RESUMEN
Bromodomain protein 4 (BRD4) is a member of the BET family, and its overexpression is closely associated with the development of many tumors. Inhibition of BRD4 shows great therapeutic potential in anti-tumor, and pan-BRD4 inhibitors show adverse effects of dose limiting toxicity and thrombocytopenia in clinical trials. To improve clinical effects and reduce side effects, more efforts have focused on seeking selective inhibitors of BD1 or BD2. Herein, a series of indole-2-one derivatives were designed and synthesized through docking-guided optimization to find BRD4-BD1 selective inhibitors, and their BRD4 inhibitory and antiproliferation activities were evaluated. Among them, compound 21r had potent BRD4 inhibitory activity (the IC50 values of 41 nM and 313 nM in BD1 and BD2 domain), excellent anti-proliferation (the IC50 values of 4.64 ± 0.30 µM, 0.78 ± 0.03 µM, 5.57 ± 1.03 µM against HL-60, MV-4-11 and HT-29 cells), and displayed low toxicity against normal cell GES-1 cells. Further studies revealed that 21r inhibited proliferation by decreasing the expression of proto-oncogene c-Myc, blocking cell cycle in G0/G1 phase, and inducing apoptosis in MV-4-11 cells in a dose-dependent manner. All the results showed that compound 21r was a potent BRD4 inhibitor with BD1 selectivity, which had potential in treatment of leukemia.
Asunto(s)
Antineoplásicos , Proteínas de Ciclo Celular , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Indoles , Factores de Transcripción , Humanos , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Estructura Molecular , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , Proto-Oncogenes Mas , Apoptosis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Proteínas que Contienen BromodominioRESUMEN
KRAS-G12C inhibitors has been made significant progress in the treatment of KRAS-G12C mutant cancers, but their clinical application is limited due to the adaptive resistance, motivating development of novel structural inhibitors. Herein, series of coumarin derivatives as KRAS-G12C inhibitors were found through virtual screening and rational structural optimization. Especially, K45 exhibited strong antiproliferative potency on NCI-H23 and NCI-H358 cancer cells harboring KRAS-G12C with the IC50 values of 0.77 µM and 1.50 µM, which was 15 and 11 times as potent as positive drug ARS1620, respectively. Furthermore, K45 reduced the phosphorylation of KRAS downstream effectors ERK and AKT by reducing the active form of KRAS (KRAS GTP) in NCI-H23 cells. In addition, K45 induced cell apoptosis by increasing the expression of anti-apoptotic protein BAD and BAX in NCI-H23 cells. Docking studies displayed that the 3-naphthylmethoxy moiety of K45 extended into the cryptic pocket formed by the residues Gln99 and Val9, which enhanced the interaction with the KRAS-G12C protein. These results indicated that K45 was a potent KRAS-G12C inhibitor worthy of further study.
Asunto(s)
Antineoplásicos , Proliferación Celular , Cumarinas , Ensayos de Selección de Medicamentos Antitumorales , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Cumarinas/química , Cumarinas/farmacología , Cumarinas/síntesis química , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Apoptosis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Evaluación Preclínica de MedicamentosRESUMEN
The bromodomain-containing protein 4 (BRD4) has gained growing interest as an effective drug target for the treatment of hepatocellular carcinoma (HCC). Herein, we designed and synthesized a series of quinoxalinone derivatives as BRD4 inhibitors via scaffold hopping. The representative compound X9 showed potent BRD4 inhibitory activity (with IC50 = 82.3 nM), and preferable antiproliferative activity against HepG2 cells (with IC50 = 1.13 ± 0.07 µM), as well as less toxicity against GES-1 cells (with IC50 = 57.24 ± 5.46 µM). Furthermore, compound X9 dose-dependently inhibited colony formation and blocked the migration of HepG2 cells by down-regulating the expression of Snail and MMP-9 while up-regulating the E-cadherin and Occludin. Besides, compound X9 efficiently down-regulated the expression of c-Myc in HepG2 cells, induced apoptosis, and arrested at G0/G1 phase. In total, quinoxalinone was a potential core as BRD4 inhibitor and compound X9 might be effective for liver cancer therapy.
Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Proteínas Nucleares/metabolismo , Relación Estructura-Actividad , Carcinoma Hepatocelular/tratamiento farmacológico , Diseño de Fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Factores de Transcripción , Proliferación Celular , Antineoplásicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Proteínas de Ciclo Celular/metabolismoRESUMEN
The PI3K/AKT/mTOR signaling pathway is one of the most common abnormal activation pathways in tumor cells, and has associated with multiple functions such as tumor cell growth, proliferation, migration, invasion, and tumor angiogenesis. Here, a series of 3-amino-1H-indazole derivatives were synthesized, and their antiproliferative activities against HT-29, MCF-7, A-549, HepG2 and HGC-27 cells were evaluated. Among them, W24 exhibited the broad-spectrum antiproliferative activity against four cancer cells with IC50 values of 0.43-3.88 µM. Mechanism studies revealed that W24 inhibited proliferation by affecting the DNA synthesis, induced G2/M cell cycle arrest and apoptosis by regulating Cyclin B1, BAD and Bcl-xL, meanwhile induced the change of intracellular ROS and mitochondrial membrane potential in HGC-27 cells. Moreover, W24 inhibited the migration and invasion of HGC-27 cells by decreasing EMT pathway related proteins and reducing the mRNA expression levels of Snail, Slug and HIF-1α. Furthermore, W24 displayed low tissue toxicity profile and good pharmacokinetic properties in vivo. Therefore, 3-amino-1H-indazole derivatives might serve as a new scaffold for the development of PI3K/AKT/mTOR inhibitor and anti-gastric cancer reagent.
Asunto(s)
Indazoles , Neoplasias , Humanos , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Neoplasias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Indazoles/química , Indazoles/farmacologíaRESUMEN
Vascular epidermal growth factor receptor-2 (VEGFR-2), as an important tyrosine transmembrane protein, plays an important role in regulating endothelial cell proliferation and migration, regulating angiogenesis and other biological functions. VEGFR-2 is aberrantly expressed in many malignant tumors, and it is also related to the occurrence, development, and growth of tumors and drug resistance. Currently, there are nine VEGFR-2 targeted inhibitors approved by US.FDA for clinical use as anticancer drugs. Due to the limited clinical efficacy and potential toxicity of VEGFR inhibitors, it is necessary to develop new strategies to improve the clinical efficacy of VEGFR inhibitors. The development of multitarget therapy, especially dual-target therapy, has become a hot research field of cancer therapy, which may provide an effective strategy with higher therapeutic efficacy, pharmacokinetic advantages and low toxicity. Many groups have reported that the therapeutic effects could be improved by simultaneously inhibiting VEGFR-2 and other targets, such as EGFR, c-Met, BRAF, HDAC, etc. Therefore, VEGFR-2 inhibitors with multi-targeting capabilities have been considered to be promising and effective anticancer agents for cancer therapy. In this work, we reviewed the structure and biological functions of VEGFR-2, and summarized the drug discovery strategies, and inhibitory activities of VEGFR-2 inhibitors with multi-targeting capabilities reported in recent years. This work might provide the reference for the development of VEGFR-2 inhibitors with multi-targeting capabilities as novel anticancer agents.
Asunto(s)
Antineoplásicos , Neoplasias , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Proliferación Celular , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
PI3Ks and HDACs play essential roles in the occurrence and progression of leukemia. Herein, a series of novel pyrazin-2(1H)-one derivatives were rationally designed and synthesized as novel dual PI3K and HDAC inhibitors based on scaffold replacement and heterozygous strategies. Most of the target compounds showed potent inhibitory potency to PI3Kα and HDAC6. Especially, compound 9q displayed PI3Kα and HDAC6 inhibitory with IC50 values of 372 nM and 4.5 nM, and anti-proliferative activity against MV4-11 cells with IC50 value of 0.093 ± 0.012 µM. Further mechanistic studies revealed that 9q induced apoptosis, arrested the cell cycle in the G2/M phase, promoted the acetylation of α-tubulin, and blocked the PI3K/AKT/mTOR signal way in MV4-11 cells. All the results demonstrated that 9q was a promising lead candidate for further development of novel PI3K/HDAC dual inhibitors for leukemia treatment.
