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Background: Chylopericardium refers to the accumulation of chylous fluid in the pericardial cavity. Non-enhanced magnetic resonance lymphangiography (MRL) can show neck and thoracic lymphatic abnormalities in the primary chylopericardium. It is not clear whether there is a relationship between neck and thoracic lymphatic abnormalities in primary chylopericardium and thoracic duct terminal release surgery. This study aimed to explore the correlation between the severity of neck and thoracic lymphatic abnormalities observed in non-enhanced MRL and the surgical outcomes in primary chylopericardium. Methods: This is a retrospective cohort study. A retrospective analysis was conducted on fifty-six patients diagnosed with primary chylopericardium between January 2016 and December 2021, all of whom underwent thoracic duct terminal release surgery. Ultrasonography, chest computed tomography (CT) and non-enhanced MRL were performed prior to the surgical intervention. Patients were categorized into four types based on the severity of neck and thoracic lymphatic abnormalities observed in the non-enhanced MRL. Clinical and laboratory examinations and surgical outcomes were compared across different types using χ 2-test or Fisher's exact test, t-test, and Kruskal-Wallis H-test. Additionally, independent factors influencing surgical outcomes were analyzed. Results: Among primary chylopericardium cases (n=56), 22 (39.2%) were classified as type I or II, 17 (30.4%) as type III, and 17 (30.4%) as type IV. Surgical outcomes were more favorable for type I or II patients than those with type III or IV, accompanied by a reduction in postoperative primary chylopericardium volume (P=0.002). Postoperative chest CT scans indicated that type I or II patients had fewer instances of large grid shadows, small grid shadows, and bronchovascular bundle thickening compared to preoperative scans (P=0.001, P=0.02, P=0.03). Age and bronchomediastinal trunk dilation emerged as independent factors influencing surgical outcomes [odds ratio (OR) 0.03, 95% confidence interval (CI): 0.003-0.220, P=0.001; OR 11.10, 95% CI: 1.70-72.39, P=0.01, respectively]. Conclusions: A more severe degree of neck and thoracic lymphatic abnormalities is associated with worse surgical outcomes. Moreover, age and bronchomediastinal trunk dilatation are independent predictors of surgical outcomes. Preoperative utilization of non-enhanced MRL for severity of lymphatic abnormalities classification in primary chylopericardium patients offers a noninvasive means of assessing surgical risk.
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Invisible inks have been applied for the secrecy of texts, symbols and binary images. Based on the photochromism of donor-acceptor Stenhouse adducts (DASAs) in the solid-state promoted by ester-containing molecules, we report the encryption of grayscale information by controlling the kinetics of photoisomerization.
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Logic-in-memory devices are a promising and powerful approach to realize data processing and storage driven by electrical bias. Here, an innovative strategy is reported to achieve the multistage photomodulation of 2D logic-in-memory devices, which is realized by controlling the photoisomerization of donor-acceptor Stenhouse adducts (DASAs) on the surface of graphene. Alkyl chains with various carbon spacer lengths (n = 1, 5, 11, and 17) are introduced onto DASAs to optimize the organic-inorganic interfaces: 1) Prolonging the carbon spacers weakens the intermolecular aggregation and promotes isomerization in the solid state. 2) Too long alkyl chains induce crystallization on the surface and hinder the photoisomerization. Density functional theory calculation indicates that the photoisomerization of DASAs on the graphene surface is thermodynamically promoted by increasing the carbon spacer lengths. The 2D logic-in-memory devices are fabricated by assembling DASAs onto the surface. Green light irradiation increases the drain-source current (Ids ) of the devices, while heat triggers a reversed transfer. The multistage photomodulation is achieved by well-controlling the irradiation time and intensity. The strategy based on the dynamic control of 2D electronics by light integrates molecular programmability into the next generation of nanoelectronics.
