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1.
Stat Med ; 43(7): 1354-1371, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38287456

RESUMEN

Many diseases are heterogeneous, comprised of multiple disease subgroups. It is of great interest but highly unlikely to find a single biomarker that can accurately detect such heterogeneous diseases across different subgroups. In this article, we propose to estimate a personalized diagnostic rule (PDR) to tailor more effective biomarkers to each individual according to a linear combination of his or her profiles. A standard grid search algorithm can be used to estimate the optimal linear PDR that maximizes the area under the receiver operating characteristics curve (AUC) among all the linear PDRs, but it is time-consuming especially when the number of variables is large. Alternatively, we developed an efficient grid rotation algorithm that provides a nearly suboptimal solution and studied its variation to find the optimal solution. We implemented the cross-validated forward variable selection method to find a subset of useful variables while avoid overfitting. Extensive simulations show that our proposed method reduces bias and variance. Analysis of a gastric cancer biomarker study and censored survival outcome data illustrates the practical utility of our proposed method. The proposed method is implemented in the open-source R package persDx.


Asunto(s)
Algoritmos , Biomarcadores de Tumor , Humanos , Curva ROC , Biomarcadores , Área Bajo la Curva
2.
BMC Genomics ; 20(Suppl 3): 296, 2019 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-32039697

RESUMEN

BACKGROUND: Chromosomal architecture, which is constituted by chromatin loops, plays an important role in cellular functions. Gene expression and cell identity can be regulated by the chromatin loop, which is formed by proximal or distal enhancers and promoters in linear DNA (1D). Enhancers and promoters are fundamental non-coding elements enriched with transcription factors (TFs) to form chromatin loops. However, the specific cooperation of TFs involved in forming chromatin loops is not fully understood. RESULTS: Here, we proposed a method for investigating the cooperation of TFs in four cell lines by the integrative analysis of DNA sequences, ChIP-Seq and ChIA-PET data. Results demonstrate that the interaction of enhancers and promoters is a hierarchical and dynamic complex process with cooperative interactions of different TFs synergistically regulating gene expression and chromatin structure. The TF cooperation involved in maintaining and regulating the chromatin loop of cells can be regulated by epigenetic factors, such as other TFs and DNA methylation. CONCLUSIONS: Such cooperation among TFs provides the potential features that can affect chromatin's 3D architecture in cells. The regulation of chromatin 3D organization and gene expression is a complex process associated with the hierarchical and dynamic prosperities of TFs.


Asunto(s)
Secuenciación de Inmunoprecipitación de Cromatina/métodos , Factores de Transcripción/metabolismo , Redes Reguladoras de Genes , Regiones Promotoras Genéticas/genética
3.
Bioorg Chem ; 92: 103219, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31476616

RESUMEN

Twenty-four 1,2-diarylbenzimidazole derivatives were designed, synthesized and biologically evaluated. It turned out that most of them were potential anticancer drugs. Among them, compound c24 showed the highest anti-tumor activity (GI50 = 0.71-2.41 µM against HeLa, HepG2, A549 and MCF-7 cells), and low toxicity to normal cells (CC50 > 100 µM against L02 cells). In the microtubule binding assay, c24 showed the most potent inhibition of microtubule polymerization (IC50 = 8.47 µM). The binding ability of compound c24 to tubulin crystal was verified by molecular docking simulation experiment. Further studies on HepG2 and HeLa cells showed that compound c24 could cause mitotic arrest of tumor cells to G2/M phase then inducing apoptosis. To sum up, compound c24 is a promising microtubule assembly inhibitor.


Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Simulación del Acoplamiento Molecular , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Polimerizacion/efectos de los fármacos , Relación Estructura-Actividad Cuantitativa , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química
4.
Xenobiotica ; 48(9): 920-926, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29050520

RESUMEN

1. YMR-65, 5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3-methoxyphenyl)-4, 5-dihydro-1H-pyrazole-1-carboxamide, is a new tubulin polymerization inhibitor with encouraging anticancer activity. 2. The validated ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) method was successfully applied to the pharmacokinetics, tissue distribution and excretion study of YMR-65 after oral and intravenous administration. The area under concentration-time curve (AUC0-∞) for YMR-65 were 151.67 ± 54.48 and 459.45 ± 49.23 ng/ml*h for oral and intravenous administration at the dosage of 1.5 mg/kg, respectively and the oral bioavailability was about 33.01%. Moreover, YMR-65 was extensively distributed in heart, liver, spleen, lung, kidney, stomach, intestine and testis and the highest were detected in heart, followed by stomach, intestine and liver. The majority of YMR-65 was excreted via feces and its accumulative excretion ratio during the period of 96 h was 19.83 ± 3.01%, but only 1.54 ± 0.37 and 0.215 ± 0.026% for urine within 96 h and bile within 10 h after intravenous administration, respectively, though the fecal and urine excretion were incomplete within 96 h. 3. In summary, this study defined the pharmacokinetic characteristics of YMR-65 in vivo and the important data can be a useful resource for further research and development.


Asunto(s)
Indoles/farmacocinética , Pirazoles/farmacocinética , Moduladores de Tubulina/farmacocinética , Administración Intravenosa , Administración Oral , Animales , Antineoplásicos/farmacocinética , Área Bajo la Curva , Cromatografía Liquida , Indoles/administración & dosificación , Masculino , Pirazoles/administración & dosificación , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodos , Distribución Tisular , Moduladores de Tubulina/administración & dosificación
5.
Molecules ; 22(7)2017 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-28696365

RESUMEN

A series of new quinoxaline derivatives of dehydroabietic acid (DAA) were designed and synthesized as potential antitumor agents. Their structures were characterized by IR, ¹H-NMR, 13C-NMR, and MS spectra and elemental analyses. All the new compounds were screened for their in vitro antiproliferative activities against three human cancer cell lines (MCF-7, SMMC-7721 and HeLa) and noncancerous human hepatocyte cells (LO2). A cytotoxic assay manifested that compound 4b showed the most potent cytotoxic activity against the three cancer cell lines, with IC50 values of 1.78 ± 0.36, 0.72 ± 0.09 and 1.08 ± 0.12 µM, respectively, and a substantially lower cytotoxicity to LO2 cells (IC50: 11.09 ± 0.57 µM). Moreover, the cell cycle analysis suggested that compound 4b caused cell cycle arrest of SMMC-7721 cells at the G0/G1 phase. In a Hoechst 33258 staining assay, compound 4b caused considerable morphological changes of the nuclei of SMMC-7721 cells, correlated with cell apoptosis. In addition, an Annexin V-FITC/PI dual staining assay confirmed that compound 4b could induce the apoptosis of SMMC-7721 cells in a dose-dependent manner.


Asunto(s)
Abietanos/síntesis química , Antineoplásicos/síntesis química , Quinoxalinas/síntesis química , Abietanos/farmacología , Antineoplásicos/farmacología , Apoptosis , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Quinoxalinas/farmacología , Relación Estructura-Actividad
6.
Bioorg Med Chem ; 22(21): 6201-8, 2014 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-25267006

RESUMEN

A series of novel 5-phenyl-1H-pyrazole derivatives (5 a-5 u) containing niacinamide moiety were synthesized and evaluated for biological activity as potential BRAF(V600E) inhibitors. Among them, compound 5h exhibited the most potent inhibitory activity with an IC50 value of 0.33 µM for BRAF(V600E). Antiproliferative assay results indicated that compound 5h has better antiproliferative activity against WM266.4 and A375 in vitro with IC50 value of 2.63 and 3.16 µM, respectively, being comparable with the positive control vemurafenib. Molecular docking of 5h into the BRAF(V600E) active site was performed to determine the probable binding mode. Furthermore, molecular docking and 3D QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Pirazoles/química , Pirazoles/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas B-raf/metabolismo , Pirazoles/síntesis química , Relación Estructura-Actividad Cuantitativa , Relación Estructura-Actividad
7.
Bioorg Med Chem ; 22(15): 4312-22, 2014 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-24909678

RESUMEN

A series of 1,3,4-thiadiazol-2-amide derivatives (6a-w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC50 values of 0.03 µM, 0.06 µM and 0.05 µM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC50=1.73 µM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.


