microtubule binding molecule that efficiently depolymerizes microtubule polymerization to evoke G2/M cell cycle arrest and subsequent cell apoptosis, contributing to proliferation inhibition of human tumor cell lines. The discovery of isopenicin A provides a new chemotype for discovery and development of promising microtubule inhibitors.


Assuntos
Antineoplásicos/isolamento & purificação , Penicillium/química , Moduladores de Tubulina/isolamento & purificação , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Microtúbulos/metabolismo , Polimerização/efeitos dos fármacos , Terpenos/isolamento & purificação , Terpenos/farmacologia , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia
7.
Cell Immunol ; 349: 104046, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32057354

RESUMO

Uncontrolled activation of NLRP3 inflammasome initiates a series of human inflammatory diseases. Targeting NLRP3 inflammasome has attracted considerable attention in developing potential therapeutic interventions. Here, we reported that dehydrocostus lactone (DCL), a main component of Saussurea lappa from the traditional Chinese medicine, inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent interleukin (IL)-1ß production in primary mouse macrophages and human peripheral blood mononuclear cells and exerted an inhibitory effect on NLRP3-driven inflammation. Mechanistically, DCL significantly blocked the ASC oligomerization, which is essential for the assembly of activated inflammasome. Importantly, in vivo experiments showed that DCL reduced IL-1ß secretion and peritoneal neutrophils recruitment in LPS-mediated inflammation mouse model, which is demonstrated to be NLRP3 dependent. These results suggest that DCL is a potent pharmacological inhibitor of NLRP3 inflammasome and may be developed as a therapeutic drug for treating NLRP3-associated diseases.


Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamação/prevenção & controle , Lactonas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sesquiterpenos/farmacologia , Adulto , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/fisiologia , Proteínas Adaptadoras de Sinalização CARD/antagonistas & inibidores , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/fisiologia , Caspase 1/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/fisiologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Interleucina-1beta/biossíntese , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Nigericina/farmacologia , Poli I-C/farmacologia , Polimerização/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Ácido Úrico/farmacologia
8.
Drugs ; 80(2): 209-215, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32020554

RESUMO

Voxelotor (Oxbryta™) is a haemoglobin S polymerization inhibitor that has been developed for the treatment of sickle cell disease. In November 2019, voxelotor received its first global approval in the USA for the treatment of sickle cell disease in adults and paediatric patients aged ≥ 12 years. The drug was granted accelerated approval based on the results of the phase III HOPE trial. Phase III clinical development of voxelotor for sickle cell disease is ongoing worldwide. Voxelotor also has Orphan Drug designation and Priority Medicine status in Europe for the treatment of sickle cell disease. This article summarizes the milestones in the development of voxelotor leading to this first approval as a disease-modifying agent for sickle cell disease.


Assuntos
Benzaldeídos/farmacologia , Aprovação de Drogas , Fármacos Hematológicos/farmacologia , Hemoglobina Falciforme/antagonistas & inibidores , Pirazinas/farmacologia , Pirazóis/farmacologia , Ensaios Clínicos Fase III como Assunto , Hemoglobina Falciforme/metabolismo , Humanos , Polimerização/efeitos dos fármacos
9.
Sci Adv ; 6(1): eaay2432, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31911947

RESUMO

The mechanism by which the cytosolic protein Zap70 physically interacts with and phosphorylates its substrate, the transmembrane protein LAT, upon T cell receptor (TCR) stimulation remains largely obscure. In this study, we found that the pharmacological inhibition of formins, a major class of actin nucleators, suppressed LAT phosphorylation by Zap70, despite TCR stimulation-dependent phosphorylation of Zap70 remaining intact. High-resolution imaging and three-dimensional image reconstruction revealed that localization of phosphorylated Zap70 to the immune synapse (IS) and subsequent LAT phosphorylation are critically dependent on formin-mediated actin polymerization. Using knockout mice, we identify mDia1 and mDia3, which are highly expressed in T cells and which localize to the IS upon TCR activation, as the critical formins mediating this process. Our findings therefore describe previously unsuspected roles for mDia1 and mDia3 in the spatiotemporal control of Zap70-dependent LAT phosphorylation at the IS through regulation of filamentous actin, and underscore their physiological importance in TCR signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Forminas/imunologia , Proteínas de Membrana/genética , Proteína-Tirosina Quinase ZAP-70/genética , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/imunologia , Actinas/antagonistas & inibidores , Actinas/química , Actinas/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Forminas/genética , Forminas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/metabolismo , Células Jurkat/imunologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Polimerização/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/efeitos dos fármacos
10.
Drug Dev Ind Pharm ; 46(2): 272-282, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31928342