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Controlling the multistage photoresponsivity remains a challenge, in part, due to the spontaneous tautomerization between isomers. Herein, we present a strategy to access three independent states (linear, cyclic keto, and cyclic enolate) of crown ether (CE)-substituted donor-acceptor Stenhouse adducts (DASAs) by limiting the tautomerization of the closed isomers. The linear-cyclic keto isomerization is reversibly triggered by treatment with metal ions (Na+ or K+) and CE, while the linear-cyclic enolate isomerization is induced by green light and heat. Density functional theory and molecular dynamics calculation results suggest that the steric effect and supramolecular interaction between the electron-donating and electron-withdrawing moieties play an important role in hindering the tautomerization between cyclic keto and cyclic enolate DASA-CE. The strategy to influence key steps in the photoswitching process inspires well-controlled multistage isomerization of photoresponsive molecules.
Asunto(s)
Éteres Corona , Simulación de Dinámica Molecular , IsomerismoRESUMEN
Giving the fact that the disorders of multiple receptor tyrosine kinases (RTKs) are characteristics of various cancers, we assumed that developing novel multi-target drugs might have an advantage in treating the complex cancers. Taking the multi-target c-Met inhibitor Foretinib as the leading compound, we discovered a novel series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety with the help of molecular docking. Among them, the most promising compound 33 showed a prominent activity against Hela (IC50 = 0.21 µM), A549 (IC50 = 0.39 µM), and MCF-7 (IC50 = 0.33 µM), which were 3.28-4.82 times more active than that of Foretinib. Additionally, compound 33 dose dependently induced apoptosis by arresting A549 cells at G1 phase. Enzymatic assays and docking analyses were further confirmed that compound 33 was a multi-target inhibitor with the strong potencies against c-Met (IC50 = 11.77 nM), MEK1 (IC50 = 10.71 nM), and Flt-3 (IC50 = 22.36 nM). In the A549 cells mediated xenograft mouse model, compound 33 inhibited the tumor growth (TGI = 64%) without obvious toxicity, establishing compound 33 as a promising candidate for cancer therapy.
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Amidas/química , Antineoplásicos , Naftiridinas/química , Quinolinas/síntesis química , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
AIM: To evaluate the prevalence and influencing factors of anxiety and depression symptoms in surgical nurses during the COVID-19 epidemic in Anhui, China. METHODS: A cross-sectional, multic'entre quantitative study was conducted among surgical nurses in Anhui province. SAS, SDS and SSRS scales were used for the investigation. Data were collected between 3 March 2020 to 19 March 2020. RESULTS: A total of 3,492 surgical nurses completed the survey. The average level of anxiety and depression of surgical nurses were higher than that of the Chinese norm. Levels of social support for surgical nurses were significantly negatively associated with the degree of anxiety and depression. Fertility status, participation in care for COVID-19 patients, likelihood of being infected with COVID-19 and social support were significantly influencing surgical nurses' anxiety degree. Similarly, these characteristics were significantly associated with the odds of depression symptoms in surgical nurses. CONCLUSION: These findings suggest that targeted psychological interventions to promote mental health of surgical nurses need to be immediately implemented.
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COVID-19 , Ansiedad/epidemiología , Estudios Transversales , Humanos , Pandemias , Prevalencia , SARS-CoV-2RESUMEN
Constructing nanostructures with abundant heterogeneous interfaces is highly efficient in improving microwave absorbing properties. Herein, a simple chemical vapor deposition (CVD) route for the in-situ growth of carbon nanotubes (CNTs) in the voids of MnO particles clusters skeleton has been developed to fabricate MnO/CNTs heterostructure composites with tunable dielectric properties. The optimized MnO/CNTs-1 composite with 45 wt% CNTs content exhibits comprehensive enhanced microwave absorption performance, with the minimum reflection loss (RLmin) can reach -50.6 dB (20 wt% in paraffin composite). The effective absorption bandwidth (RL < -10 dB, 90% absorption) up to 13.7 GHz was achieved by adjusting the thickness from 2 to 5 mm, covering the entire C, X and Ku bands. Herein, the MnO particles and CNTs networks act as skeleton and crosslinker, respectively. The MnO particles attached throughout the CNTs networks can provide multiple interfacial polarization and multiple scattering/reflection. Our works provide new insights for the facile designing lightweight nanostructure to enhance the microwave absorption performance of the CNTs.