Asunto(s)
Amidas/química , Amidas/farmacología , Antineoplásicos/síntesis química , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/farmacología , Amidas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células Hep G2 , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Células MCF-7 , Conformación Molecular , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Relación Estructura-Actividad Cuantitativa , Moduladores de Tubulina/química
8.
Int J Antimicrob Agents ; 63(5): 107124, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38412930

RESUMEN

For successful viral propagation within infected cells, the virus needs to overcome the cellular integrated stress response (ISR), triggered during viral infection, which, in turn, inhibits general protein translation. This paper reports a tactic employed by viruses to suppress the ISR by upregulating host cell polyribonucleotide nucleotidyltransferase 1 (PNPT1). The propagation of adenovirus, murine cytomegalovirus and hepatovirus within their respective host cells induces PNPT1 expression. Notably, when PNPT1 is knocked down, the propagation of all three viruses is prevented. Mechanistically, the inhibition of PNPT1 facilitates the relocation of mitochondrial double-stranded RNAs (mt-dsRNAs) to the cytoplasm, where they activate RNA-activated protein kinase (PKR). This activation leads to eukaryotic initiation factor 2α (eIF2α) phosphorylation, resulting in the suppression of translation. Furthermore, by scrutinizing the PNPT1 recognition element and screening 17,728 drugs and bioactive compounds approved by the US Food and Drug Administration, lanatoside C was identified as a potent PNPT1 inhibitor. This compound impedes the propagation of adenovirus, murine cytomegalovirus and hepatovirus, and suppresses production of the severe acute respiratory syndrome coronavirus-2 spike protein. These discoveries shed light on a novel strategy to impede pan-viral propagation by activating the host cell mt-dsRNA-PKR-eIF2α signalling axis.


Asunto(s)
eIF-2 Quinasa , Humanos , Animales , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/antagonistas & inhibidores , eIF-2 Quinasa/genética , Antivirales/farmacología , Muromegalovirus/fisiología , Muromegalovirus/efectos de los fármacos , Ratones , Factor 2 Eucariótico de Iniciación/metabolismo , Replicación Viral/efectos de los fármacos , ARN Bicatenario/genética , Adenoviridae/genética , Adenoviridae/efectos de los fármacos , Fosforilación , SARS-CoV-2/efectos de los fármacos
9.
Cell Res ; 33(1): 30-45, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36241718

RESUMEN

Mutations of the RAS oncogene are found in around 30% of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRASG12C mutant. Here we report that RAS-ON (RASON), a novel protein encoded by the long intergenic non-protein coding RNA 00673 (LINC00673), is a positive regulator of oncogenic RAS signaling. RASON is aberrantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) patients, and it promotes proliferation of human PDAC cell lines in vitro and tumor growth in vivo. CRISPR/Cas9-mediated knockout of Rason in mouse embryonic fibroblasts inhibits KRAS-mediated tumor transformation. Genetic deletion of Rason abolishes oncogenic KRAS-driven pancreatic and lung cancer tumorigenesis in LSL-KrasG12D; Trp53R172H/+ mice. Mechanistically, RASON directly binds to KRASG12D/V and inhibits both intrinsic and GTPase activating protein (GAP)-mediated GTP hydrolysis, thus sustaining KRASG12D/V in the GTP-bound hyperactive state. Therapeutically, deprivation of RASON sensitizes KRAS mutant pancreatic cancer cells and patient-derived organoids to EGFR inhibitors. Our findings identify RASON as a critical regulator of oncogenic KRAS signaling and a promising therapeutic target for KRAS mutant cancers.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , ARN Largo no Codificante , Humanos , Animales , Ratones , ARN Largo no Codificante/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Genes ras , Fibroblastos/metabolismo , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Guanosina Trifosfato , Mutación/genética , Neoplasias Pancreáticas
10.
Chem Asian J ; 17(16): e202200342, 2022 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-35713953