RESUMO

Objectives: The study aimed to develop safe, effective, and targeted drug delivery system for administration of nonsteroidal anti-inflammatory drugs (NSAIDs) in the form of microgels. We developed pH responsive microgels to overcome the mucosal damage caused by traditional immediate release dosage forms. Colon targeting and controlled release formulations have the potential to improve efficacy and reduce undesirable effects associated with NSAIDs.Methods: The pH sensitive oral hydrogel demonstrates the potential to target the colon. Cellulose acetate phthalate (CAP) and hydroxyethyl methacrylate (HEMA) based microgel particles were produced using a free radical polymerization technique using ammonium persulfate (APS) initiator and methylenebisacrylamide (MBA) as the crosslinking agent. Swelling and in-vitro drug release studies were performed at a range of pH conditions. The produced formulations were characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy (SEM), and X-ray diffraction. Biocompatibility of the microgels was analyzed in cytotoxicity studies.Key findings: The swelling and release rate were negligible at pH 1.2, which confirmed the pH-responsiveness of CAP-co-poly(HEMA). The co-polymeric system prevents the release of ketoprofen sodium in the stomach owing to limited swelling at gastric pH, whilst promoting release at the basic pH observed in the colon. SEM images confirmed porous nature of the microgels that facilitate effective drug diffusion through the polymeric matrix. Cytotoxicity studies revealed biocompatibility of hydrogels.Conclusion: These investigations showed that that the controlled drug release and gastro-protective drug delivery of NSAIDS was achieved using CAP-co-poly(HEMA) microgel particles.


Assuntos
Cetoprofeno/administração & dosagem , Cetoprofeno/química , Metacrilatos/química , Microgéis/química , Acrilamidas/química , Administração Oral , Sulfato de Amônio/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Varredura Diferencial de Calorimetria/métodos , Celulose/análogos & derivados , Celulose/química , Colo/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Hidrogéis/química , Concentração de Íons de Hidrogênio , Polimerização/efeitos dos fármacos , Polímeros/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Termogravimetria/métodos , Difração de Raios X/métodos
11.
Ann N Y Acad Sci ; 1466(1): 73-82, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31814150

RESUMO

The asymmetric inheritance of NUMB during mitosis determines future daughter cell fates in multiple model organisms. NUMB asymmetric inheritance has also been postulated for hematopoietic stem cell (HSC) divisions but remained controversial until recently. To reconcile conflicting reports, we revisited the evidence for asymmetric inheritance of NUMB during HSC divisions. We demonstrate that previously used strategies to identify dividing cells in fixed samples suffer from multiple systematic errors. Nonmitotic cells in close proximity are frequently mistaken as dividing cells, while mitotic cells are not detected. Furthermore, microtubule depolymerization by either nocodazole or low temperatures prevents the reliable detection of mitosis and introduces mitotic artifacts. Without artificial microtubule depolymerization and by the use of reliable mitotic markers, we find NUMB differences in daughter cells to be reduced and restricted to cells with low NUMB expression and thus low signal over background. This bias fits the expected random distribution of simulated noise data, suggesting that the putative asymmetric inheritance of NUMB in HSCs could be merely technical noise. We conclude that functionally relevant asymmetric inheritance of NUMB and other factors in mitotic HSCs and other cells cannot be conclusively demonstrated using snapshot data and requires alternative approaches, such as continuous quantitative single-cell analysis.