Asunto(s)
Antineoplásicos , Leucemia , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Leucemia/tratamiento farmacológico , Diseño de Fármacos , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento MolecularRESUMEN
The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer. Coumarin is a highly privileged moiety for the development of novel anticancer drugs which has been identified in clinical trials for the treatment of various cancers. Herein, we modified BRD4i ABBV-075 with a coumarin ring and synthesized a novel series of coumarin derivatives as BRD4 inhibitors. Among them, the representative compound 27d showed excellent BRD4 inhibitory activities with an IC50 value of 99 nM in the TR-FRET assay. Compared with ABBV-075, compound 27d displayed a favorable cell proliferation inhibitory activity in solid tumors, such as MCF-7, HGC-27 and HepG-2. Further mechanism investigation illustrated that 27d-treatment resulted in G0/G1 phase arrest and promoted apoptosis of MCF-7 cells. Compound 27d also blocked colony formation in a concentration-dependent manner in McF-7 cell lines. As the downstream-protein of BRD4, the expression of c-Myc was decreased in a dose-dependent manner after the treatment of compound 27d. Moreover, compound 27d also exhibited good in vivo and in vitro metabolic stability. All the findings meaningfully make it as a promising lead compound for further drug development.
Asunto(s)
Antineoplásicos , Proteínas Nucleares , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Cumarinas/farmacología , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Relación Estructura-Actividad , Factores de TranscripciónRESUMEN
A new series of N-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-amine derivatives as tubulin polymerization inhibitors were synthesized, and evaluated for the anti-proliferative activities. A structure-activity relationship study revealed that the free amino moiety of 1H-pyrazolo[3,4-b]pyridin-3-amine played an essential role in the anti-proliferative activities. Especially, compound 15c displayed the strongest anti-proliferation against MCF-7 cells with IC50 value of 0.067 ± 0.003 µM, and high selectivity over the normal human embryonic lung WI-38 cells with IC50 value of 23.41 ± 1.53 µM. Further mechanistic studies revealed that 15c showed strong anti-tubulin polymerization activity, changed the morphology of tubulin, and arrested the cell cycle at the G2/M transition in MCF-7 cells. Molecular docking analysis suggested that 15c well occupied the colchicine-binding pocket of tubulin. Additionally, 15c demonstrated anti-angiogenic activities with blocking the migration, invasion and tube formation, disrupting the newly formed tube, and regulating both MMP-9 and TIMP-1 in HUVEC cells. In summary, our results highlight that compound 15c is a potential antitumor compound that are worthy of further development.
Asunto(s)
Aminas/farmacología , Antineoplásicos/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/metabolismo , Aminas/síntesis química , Aminas/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Movimiento 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 , Simulación del Acoplamiento Molecular , Estructura Molecular , Polimerizacion/efectos de los fármacos , Pirazoles/síntesis química , Pirazoles/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Porcinos , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/químicaRESUMEN
A series of novel 4-substituted phthalazinones as Aurora B kinase inhibitors was synthesized and evaluated the anti-proliferative activities against A549, HCT116, MCF-7 and HepG2 cells. 1-(4-(2-((4-Oxo-3,4-dihydrophthalazin-1-yl)amino)ethyl) phenyl)-3-(3-(trifluoromethyl)phenyl)urea (17b) exhibited the most potent anti-proliferative activity against HCT116 cells with IC50 value of 4.35 ± 1.21 µM, as well as the moderate Aurora B inhibitory activity with the IC50 value of 142 nM. Furthermore, 17b inhibited the phosphorylation of Aurora B on Thr232, leading to cell cycle arrest in the G2/M phase by down-regulating the expression of CyclinB1 and Cdc2 proteins, and apoptosis by up-regulating the expression of BAD and Bax proteins in HCT116 cells. In addition, a docking study revealed that 17b could form key hydrogen bonds with Ala173, Glu171 and Glu177 in Aurora B. All the results reveal that 17b is worthy of further development as an Aurora B kinase inhibitor.
Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasa B/antagonistas & inhibidores , Ftalazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Apoptosis/efectos de los fármacos , Aurora Quinasa B/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Pruebas de Enzimas , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Fosforilación/efectos de los fármacos , Ftalazinas/síntesis química , Ftalazinas/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
In order to explore novel Aurora kinase inhibitors, a series of novel 2,4-disubstituted pyrimidines were designed, synthesized and evaluated their in vitro anti-proliferative activities against a panel of cancerous cell lines (A549, HCT-116 and MCF-7). Among them, compound 12a showed the moderate to high anti-proliferative activities against A549 (IC50 = 12.05 ± 0.45 µM), HCT-116 (IC50 = 1.31 ± 0.41 µM) and MCF-7 (IC50 = 20.53 ± 6.13 µM) cells, as well as the Aurora A and Aurora B inhibitory activities with the IC50 values of 309 nM and 293 nM, respectively. Furthermore, compound 12a induced apoptosis by upregulated the pro-apoptotic proteins Bax and decreased the anti-apoptotic protein Bcl-xl in HCT-116 cells. Moreover, the molecular docking study showed that compound 12a had good binding modes with Aurora A and Aurora B and the bioinformatics prediction discovered that compound 12a exhibited good drug likeness using SwissADME. Taken together, these results indicated that 12a may be a potential anticancer compound that was worthy of further development as Aurora kinase inhibitor.
Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Apoptosis/efectos de los fármacos , Aurora Quinasa A/metabolismo , Aurora Quinasa B/metabolismo , Sitios de Unión , Línea Celular Tumoral , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Pirimidinas/metabolismo , Pirimidinas/farmacología , Relación Estructura-Actividad , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis, and a number of Aurora kinase inhibitors have been evaluated in the clinic. Herein we report the synthesis and their antiproliferation of 3,5-disubstituted-2-aminopyrazines as kinases inhibitors. Amongst, 4-((3-amino-6- (3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)oxy)-N-(3-chlorophenyl) benzamide (12Aj) exhibited the strongest antiproliferative activities against U38, HeLa, HepG2 and LoVo cells with IC50 values were 11.5 ± 3.2, 1.34 ± 0.23, 7.30 ± 1.56 and 1.64 ± 0.48 µM, as well as inhibited Aurora A and B with the IC50 values were 90 and 152 nM, respectively. Molecular docking studies indicated that 12Aj appeared to form stable hydrogen bonds with either Aurora A or Aurora B. Furthermore, 12Aj arrested HeLa cell cycle in G2/M phase by regulating protein levels of cyclinB1 and cdc2. In addition, the bioinformatics prediction further revealed that 12Aj possessed good drug likeness using SwissADME. These results suggested that 12Aj was worthy of future development of potent anticancer agents as pan-Aurora kinases.
Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Aurora Quinasa A/metabolismo , Aurora Quinasa B/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazinas/síntesis química , Pirazinas/química , Relación Estructura-ActividadRESUMEN
Antioxidants have been the subject of intense research interest due to their numerous health benefits. In this work, a series of new conjugates of hydroxytyrosol and coumarin were synthesized and evaluated for their free radical scavenging, toxicity and antioxidant mechanism in vitro. The all target compounds 14a-t exhibited better radical scavenging activity than BHT, hydroxytyrosol, and coumarin in both DPPH radical and ABTS+ radical cation scavenging assays. The structure-activity relationships study indicated that the number and position of hydroxyl groups on the coumarin ring were vital to a good antioxidant capacity. Furthermore, the most promising compound 14q showed less toxicity in hemolysis assay and weaker antiproliferative effects than BHT against normal WI-38 and GES cells, and enhanced viability of H2O2-induced HepG2 cells. Additionally, 14q decreased the apoptotic percentage of HepG2 cells, reduced the ROS produce and LDH release, and improved GSH and SOD levels in H2O2-treated HepG2 cells. Lastly, 14q exhibited more stability than hydroxytyrosol in methanol solution. These results revealed that conjugations of hydroxytyrosol and coumarin show better antioxidant capacity, and are the efficacious approach to finding novel potential antioxidant.
Asunto(s)
Antioxidantes/farmacología , Cumarinas/farmacología , Alcohol Feniletílico/análogos & derivados , Antioxidantes/síntesis química , Antioxidantes/química , Apoptosis/efectos de los fármacos , Benzotiazoles/antagonistas & inhibidores , Compuestos de Bifenilo/antagonistas & inhibidores , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cumarinas/química , Relación Dosis-Respuesta a Droga , Humanos , Peróxido de Hidrógeno/antagonistas & inhibidores , Peróxido de Hidrógeno/farmacología , Estructura Molecular , Alcohol Feniletílico/química , Alcohol Feniletílico/farmacología , Picratos/antagonistas & inhibidores , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Ácidos Sulfónicos/antagonistas & inhibidoresRESUMEN
The key functions of microtubules and the mitotic spindle in cell division make them attractive targets for cancer therapy. In this study, a series of 1-(benzofuran-3-yl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole derivatives was synthesized, and their antiproliferative activities against HCT116, HeLa, HepG2, and A549 cells were evaluated. 6-Methoxy-N-phenyl-3-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)benzofuran-2-carboxamide (17g) exhibited the strongest antiproliferative activities, with IC50 values ranging from 0.57 to 5.7⯵M. Mechanistic studies showed that 17g inhibited tubulin polymerization, leading to the disruption of mitotic spindle formation, cell cycle arrest in the G2/M phase, and apoptosis of A549 cells. A docking study indicated that 17g was a good molecular fit at the colchicine binding site of tubulin. These results showed that 17g is a potential anticancer compound that is worthy of further development as a tubulin polymerization inhibitor.