RESUMEN

Intravesical instillation of chemotherapeutic drugs such as epirubicin (EPI) is routinely used to prevent tumor recurrence and progression after transurethral resection of bladder tumor. However, the lack of tumor selectivity often causes severe damage to normal bladder urothelium leading to intolerable side effects. Here, we analyzed abnormal changes in glycosylation in bladder cancer and identified mannose as the most aberrantly expressed glycan on the surface of bladder cancer cell lines and human bladder tumor tissues. We then constructed a lectin-drug conjugate by linking concanavalin A (ConA) - a lectin that specifically binds to mannose, with EPI through a pH-sensitive linker. This ConA-EPI conjugate conferred EPI with mannose-targeting ability and selectively internalized cancer cells in vitro. This conjugate showed selective cytotoxicity to cancer cells in vitro and better antitumor activity in an orthotopic mouse model of bladder cancer. Our lectin-drug conjugation strategy makes targeted intravesical chemotherapy of bladder cancer possible.


Asunto(s)
Neoplasias de la Vejiga Urinaria , Administración Intravesical , Animales , Antibióticos Antineoplásicos , Concanavalina A/farmacología , Epirrubicina/efectos adversos , Humanos , Manosa , Ratones , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/cirugía
11.
Eur J Med Chem ; 244: 114808, 2022 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-36228411

RESUMEN

KRASG12C is the most prevalent KRAS mutation in non-small cell lung cancer (NSCLC) and has emerged as a promising therapeutic target. Herein, two series of novel 4(1H)-quinolinone and urea compounds were designed based on the reported KRASG12C inhibitor SH-9. Many compounds showed significantly growth inhibitory activity against human NSCLC cells with KRASG12C mutation in cell viability assays. Compound 20a exhibited an IC50 value of 0.5 µM in KRASG12C-mutant NCI-H358 cells with 21-fold selectivity over KRASWT NCI-H2228 cells. LC-MS analysis indicated that compounds 14c, 14h and 20a covalently bound to KRASG12C rather than KRASWT. Moreover, these compounds could remarkably trap KRASG12C in its inactive state by blocking SOS1-mediated GDP/GTP exchange. Furthermore, treatment of NCI-H358 but not NCI-H2228 cells with 20a dose-dependently reduced the phosphorylation of KRAS downstream effectors ERK and AKT. Importantly, 20a significantly inhibited tumor growth in NCI-H358 xenograft models by suppressing KRASG12C signalling. These results indicate that 20a is a promising candidate worthy of further investigation.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Quinolonas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Neoplasias Pulmonares/patología , Quinolonas/farmacología , Quinolonas/uso terapéutico , Urea/farmacología , Urea/uso terapéutico , Línea Celular Tumoral , Mutación
12.
J Pharm Anal ; 11(3): 330-339, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34277121