Assuntos
Divisão Celular Assimétrica/fisiologia , Diferenciação Celular , Divisão Celular/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Divisão Celular Assimétrica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Padrões de Herança/efeitos dos fármacos , Padrões de Herança/fisiologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Mitose/efeitos dos fármacos , Mitose/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Nocodazol/farmacologia , Polimerização/efeitos dos fármacos , Distribuição Tecidual , Moduladores de Tubulina/farmacologia
12.
Eur J Med Chem ; 186: 111894, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31787361

RESUMO

Green chemistry is becoming the favored approach to preparing drug molecules in pharmaceutical industry. Herein, we developed a clean and efficient method to synthesize 3-benzoylquinoxalines via activated carbon promoted aerobic benzylic oxidation under "on-water" condition. Moreover, biological studies with this class of compounds reveal an antiproliferative profile. Further structure modifications are performed and the investigations exhibited that the most active 12a could inhibit the microtubule polymerization by binding to tubulin and thus induce multipolar mitosis, G2/M phase arrest, and apoptosis of cancer cells. In addition, molecular docking studies allow the rationalization of the pharmacodynamic properties observed. Our systematic studies provide not only guidance for applications of O2/AC/H2O system, but also a new scaffold targeting tubulin for antitumor agent discovery.


Assuntos
Antineoplásicos/farmacologia , Compostos de Benzil/química , Quinoxalinas/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Carbono/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Formiatos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Oxirredução , Polimerização/efeitos dos fármacos , Quinoxalinas/síntese química , Quinoxalinas/química , Relação Estrutura-Atividade , Ácidos Sulfúricos/química , Ácido Trifluoracético/química
13.
J Pept Sci ; 26(3): e3239, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31847053

RESUMO

Bicyclic analogues of celogentin C have been synthesized in which the side chain-side chain cross-links are replaced by thioether bonds. Several of the simplified bicyclic peptides displayed potent inhibition of tubulin polymerization.


Assuntos
Peptídeos Cíclicos/farmacologia , Tubulina (Proteína)/química , Cromatografia Líquida de Alta Pressão , Estrutura Molecular , Peptídeos Cíclicos/química , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 187: 111968, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31865012

RESUMO

Tubulin inhibitors that bind to the colchicine site are widely studied anticancer agents. In continuous our researches, we designed a series of novel indazole derivatives as microtubule-targeting agents (MTAs). The structure-activity relationships (SARs) investigations indicated that a 3,4,5-trimethoxyphenyl moiety and a methyl or methoxy substitution were preferred for the better antiproliferative activity. The indazole derivatives 3c and 3f showed noteworthy low nanomolar potency against HepG2, HCT116, SW620, HT29 and A549 tumor cells. In mechanism studies, 3c and 3f were proved to target the colchicine site, inhibited tubulin polymerization and disrupted cellular microtubule networks, arrested HCT116 cell in G2/M phase and induced cell apoptosis. In the HCT116 xenografts mouse model, 3c and 3f suppressed tumor growth by 45.3% and 58.9% at an orally dose of 25 mg/kg without causing obvious weight loss. The indazole 3f may serve as a good lead or drug candidate for colorectal cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Colchicina/farmacologia , Descoberta de Drogas , Indazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colchicina/síntese química , Colchicina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/síntese química , Indazóis/química , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
15.
Int J Biol Macromol ; 145: 154-164, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31866539

RESUMO

Glioblastoma (GBM) represents the most common, aggressive and deadliest primary tumors with poor prognosis as available therapeutic approaches fail to control its aberrant proliferation and high invasiveness. Thus, the therapeutic agents targeting these two characteristics will be more effective. In present study, a novel polypeptide (MM15), which was originally purified from Meretrix meretrix Linnaeus and has been proven to possess potent antitumor activity by our laboratory, was recombinant expressed and identified as a tropomyosin homologous protein. The recombinant polypeptide (re-MM15) could induce the U87 cell cycle arrest in G2/M phase and cell apoptosis by inducing tubulin polymerization. Additionally, re-MM15 displayed the significant inhibition to the migration and invasion of U87 cells through downregulating FAK/Akt/MMPs signaling. Furthermore, the in vivo analysis suggested that re-MM15 significantly blocked tumor growth in U87 xenograft model. Collectively, our results indicated that re-MM15, with anti-GBM properties in vitro and in vivo, has promising potential as a new anticancer candidate for GBM.