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Rewritable paper is meaningful to the recyclable and sustainable utilization of environmental resources and thus has been extensively investigated for several decades. In this work, we demonstrated an efficient and convenient strategy to fabricate rewritable paper based on reversible hydrochromism of donor-acceptor Stenhouse adducts (DASAs). The kinetics and efficiency of isomerization could be well-controlled by adjusting the surrounding temperature and humidity. Monocolored rewritable paper was prepared by coating cyclic DASA·xH2O on the paper surface. Writing, printing, stamping and patterning were realized on the rewritable paper. The information could be controllably erased by treatment in a humid atmosphere. More importantly, the rewritable paper was upgraded to multicolored by combination of two DASA materials. The color of chirography was switched by controlling the writing speed.
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In this study, a series of pyrrolo [2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one fragment were synthesized and their biological activity were tested. Most of the target compounds displayed moderate to excellent activity against one or more cancer cell lines and low activity against human normal cell LO2 in vitro. The most promising compound 51, of which the IC50 values were 0.66 µM, 0.38 µM and 0.44 µM against cell lines A549, Hela and MCF-7, shown more remarkable activity and better apoptosis effect than the positive control Cabozantinib. The structure-activity relationships (SARs) indicated that double-EWGs (such as R3 = 2-Cl-4-CF3) on the terminal phenyl rings was a key factor in improving the biological activity. In addition, the further research on compound 51 mainly included c-Met kinase activity and selectivity, concentration dependence, and molecular docking.
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Antineoplásicos/farmacología , Naftiridinas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Anilidas/metabolismo , Anilidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Naftiridinas/síntesis química , Naftiridinas/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/metabolismo , Piridinas/metabolismo , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Pirroles/síntesis química , Pirroles/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment were designed, synthesized, and evaluated for their biological activity. Most compounds showed effective inhibitory activity against cancer cell lines of A549, HeLa and MCF-7. Among them, the most promising compound 40 showed excellent activity against A549, HeLa and MCF-7 cell lines with IC50 values of 1.03, 1.15 and 2.59 µM, respectively, which was 2.606.95 times more active than that of Golvatinib. The structure-activity relationships (SARs) showed that the introduction of 5-methylpyridazin-3(2H)-one to "5-atom linker" and the modification of the amide with morpholine group were beneficial for enhancing the inhibitory activity of compounds. In addition, the further research on compound 40 mainly include c-Met kinase activity, concentration dependence, apoptosis (acridine orange staining), and molecular docking.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Diseño de Fármacos , Antineoplásicos/química , Benzamidas/química , Dominio Catalítico , Línea Celular Tumoral , Supervivencia Celular , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Proteínas Proto-Oncogénicas c-met/química , Relación Estructura-ActividadRESUMEN
A series of pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety were designed, synthesized and evaluated for the anti-proliferative on three cancer cell lines (A549, HepG2 and MCF-7) in vitro. Most of the compounds showed moderate to high potency. Some excellent compounds were tested for the inhibitory activity of c-Met kinase. Compound 34 (c-Met IC50 = 17 nM) was investigated the selectivity against Flt-3, c-Kit, VEGFR-2, ALK, PDGFR-ß and RON. Structure-activity relationship studies indicated that hydrogen, fluorine atom, and mono-electron-withdrawing groups (mono-EWGs, such as R2 = F) on R, R1 and R2, respectively, were beneficial for the anti-proliferative activities of the target compounds. Besides, we have took further study on the combined mode between compound 34 and c-Met kinase through molecular docking.