RESUMEN

The study aimed to achieve enhanced targeted cytotoxicity and cell-internalization of cisplatin-loaded deoxyribonucleic acid-nanothread (CPT-DNA-NT), mediated by scavenger receptors into HeLa cells. DNA-NT was developed with stiff-topology utilizing circular-scaffold to encapsulate CPT. Atomic force microscopy (AFM) characterization of the DNA-NT showed uniformity in the structure with a diameter of 50-150 nm and length of 300-600 nm. The successful fabrication of the DNA-NT was confirmed through native-polyacrylamide gel electrophoresis analysis, as large the molecular-weight (polymeric) DNA-NT did not split into constituting strands under applied current and voltage. The results of cell viability confirmed that blank DNA-NT had the least cytotoxicity at the highest concentration (512 nM) with a viability of 92% as evidence of its biocompatibility for drug delivery. MTT assay showed superior cytotoxicity of CPT-DNA-NT than that of the free CPT due to the depot release of CPT after DNA-NT internalization. The DNA-NT exhibited targeted cell internalizations with the controlled intracellular release of CPT (from DNA-NT), as illustrated in confocal images. Therefore, in vitro cytotoxicity assessment through flow cytometry showed enhanced apoptosis (72.7%) with CPT-DNA-NT (compared to free CPT; 64.4%). CPT-DNA-NT, being poly-anionic, showed enhanced endocytosis via scavenger receptors.

13.
Autophagy ; 17(11): 3592-3606, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33629929

RESUMEN

Glioma is the most common primary malignant brain tumor with poor survival and limited therapeutic options. The non-psychoactive phytocannabinoid cannabidiol (CBD) has been shown to be effective against glioma; however, the molecular target and mechanism of action of CBD in glioma are poorly understood. Here we investigated the molecular mechanisms underlying the antitumor effect of CBD in preclinical models of human glioma. Our results showed that CBD induced autophagic rather than apoptotic cell death in glioma cells. We also showed that CBD induced mitochondrial dysfunction and lethal mitophagy arrest, leading to autophagic cell death. Mechanistically, calcium flux induced by CBD through TRPV4 (transient receptor potential cation channel subfamily V member 4) activation played a key role in mitophagy initiation. We further confirmed TRPV4 levels correlated with both tumor grade and poor survival in glioma patients. Transcriptome analysis and other results demonstrated that ER stress and the ATF4-DDIT3-TRIB3-AKT-MTOR axis downstream of TRPV4 were involved in CBD-induced mitophagy in glioma cells. Lastly, CBD and temozolomide combination therapy in patient-derived neurosphere cultures and mouse orthotopic models showed significant synergistic effect in both controlling tumor size and improving survival. Altogether, these findings showed for the first time that the antitumor effect of CBD in glioma is caused by lethal mitophagy and identified TRPV4 as a molecular target and potential biomarker of CBD in glioma. Given the low toxicity and high tolerability of CBD, we therefore propose CBD should be tested clinically for glioma, both alone and in combination with temozolomide.Abbreviations: 4-PBA: 4-phenylbutyrate; AKT: AKT serine/threonine kinase; ATF4: activating transcription factor 4; Baf-A1: bafilomycin A1; CANX: calnexin; CASP3: caspase 3; CAT: catalase; CBD: cannabidiol; CQ: chloroquine; DDIT3: DNA damage inducible transcript 3; ER: endoplasmic reticulum; GBM: glioblastoma multiforme; GFP: green fluorescent protein; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PARP1: poly(ADP-ribose) polymerase; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; SLC8A1: solute carrier family 8 member A1; SQSTM1: sequestosome 1; TCGA: The cancer genome atlas; TEM: transmission electron microscopy; TMZ: temozolomide; TRIB3: tribbles pseudokinase 3; TRPC: transient receptor potential cation channel subfamily C; TRPV4: transient receptor potential cation channel subfamily V member 4.


Asunto(s)
Cannabidiol/uso terapéutico , Glioma/tratamiento farmacológico , Mitofagia/efectos de los fármacos , Canales Catiónicos TRPV/metabolismo , Animales , Antineoplásicos Alquilantes/farmacología , Muerte Celular Autofágica/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Cannabidiol/farmacología , Línea Celular Tumoral , Glioma/metabolismo , Glioma/patología , Humanos , Masculino , Ratones , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Trasplante de Neoplasias , Canales Catiónicos TRPV/fisiología , Temozolomida/farmacología
14.
Curr Med Chem ; 27(40): 6787-6814, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31580244