Asunto(s)
Antineoplásicos/farmacología , Benzofuranos/farmacología , Triazoles/farmacología , Tubulina (Proteína)/metabolismo , Células A549 , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Benzofuranos/síntesis química , Benzofuranos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Simulación del Acoplamiento Molecular , Estructura Molecular , Polimerizacion/efectos de los fármacos , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
To find novel effective Aurora kinases inhibitors, a series of structurally interesting nitroxide labeled pyrimidines were synthesized and evaluated their anti-proliferative and Aurora kinases inhibitory activities. Among them, butyl 2-(3-((5-fluoro-2-((4-((1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)carbamoyl) phenyl) amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)acetate (22) possessed the most potent anti-proliferative effects against four carcinoma cell lines with IC50 values in range of 0.89-11.41⯵M, and kinases inhibition against Aurora A and B with the IC50 values were 9.3 and 2.8â¯nM, respectively. Furthermore, compound 22 blocked the phosphorylation of Aurora A (T288), Aurora B (Thr232) and HisH3, decreased the expression of proteins TPX2, Eg5 and Bora, as well as disrupted the mitotic spindle formation in HeLa cells. Molecular docking studies indicated that compound 22 well interact with both Aurora A and B. The results showed that compound 22 is a potential anticancer agent as promising pan-Aurora kinase inhibitor.
Asunto(s)
Aurora Quinasas/antagonistas & inhibidores , Óxidos de Nitrógeno/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , FosforilaciónRESUMEN
A series of conjugates of podophyllotoxin and coumarin were prepared using the click reaction, and their cytotoxicities against A549, HepG2, HeLa, and LoVo cells were evaluated. Among them, compound 14e exhibited the strongest cytotoxicities against these cancer cells with IC50 values of 4.9-17.5⯵M. Furthermore, 14e disrupted microtubules and induced cell cycle arrest at G1 phase by regulating P21 and Cyclin D1 in LoVo cells. In addition, 14e bond CT DNA and selectively inhibited Topo IIß over Topo IIα. Molecular docking model showed that 14e appeared to form stable hydrogen bonds with several DNA bases and residue Gln778. Taken together, these conjugates have the potential to be developed as anti-tumor drugs.
Asunto(s)
Puntos de Control del Ciclo Celular/efectos de los fármacos , Cumarinas/uso terapéutico , ADN/metabolismo , Podofilotoxina/química , Cumarinas/farmacología , ADN-Topoisomerasas de Tipo II/metabolismo , Humanos , Relación Estructura-ActividadRESUMEN
The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Herein, we reported a series of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl with selective inhibition of Aurora A in either enzymatic assays or cellular phenotypic assays, and displaying more potent anti-proliferation compared with that of VX-680. The most potent compound 10a forms better interaction with Aurora A than Aurora B in molecular docking. Mechanistic studies revealed that 10a disrupt the spindle formation, block the cell cycle progression in the G2/M phase and induce apoptosis in HeLa cell. These results suggested that the produced series of compounds are potential anticancer agents for further development as selective Aurora A inhibitors.
Asunto(s)
Compuestos de Anilina/farmacología , Óxidos N-Cíclicos/farmacología , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Apoptosis/efectos de los fármacos , Aurora Quinasa A/química , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Óxidos N-Cíclicos/síntesis química , Óxidos N-Cíclicos/química , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Piperidinas/síntesis química , Piperidinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Huso Acromático/efectos de los fármacosRESUMEN
A series of 4ß-(thiazol-2-yl)amino-4'-O-demethyl-4-deoxypodophyllotoxins were synthesized, and their cytotoxicities were evaluated against four human cancer cell lines (A549, HepG2, HeLa, and LOVO cells) and normal human diploid fibroblast line WI-38. Some of the compounds exhibited promising antitumor activity and less toxicity than the anticancer drug etoposide. Among them, compounds 15 and 17 were found to be the most potent synthetic derivatives as topo-II inhibitors, and induced DNA double-strand breaks via the p73/ATM pathway as well as the H2AX phosphorylation in A549 cells. These compounds also arrested A549 cells cycle in G2/M phase by regulating cyclinB1/cdc2(p34). Taken together, these results show that a series of compounds are potential anticancer agents.