Assuntos
Proliferação de Células/efeitos dos fármacos , Glioma/tratamento farmacológico , Metaloproteinases da Matriz/metabolismo , Microtúbulos/metabolismo , Peptídeos/farmacologia , Polimerização/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tropomiosina/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioma/metabolismo , Células HCT116 , Células HeLa , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Células NIH 3T3 , Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Eur J Med Chem ; 186: 111846, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740055

RESUMO

A series of 2-aryl-4-(3,4,5-trimethoxybenzoyl)-5-substituted-1,2,3-triazoles were designed, synthesized and evaluated for the anticancer activities. Based on the model of DMAM-colchicine-tubulin complex interactions, various saturated nitrogen-containing heterocycles were introduced to the C5-position of 1,2,3-triazol to interact with a tolerant region at the entrance of the binding-pocket and increase the aqueous solubility of the compounds. All designed compounds were concisely synthesized by one-pot oxidative cyclization. Most compounds exhibited moderate antiproliferative activity with IC50 values in the micromolar to sub-micromolar range. Among them, 5g posed N-acyl-piperazine moiety at the C5-position of B-ring showed most potent against cancer cells, with IC50 values of 0.084-0.221 µM 5g potently disrupted microtubule/tubulin dynamics, induced cell cycle arrest at G2/M phase in SGC-7901 cells. In addition, molecular modeling studies suggested that 5g probably binds to the colchicine site of tubulin.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Triazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Modelos Moleculares , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Células Tumorais Cultivadas
17.
Eur J Med Chem ; 186: 111865, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31735573

RESUMO

We here report the discovery of isoquinoline-based biaryls as a new scaffold for colchicine domain tubulin inhibitors. Colchicinoid inhibitors offer highly desirable cytotoxic and vascular disrupting bioactivities, but their further development requires improving in vivo robustness and tolerability: properties that both depend on the scaffold structure employed. We have developed isoquinoline-based biaryls as a novel scaffold for high-potency tubulin inhibitors, with excellent robustness, druglikeness, and facile late-stage structural diversification, accessible through a tolerant synthetic route. We confirmed their bioactivity mechanism in vitro, developed soluble prodrugs, and established safe in vivo dosing in mice. By addressing several problems facing the current families of inhibitors, we expect that this new scaffold will find a range of in vivo applications towards translational use in cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Isoquinolinas/farmacologia , Microtúbulos/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Células HeLa , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Microscopia Confocal , Microtúbulos/metabolismo , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
18.
Spectrochim Acta A Mol Biomol Spectrosc ; 225: 117516, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31518754

RESUMO

We describe a sensitive turn-on fluorescent assay for antioxidants by using fluorescence-tunable graphene quantum dots (GQDs). GQDs exhibited strong fluorescence without dopamine (DA). DA could self-polymerize to a thin polydopamine (PDA) film on the surface of GQDs under alkaline environment, resulting in the fluorescence quenching of GQDs via fluorescence resonance energy transfer (FRET). However, the self-polymerization of DA could be effectively inhibited in the presence of antioxidants including glutathione (GSH), ascorbic acid (AA), cysteine (Cys), and homocysteine (Hcys). Thus, the fluorescence of GQDs restored. The "turn-on" sensing of antioxidants could be achieved with high sensitivity. The detection limit for GSH, AA, Cys, and Hcys could be achieved as low as 2.4 nM, 1.5 nM, 4.2 nM, and 4.4 nM, respectively. Finally, the GQDs@PDA system was applied for monitoring cerebral antioxidants in rat brain microdialysates. This work promises new opportunities to evaluate antioxidant capacity in physiological and pathological fields.