RESUMEN

Due to the three domains of the colchicine-site which is conducive to the combination with small molecule compounds, colchicine-site on the tubulin has become a common target for antitumor drug development, and accordingly, a large number of tubulin inhibitors binding to the colchicine-site have been reported and evaluated over the past years. In this study, tubulin inhibitors targeting the colchicine-site and their application as antitumor agents were reviewed based on the literature from 2015 to 2019. Tubulin inhibitors were classified into ten categories according to the structural features, including colchicine derivatives, CA-4 analogs, chalcone analogs, coumarin analogs, indole hybrids, quinoline and quinazoline analogs, lignan and podophyllotoxin derivatives, phenothiazine analogs, N-heterocycle hybrids and others. Most of them displayed potent antitumor activity, including antiproliferative effects against Multi-Drug-Resistant (MDR) cell lines and antivascular properties, both in vitro and in vivo. In this review, the design, synthesis and the analysis of the structure-activity relationship of tubulin inhibitors targeting the colchicine-site were described in detail. In addition, multi-target inhibitors, anti-MDR compounds, and inhibitors bearing antitumor activity in vivo are further listed in tables to present a clear picture of potent tubulin inhibitors, which could be beneficial for medicinal chemistry researchers.


Asunto(s)
Moduladores de Tubulina/química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Colchicina , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/uso terapéutico
15.
Expert Opin Ther Pat ; 29(9): 675-688, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31370713

RESUMEN

Introduction: RAF kinase inhibitors block and regulate RAS/RAF/MEK/ERK signaling, which is a key to tumor treatment. At present, although RAF kinase inhibitors have good efficacy, there are few such drugs with low toxicity, and thus, it is urgent to find novel RAF kinase inhibitors associated with higher activity and fewer adverse reactions. This review highlights the anti-tumor effects of several published RAF kinase inhibitors and might be helpful in providing new ideas for the development of novel drug candidates in the future. Areas covered: This article covers the pertinent literature published on RAF kinase inhibitors from 2010 to 2018, as well as the potential use of these compounds as therapeutics for cancer. Expert opinion: To date, many RAF kinase inhibitors with different structures have been studied, many of which have prominent inhibitory activities toward RAF kinase. Further, the specificity of these drugs offers hope for the targeted therapy of tumors. Although RAF kinase inhibition has achieved promising results for the treatment of many cancers, overcoming limitations associated with drug resistance and safety comprises a new direction for the optimization and improvement of RAF kinase inhibitors.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Quinasas raf/antagonistas & inhibidores , Animales , Desarrollo de Medicamentos/métodos , Resistencia a Antineoplásicos , Humanos , Terapia Molecular Dirigida , Neoplasias/enzimología , Patentes como Asunto , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Quinasas raf/metabolismo
16.
Eur J Med Chem ; 163: 896-910, 2019 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-30580241

RESUMEN

In current work, a class of novel 4,5-dihydro-1H-pyrazole-1-carboxylate derivatives (E01-E28) were designed, synthesized and evaluated. Among them, the most potent compound E24 exhibited comparable activity against a panel of cancer cells (GI50 ranging 0.05-0.98 µM) and tubulin polymerization inhibition (IC50 = 1.49 µM) with reference drug CA-4(P) (GI50 ranging 0.019-0.32 µM, IC50 = 2.18 µM). The following assays indicated that compound E24 disturbed the dynamics of tubulin catastrophe and rescue, which triggered G2/M arrest, leading to ROS accumulation, cleavage of PARP and apoptosis. Molecular dynamics simulation validated that compound E24 could tightly bind into tubulin heterodimers with ß Lys 254 and ß Cys 241 of tubulin in the docking pose. Metabolic stability and pharmacokinetics parameters were also determined. The half time (t1/2) displayed species differences in three microsomes. The plasma elimination half-life (t1/2), peak plasma concentration (Cmax), mean retention time (MRT), the area under the curve (AUC0-∞) and distribution volume (Vz) of E24 after intravenous administration were 0.90 ± 0.22 h, 594.50 ± 97.23 ng/mL, 1.09 ± 0.22 h, 413.67 ± 105.64 ng/mL*h and 5.03 ± 1.82 L/kg, respectively. In HeLa-xenografts, compound E24 exhibited obvious antitumor efficacy via the suppression of tumor growth without weight loss of body or organ. In brief, compound E24 might be a hopeful candidate with excellent properties for oncotherapy as tubulin polymerization inhibitor.