Asunto(s)
Antineoplásicos/farmacología , ADN-Topoisomerasas de Tipo II/metabolismo , Péptidos/farmacología , Inhibidores de Topoisomerasa II/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Fibroblastos/efectos de los fármacos , Humanos , Estructura Molecular , Péptidos/síntesis química , Péptidos/química , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/químicaRESUMEN
A series of 2,4-disubstituted phthalazinones were synthesized and their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects were evaluated. Among them, N-cyclohexyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-1-oxophthalazin-2(1H)-yl) methyl) benzamide (12c) exhibited the most potent antiproliferation against five carcinoma cell lines (HeLa, A549, HepG2, LoVo and HCT116 cells) with IC50 values in range of 2.2-4.6⯵M, while the IC50 value of reference compound VX-680 was 8.5-15.3⯵M. Moreover, Aurora kinase assays exhibited that compound 12c was potent inhibitor of AurA and AurB kinase with the IC50 values were 118⯱â¯8.1 and 80⯱â¯4.2â¯nM, respectively. Molecular docking studies indicated that compound 12c forms better interaction with both AurA and AurB. Furthermore, compound 12c induced G2/M cell cycle arrest in HeLa cells by regulating protein levels of cyclinB1 and cdc2. These results suggested that 12c is a promising pan-Aurora kinase inhibitor for the potential treatment of cancer.
Asunto(s)
Aurora Quinasas/antagonistas & inhibidores , Ftalazinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Aurora Quinasas/metabolismo , Sitios de Unión , Proteína Quinasa CDC2/metabolismo , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclina B1/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HCT116 , Células HeLa , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Fosforilación/efectos de los fármacos , Ftalazinas/metabolismo , Ftalazinas/farmacología , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-ActividadRESUMEN
We have found that the deoxypodophyllotoxin-5-fluorouracil conjugate, 4'-O-demethyl-4-deoxyppodophyllotoxin-4'-yl 4-((6-(2-(5-fluorouracil-yl)acetamido) hexyl)amino)-4-oxobutanoate (C069), possessed superior cytotoxicities and less toxicity compared with etoposide. In this paper, the anti-angiogenic and vascular disrupting activities of C069 were examined with several in vitro and in vivo models. First, we demonstrated that C069 significantly inhibited the proliferation, migration, tube formation and disrupted the formed tube-like structures of HUVE cells, and inhibited angiogenesis in chicken chorioallantoic membrane assay. Furthermore, we found that C069 inhibited tube formation of HUVE cells by down-regulating the MMP-2, MMP-9, and phosphorylation of Akt and ß-catenin. These results provided the initial evidence that C069 exerts potent anti-angiogenic and vascular disrupting effects.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Proliferación Celular/efectos de los fármacos , Fluorouracilo/química , Neovascularización Fisiológica/efectos de los fármacos , Podofilotoxina/análogos & derivados , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Medicamentos Herbarios Chinos , Etopósido/toxicidad , Células Endoteliales de la Vena Umbilical Humana , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Fosforilación/efectos de los fármacos , Podofilotoxina/química , Podofilotoxina/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , beta Catenina/metabolismoRESUMEN
A series of N-(aminosulfonyl)-4-podophyllotoxin carbamates were synthesized via the Burgess-type intermediate, and their antiproliferative activities were evaluated. Most of them possessed more potent cytotoxic effects against four human tumor cell lines (HeLa, A-549, HCT-8 and HepG2) and less toxic to normal human fetal lung fibroblast WI-38 cells than etoposide. In particular, N-(morpholinosulfonyl)-4-podophyllotoxin carbamate (9) exhibited the most potent activity towards these four tumor cells with IC50 values in the range of 0.5-16.5µM. Furthermore, immunofluorescence analysis revealed that 9 induced cell apoptosis by up-regulating the expression of p53 and ROS. Meanwhile, 9 effectively inhibited tubulin polymerization and microtubule assembly at cellular levels in HeLa cells. In addition, 9 could induce cell cycle arrest in the G2/M phase in HeLa cells by up-regulating levels of cyclinB1 and cdc2 and decreasing the expression of p-cdc2. These results indicated that 9 had potential for further development as anticancer agents.