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4-Quinolonas/síntesis química , Antineoplásicos/uso terapéutico , Piridinas/síntesis química , 4-Quinolonas/química , Antineoplásicos/farmacología , Humanos , Estructura Molecular , Piridinas/química , Relación Estructura-ActividadRESUMEN
Investigating lightweight electromagnetic microwave absorption materials is still urgent because of the issue related to the electromagnetic pollution or military defense. Our findings indicate that core-shell MnO@carbon nanowires (MnO@C NWs) achieve substantially enhanced microwave absorption, suggesting the suitable impedance matching induced by the synergetic effect between MnO and carbon. Furthermore, the peapod-like MnO@C NWs with internal void space can be facially synthesized by partial etching of core-shell MnO@C NWs. The peapod-like MnO@C NWs with internal voids/cavities exhibit dramatically enhanced electromagnetic microwave absorption property when the carbon content is about 64 wt %, a minimum reflection loss (RL) of -55 dB at 10 wt % loading was observed at 13.6 GHz, and the bandwidth of RL less than -10 dB (90% absorption) covers 6.2 GHz at the thickness of 2 mm. The excellent electromagnetic microwave absorption performance is superior to the most of MnO x/C composites in the literatures, which probably benefits from the dielectric polarization among conductive network structure between MnO and carbon, as well as the multiple reflection and absorption induced by internal void space. Our work is expected to pave an effective way to extend the electromagnetic microwave absorption performance of MnO/C composites through partial etching to create a void space.
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Clinically significant portal hypertension (CSPH) is associated with an incremental risk of esophageal varices and overt clinical decompensations. However, hepatic venous pressure gradient (HVPG) measurement, the gold standard for defining CSPH (HVPG≥10â¯mmâ¯Hg) is invasive and therefore not suitable for routine clinical practice. This study aims to develop and validate a radiomics-based model as a noninvasive method for accurate detection of CSPH in cirrhosis. The prospective multicenter diagnostic trial (CHESS1701, ClinicalTrials.gov identifier: NCT03138915) involved 385 patients with cirrhosis from five liver centers in China between August 2016 and September 2017. Patients who had both HVPG measurement and contrast-enhanced CT within 14â¯days prior to the catheterization were collected. The noninvasive radiomics model, termed rHVPG for CSPH was developed based on CT images in a training cohort consisted of 222 consecutive patients and the diagnostic performance was prospectively assessed in 163 consecutive patients in four external validation cohorts. rHVPG showed a good performance in detection of CSPH with a C-index of 0·849 (95%CI: 0·786-0·911). Application of rHVPG in four external prospective validation cohorts still gave excellent performance with the C-index of 0·889 (95%CI: 0·752-1·000, 0·800 (95%CI: 0·614-0·986), 0·917 (95%CI: 0·772-1·000), and 0·827 (95%CI: 0·618-1·000), respectively. Intraclass correlation coefficients for inter- and intra-observer agreement were 0·92-0·99 and 0·97-0·99, respectively. A radiomics signature was developed and prospectively validated as an accurate method for noninvasive detection of CSPH in cirrhosis. The tool of rHVPG assessment can facilitate the identification of CSPH rapidly when invasive transjugular procedure is not available.