Asunto(s)
Antineoplásicos/síntesis química , Polimerizacion/efectos de los fármacos , Moduladores de Tubulina/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Xenoinjertos , Humanos , Ratones , Poli(ADP-Ribosa) Polimerasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química
17.
Chem Biol Drug Des ; 94(5): 1894-1904, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31106514

RESUMEN

Several novel cycloalkyl-fused 2,3-diaryl pyrazole derivatives were designed, synthesized, and evaluated as potential anti-tubulin agents. Compound A10 exhibited the most potent antiproliferative activity against a panel of cancer lines (IC50  = 0.78-2.42 µM) and low cytotoxicity against 293T & L02 (CC50 values of 131.74 and 174.89 µM, respectively). Moreover, A10 displayed inhibition of tubulin polymerization in vitro, arrested the G2/M phase of the cell cycle, changed morphology of tubulin, increased intracellular reactive oxygen species, and induced apoptosis of HeLa cells. Docking simulation and 3D-QSAR models were performed to elaborate on the anti-tubulin mechanism of the derivatives. The inhibition of monoclonal colony formation provided more intuitional data to verify the possibility of A10 as a novel tubulin assembling inhibitor.


Asunto(s)
Antineoplásicos/síntesis química , Hidrocarburos Cíclicos/síntesis química , Hidrocarburos Cíclicos/metabolismo , Pirazoles/síntesis química , Moduladores de Tubulina/síntesis química , Tubulina (Proteína)/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrocarburos Cíclicos/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Conformación Proteica , Pirazoles/farmacología , Relación Estructura-Actividad Cuantitativa , Especies Reactivas de Oxígeno/metabolismo , Moduladores de Tubulina/farmacología
18.
Eur J Med Chem ; 156: 722-737, 2018 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-30041136

RESUMEN

In the present work, twenty-five nicotinoyl pyrazoline derivates bearing N-methyl indole moiety have been designed and synthesized. The biological evaluation of these compounds as tubulin assembly inhibitors revealed that most of them were potential antitumor agents. Among them, compound 28 exhibited most potency against cancer cell line panels (GI50 = 29-90 nM for HeLa, HepG2 and MCF-7 cells) without toxicity to non-tumor cells (CC50 > 300 µM for 293 T cell), bound to the colchicine site of tubulin and displayed excellent inhibitory activity in tubulin assembly assay (IC50 = 1.6 µM, better than CA-4). Molecular dynamics simulation was carried out to validate the docking pose of compound 28 with tubulin crystalline. Further investigation on HepG2 and HeLa cells demonstrated that compound 28 could cause mitosis arrest to G2/M phase, and subsequently induced cell apoptosis. The efficiency in vivo of compound 28 was also evaluated on HeLa-Xenograft nude mice, and the relative tumor inhibition ration was up to 61.52% without noticeable weight loss and tissue damage (examined by H&E staining), which was comparable to CA-4 (inhibited 59.92%). In brief, compound 28 is a promising candidate for tumor therapy as tubulin assembly inhibitor.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Pirazoles/química , Pirazoles/uso terapéutico , Moduladores de Tubulina/química , Moduladores de Tubulina/uso terapéutico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Diseño de Fármacos , Femenino , Células HEK293 , Células HeLa , Humanos , Indoles/química , Indoles/farmacología , Indoles/uso terapéutico , Ratones Desnudos , Mitosis/efectos de los fármacos , Modelos Moleculares , Neoplasias/metabolismo , Neoplasias/patología , Pirazoles/farmacología , Moduladores de Tubulina/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología
19.
Eur J Pharm Sci ; 121: 74-84, 2018 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-29772274