Assuntos
Antioxidantes/análise , Dopamina/química , Pontos Quânticos/química , Antioxidantes/farmacologia , Ácido Ascórbico/análise , Ácido Ascórbico/farmacologia , Química Encefálica , Cisteína/análise , Cisteína/farmacologia , Estudos de Viabilidade , Fluorescência , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes/química , Glutationa/análise , Glutationa/farmacologia , Grafite , Homocisteína/análise , Homocisteína/farmacologia , Indóis/química , Limite de Detecção , Microdiálise , Polimerização/efeitos dos fármacos , Polímeros/química , Pontos Quânticos/ultraestrutura
19.
Eur J Med Chem ; 187: 111949, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31830637

RESUMO

A combination therapeutic regimen via introducing tryptophan 2,3-dioxygenase inhibitors into microtubule inhibitors was performed and evaluated for their antitumor activity. Thereinto, HT2, composed of combretastatin A-4 (CA-4) and tryptophan-2,3-dioxygenase (TDO) inhibitor by a linker, displayed the most potent activity with 10-fold higher than its parent CA-4 against HepG2, A549 and HCT-116 cancer cell lines. Mechanism studies suggested that HT2 inhibited tubulin polymerization and cell migration, caused G2 phase arrest, induced apoptosis by mitochondrial mediated apoptotic pathway, concurrent depolarized the mitochondria membrane potentials and caused reactive oxygen species (ROS) production in HepG2 cells. Moreover, HT2 could enhance T-cell immune responses in vitro by releasing a TDO inhibitor to suppress TDO expression and blockade kynurenine production. As expected, HT2 could remarkably promote the antitumor activity of CA-4 in either immunocompetent H22 or immunodeficient A549 tumor xenograft models without observable toxic effects. More importantly, HT2 increased the level of splenic and tumor-infiltrated T cells and in turn effectively boosted the inhibition effect in H22 xenografted tumor growth. Collectively, this immunochemotherapeutic strategy can be applied to promote chemotherapeutic effect.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fatores Imunológicos/farmacologia , Microtúbulos/efeitos dos fármacos , Triptofano Oxigenase/antagonistas & inibidores , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Imunomodulação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Triptofano Oxigenase/metabolismo
20.
ChemMedChem ; 14(24): 2052-2060, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31674147

RESUMO

Molecular hybridization approach is a promising structural modification tool to design new chemical entities (NCEs) by mimicking two different pharmacophoric units into one scaffold to enhance the biological properties. With this aim, combretastatin-A4 acids were integrated with sulfonyl piperazine scaffolds as a one molecular platform and evaluated for their in vitro antiproliferative activity against a panel of human cancer lines cell lines namely, lung (A549), mouse melanoma (B16F10), breast (MDA MB-231and MCF-7) and colon (HCT-15) by MTT assay. Amongst which the compound (E)-3-(4-Chlorophenyl)-1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (5 ab) displayed significant IC50 values in the range of 0.36 to 7.08 µm against the selected cancer cell lines. Moreover, 5 ab was found to be the most potent member of this series with IC50 0.36±0.02 µm. Further investigations revealed that the compound 5 ab displayed significant inhibition of tubulin assembly with IC50 5.24±0.06 µm and molecular docking studies also disclosed the binding of 5 ab effectively in CA4 binding space at the colchicine binding site. The flow cytometric analysis demonstrated that the compound 5 ab caused cell cycle arrest at G2/M phase in A549 cells. Compound 5 ab induced apoptosis in A549 cells which was further evaluated by different staining assays such as DAPI and AO which undoubtedly speculated, the induction of apoptosis. To study the anti-migration with 5 ab, cell migration/scratch wound assay was performed and the extent of apoptosis was studied by Annexin-V, including mitochondrial potential by JC-1 staining.


Assuntos
Antineoplásicos/farmacologia , Piperazinas/farmacologia , Estilbenos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Polimerização/efeitos dos fármacos , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
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