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Biomarcadores , Hipertensión Portal/diagnóstico por imagen , Hipertensión Portal/etiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Femenino , Humanos , Hipertensión Portal/sangre , Procesamiento de Imagen Asistido por Computador , Cirrosis Hepática/sangre , Masculino , Variaciones Dependientes del Observador , Curva ROC , Reproducibilidad de los Resultados , Tomografía Computarizada por Rayos X/métodos , Tomografía Computarizada por Rayos X/normasRESUMEN
A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety were designed, synthesized and evaluated for their biological activities. The target compounds exhibited moderate to high antiproliferative activity against three cancer cell lines (A549, HepG2 and MCF-7) and several compounds (25, 27, 33, 37, 41, 43, 49 and 53) were evaluated for the activity against c-Met kinase. The most promising compound 33 (IC50 c-Metâ¯=â¯2.36â¯nM) showed excellent activity against A549, HepG2 and MCF-7â¯cell lines with IC50 values of 0.23⯵M, 0.42⯵M and 0.21⯵M, respectively, which was 1.5-2.1 times of the positive control. Furthermore, compound 33 was evaluated for the activity against Flt3, PDGFR-α, PDGFR-ß, c-Kit, Flt4, ALK and EGFR kinase. Structure activity relationship studies indicated that mono-EWGs (such as R2â¯=â¯F) at 4-position of moiety C was a key factor in improving the antitumor activity. In addition, further research on compound 33 was mainly including concentration dependence, apoptosis (acridine orange staining), apoptosis result analyzing and molecular docking.
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Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Naftiridinas/química , Naftiridinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Naftiridinas/síntesis química , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Proteínas Proto-Oncogénicas c-met/metabolismo , Quinolinas/síntesis química , Relación Estructura-ActividadRESUMEN
Six series of pyrrolo[2,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine derivatives bearing 1,2,3-triazole moiety were designed and synthesized, and some bio-evaluation was also carried out. As a result, four points can be summarized: Firstly, some of compounds exhibited excellent cytotoxicity activity and selectivity with the IC50 values in single-digit µm level. In particular, the most promising compound 16d showed equal activity to lead compound foretinib against A549, HepG2, and MCF-7 cell lines, with the IC50 values of 4.79 ± 0.82, 2.03 ± 0.39, and 2.90 ± 0.43 µm, respectively. Secondly, the SARs and docking studies indicated that the in vitro antitumor activity of pyrrolo[2,3-d]pyrimidine derivatives bearing 1,2,3-triazole moiety was superior to the pyrazolo[3,4-d]pyrimidine derivatives bearing 1,2,3-triazole moiety. Thirdly, three selected compounds (16d, 18d, and 20d) were further evaluated for inhibitory activity against the c-Met kinase, and the 16d could inhibit the c-Met kinase selectively by experiments of enzyme-based selectivity. What is more, 16d could induce apoptosis of HepG2 cells and inhibitor the cell cycle of HepG2 on G2/M phase by acridine orange staining and cell cycle experiments, respectively.
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Antineoplásicos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirazoles/química , Piridinas/química , Pirimidinas/química , Pirroles/química , Triazoles/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/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 Hep G2 , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Células MCF-7 , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirazoles/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
Two series of aromatic hydrazone derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (7a-r, 8a-i, 12a-b, 13a-c, 16a-d and 17a-e) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, HepG2, MCF-7and PC-3). Two selected compounds (7c and 17e) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2 and EGFR kinases. The data indicated that targets compounds were selective for c-Met kinase. And the most promising compound 7c was further studied in terms of dose-dependent, time-dependent and cell apoptosis. Most of the compounds showed excellent cytotoxicity activity, especially the most promising compound 7c with the IC50 values of 0.82⯱â¯0.08⯵M, 1.00⯱â¯0.11⯵M, 0.93⯱â¯0.28⯵M and 0.92⯱â¯0.17⯵M against A549, HepG2, MCF-7 and PC-3â¯cell lines and 0.506⯵M against c-Met kinase. Structure-activity relationships (SARs) and docking studies indicated that the activities of the phenyl hydrazone derivatives (7a-r and 8a-i) were superior to that of the heterocyclic hydrazone series (12a-b, 13a-c, 16a-d and 17a-e). What's more, the further studies indicated that the target compounds can induce apoptosis of A549â¯cells and arrest efficiently the cell cycle progression in G2/M phase of A549â¯cells.