RESUMEN

YMR-65​, 5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3-methoxyphenyl)-4, 5-dihydro-1H-pyrazole-1-carboxamide, is a potential tubulin inhibitor exhibiting good anticancer activity. In our study, we illustrated the biological activities in HepG2 cells and the pharmacodynamic and pharmacokinetic profiles were evaluated in murine H22 hepatoma-bearing mice. Molecular docking assay and colchicine competition assay indicated that YMR-65 could bind tightly to the colchicine binding site of tubulin. Further investigation demonstrated that YMR-65 arrested cells in the G2/M phase of cell cycle and induced apoptosis in HepG2 cells. Compared with control group, the tumor growth inhibition determined by final relative volume of tumor/the initial tumor volume were 32.57%, 24.00% and 34.95%, respectively, for YMR-65 (10 mg/kg), YMR-65 (20 mg/kg) and CA4P (10 m/kg) groups. Besides there were no obvious body change or tissue damage (enhanced by histopathology study). YMR-65 administration at 10 and 20 mg/kg in H22 tumor-bearing mice resulted in 1.87- and 1.80-fold longer half time (t1/2) and 0.36- and 0.78-fold lower area under concentration-time curve (AUC0-∞) in plasma in contrast with normal mice at 10 mg/kg. Furthermore, YMR-65 showed a wide distribution to various tissues or tumor and the highest distribution index (the ratio of AUCtissue or tumor/AUCplasma) was found in tumor, which implied that it might accumulate in tumor after administration. In brief, our results indicated that YMR-65 was a promising candidate with high antitumor efficacy and low tissue damage.


Asunto(s)
Antineoplásicos/farmacología , Indoles/farmacología , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Pirazoles/farmacología , Moduladores de Tubulina/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Colchicina/metabolismo , Humanos , Indoles/sangre , Indoles/farmacocinética , Indoles/uso terapéutico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Simulación del Acoplamiento Molecular , Pirazoles/sangre , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Distribución Tisular , Moduladores de Tubulina/farmacocinética , Moduladores de Tubulina/uso terapéutico , Carga Tumoral/efectos de los fármacos
20.
Chem Biol Drug Des ; 90(1): 112-118, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28032450

RESUMEN

A series of new 1-phenylsulphonyl-2-(1-methylindol-3-yl)-benzimidazole derivatives were designed, synthesized and evaluated as potential inhibitors of tubulin polymerization and anthropic cancer cell lines. Among them, compound 33 displayed the most potent tubulin polymerization inhibitory activity in vitro (IC50  = 1.41 µM) and strong antiproliferative activities against A549, Hela, HepG2 and MCF-7 cell lines in vitro with GI50 value of 1.6, 2.7, 2.9 and 4.3 µM, respectively, comparable with the positive control colchicine (GI50 value of 4.1, 7.2, 9.5 and 14.5 µM, respectively) and CA-4 (GI50 value of 2.2, 4.3, 6.4 and 11.4 µM, respectively). Simultaneously, we evaluated that compound 33 could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Immunofluorescence microscopy also clearly indicated compound 33 a potent antimicrotubule agent. Docking simulation showed that compound 33 could bind tightly with the colchicine-binding site and act as a tubulin inhibitor. Three-dimensional-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent tubulin assembling inhibitory activity in the future.


Asunto(s)
Bencimidazoles/química , Moduladores de Tubulina/síntesis química , Tubulina (Proteína)/metabolismo , Células A549 , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Sitios de Unión , Puntos de Control del Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Colchicina/química , Colchicina/metabolismo , Colchicina/farmacología , Cristalografía por Rayos X , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Ratones , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Relación Estructura-Actividad Cuantitativa , Tubulina (Proteína)/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología
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