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Antineoplásicos/farmacología , Hidrazonas/farmacología , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridinas/farmacología , Pirroles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrazonas/química , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/metabolismo , Piridinas/síntesis química , Piridinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
A series of 2-substituted-4-phenoxypyridine derivatives were designed, synthesized, and evaluated for their antiproliferative activity against 4 cancer cell lines (A549, HT-29, H460, and U87MG) in vitro. Most compounds showed moderate to excellent potency. Nine tyrosine kinases (c-Met, Flt-3, ALK, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-ß, c-Kit, and EGFR) were used to evaluate the inhibitory activities with the most promising analogue 39, which showed the Flt-3/c-Met IC50 values of 2.18/2.61â¯nM. Structure-activity relationship studies indicated that n-Pr served as R1 group showed a higher preference, and stronger mono-EWGs on the phenyl ring (such as R2â¯=â¯4-F) was benefited to the potency.
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Antineoplásicos/química , Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas , Piridinas/síntesis química , Piridinas/química , Relación Estructura-ActividadRESUMEN
A series of pyrrolo[2,3-b]pyridine derivatives bearing the 1,8-naphthyridin-2-one moiety were synthesized, and evaluated for their antiproliferative activity against four cancer cell lines (HT-29, A549, H460, and U87MG) and six tyrosine kinases (c-Met, Flt-3, PDGFR-ß, VEGFR-2, EGFR, and c-Kit) inhibitory activities in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 32 showing Flt-3/c-Met IC50 value of 1.16/1.92 nM. Structure-activity relationship studies indicated that the hydrogen atom served as R1 group was benefited to the potency, and mono-electron-withdrawing groups (mono-EWGs) on the phenyl ring (such as R3 = 4-F) showed a higher preference for antiproliferative activity.
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Antineoplásicos/farmacología , Naftiridinas/farmacología , Piridinas/farmacología , Pirroles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Naftiridinas/química , Piridinas/síntesis química , Piridinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-ActividadRESUMEN
Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds (35, 39 and 43) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC50 values of 0.58⯱â¯0.15⯵M, 0.47⯱â¯0.06⯵M and 0.74⯱â¯0.12⯵M, which were 3.73-5.39-fold more activity than Foretinib, respectively. The experiments of enzyme-based showed that 43 restrain the c-Met selectively, with the IC50 values of 16â¯nM, which showed equal activity to Foretinib (14â¯nM) and better than the compound 5 (90â¯nM). Moreover, AO and Annexin V/PI staining and docking studies were carried out.
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Antineoplásicos/farmacología , Ácidos Picolínicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirimidinas/farmacología , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/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 , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
In continue to our previous research, eight series of pyrrolo[2,3-b]pyridine and pyrrolo[2,3-d]pyrimidine derivatives bearing pyridazinone moiety were designed, synthesized, and the in vitro antitumor activity was evaluated against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). Some selected compounds (22f, 22g, 26c and 26e) were evaluated for the activity against c-Met kinase, and according to the results of kinase inhibitory activity, the compound 22g was further evaluated for other four tyrosine kinases (Flt-3, VEGFR-2, c-Kit and EGFR) to test the enzyme-based selectivity. The most promising compound 22g showed excellent activity than lead compound Foretinib against A549, HepG2, MCF-7 and PC-3 cell lines, with the IC50 values of 2.19 ± 0.45 µM, 1.32 ± 0.26 µM, 6.27 ± 1.04 µM and 4.63 ± 0.83 µM. The structure-activity relationships (SARs) and docking studies indicated that the pyrrolo[2,3-b]pyridine derivatives bearing 4-oxo-pyridazinone moiety was superior to the pyrrolo[2,3-d]pyrimidine derivatives bearing 6-oxo-pyridazinone moiety. What's more, the target compounds modified with X and Y (X = H, Y = H) were favorable to the activity. And electron drawing groups (EWGs) of 4-Cl-3CF3 on the aryl group show the best activity.