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1.
Bioorg Med Chem ; 29: 115856, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33199201

RESUMEN

NIK is a critical regulatory protein of the non-classical NF-kB pathway, and its dysregulated activation has been proved to be one of the pathogenic factors in a variety of autoimmune diseases and inflammatory diseases. Nevertheless, its corresponding development of inhibitors faces many obstacles, including the lack of structure types of known inhibitors, immature activity evaluation methods of compounds in vitro. In this study, a series of quinoline derivatives were obtained through rational design and chemical synthesis. Among them, the representative compounds 17c and 24c have excellent inhibitory activities on LPS-induced macrophage (J774) nitric oxide release and anti-Con A-stimulated primary T cell proliferation. This evaluation method has good universality and overcomes the obstacles mentioned above, which are faced by the current inhibitor research to a certain extent. Besides, the compound's toxicity against the growth of T cells under non-stress conditions was evaluated, for the first time, as an indicator for the investigation to avoid potential safety risks. Pharmacokinetic properties evaluation of the less toxic compound 24c confirmed its good metabolic behavior (especially oral properties, F% = 21.7%), and subsequent development value.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Descubrimiento de Drogas , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinolinas/farmacología , Linfocitos T/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Proteínas Serina-Treonina Quinasas/metabolismo , Quinolinas/síntesis química , Quinolinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Quinasa de Factor Nuclear kappa B
2.
Nanotechnology ; 31(20): 205201, 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-31952059

RESUMEN

We present a systematic study on the effects of CF4 plasma immersion ion implantation (PIII) in Si on the phase evolution of ultra-thin Ni silicides. For 3 nm Ni, NiSi2 was formed on Si substrates with and without CF4 PIII at temperature as low as 400 °C. For 6 nm Ni, NiSi was formed on pure Si, while epitaxial NiSi2 was obtained on CF4 PIII Si. The incorporation of C and F atoms in the thin epitaxial NiSi2 significantly reduces the layer resistivity. Increasing the Ni thickness to 8 nm results in the formation of NiSi, where the thermal stability of NiSi, the NiSi/Si interface and Schottky contacts are significantly improved with CF4 PIII. We suggest that the interface energy is lowered by the F and C dopants present in the layer and at the interface, leading to phase evolution of the thin Ni silicide.

3.
Orthop Surg ; 14(12): 3367-3377, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36222205

RESUMEN

OBJECTIVE: The debate on the superiority of single- or double-bundle for anterior cruciate ligament reconstruction has not ceased. The comparative studies on intra-articular biomechanics after different surgical reconstructions are rare. This study is to evaluate the biomechanical stress distribution intra-knee after single- and double-bundle anterior cruciate ligament reconstruction by three-dimensional finite element analysis, and to observe the change of stress concentration under the condition of vertical gradient loads. METHODS: In this study, magnetic resonance imaging data were extracted from patients and healthy controls for biomechanical analysis. Patients included in the three models were matched in age and sex. The strength and distribution of induced stresses were analyzed in two frequently used procedures, anatomical single-bundle anterior cruciate ligament reconstruction and anatomical double-bundle anterior cruciate ligament reconstruction, using femoral-graft-tibial system under different loads, to mimic a post-operation mechanical motion. The three-dimensional finite-element models for normal ligament and two surgical methods were applied. A vertical force simulating daily walking was performed on the models to assess the interfacial stresses and displacements of intra-articular tissues and ligaments. The evaluation results mainly included the stress of each part of ligament and meniscus. The stress values of different parts of three models were extracted and compared. RESULTS: The stress of ligament/graft at femoral side of three finite-element models was significantly higher than at tibial side, while the highest level was observed in single-bundle reconstruction finite-element model. With the increase of force, the maximum stress in the medial (7.1-7.1 MPa) and lateral (4.9-7.4 MPa) meniscus of single-bundle reconstruction finite-element model shifted from the anterior horn to the central area (p = 0.0161, 0.0479, respectively). The stress was shown to be at a lower level at femoral side and posterior cruciate ligament of intra-knee in two reconstruction finite-element models than that in normal finite-element models, while presented higher level at the tibial side than normal knee (p = 0.3528). The displacement of the femoral side and intra-knee areas in reconstruction finite-element models was greater than that in normal finite-element model (p = 0.0855). CONCLUSION: Compared with the single-bundle technique, the graft of double-bundle anterior cruciate ligament reconstruction has better stress dissipation effect and can prevent postoperative meniscus tear more effectively.


Asunto(s)
Reconstrucción del Ligamento Cruzado Anterior , Humanos , Análisis de Elementos Finitos , Marcha , Ligamentos
4.
Eur J Med Chem ; 238: 114461, 2022 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-35605362

RESUMEN

Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and a potential therapeutic target in hematologic malignancies. Selective and transient CDK9 inhibition reduces Mcl-1 expression and induces apoptosis in Mcl-1-dependent tumor cells for survival. Here, we describe our efforts to discover a novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one as CDK9 inhibitors. Compound 32k was identified as a selective CDK9 inhibitor with short pharmacokinetic and physicochemical properties suitable for intravenous administration. Short-term treatment with 32k resulted in a rapid dose-dependent decrease in cellular p-Ser2-RNAPII, Mcl-1 and c-Myc, leading to apoptosis in the MV4-11 cell line. Correspondingly, significant in vivo antitumor efficacy was observed in xenograft models derived from multiple hematological tumors with intermittent 32k dosing. These results provide evidence that selective transient CDK9 inhibitors could be used for the treatment of hematologic malignancies.


Asunto(s)
Antineoplásicos , Neoplasias Hematológicas , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Quinasa 9 Dependiente de la Ciclina/metabolismo , Neoplasias Hematológicas/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico
5.
J Med Chem ; 64(17): 12548-12571, 2021 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-34415148

RESUMEN

Hematologic malignancies (HM) start in blood forming tissue or in the cells of the immune system. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them control cellular transcription. CDK inhibition can trigger apoptosis and could be particularly useful in hematological malignancies. Herein, we describe our efforts toward the discovery of a novel series of quinazoline derivatives as CDK inhibitors. Intensive structural modifications lead to the identification of compound 37d as the most active inhibitors of CDKs 1, 2, 4, 8 and 9 with balancing potency and selectivity against CDKs. Further biological studies revealed that compound 37d can arrest the cell cycle and induce apoptosis via activating PARP and caspase 3. More importantly, compound 37d showed good antitumor efficacy in multiple HM mice xenograft models with no obvious toxicity. These results indicated that CDK 1, 2, 4, 8, and 9 inhibitors could be potentially used to treat certain hematologic malignancies.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Antineoplásicos/química , Área Bajo la Curva , Dominio Catalítico , Línea Celular Tumoral , Quinasa 9 Dependiente de la Ciclina/química , Quinasa 9 Dependiente de la Ciclina/metabolismo , Semivida , Humanos , Ratones , Estructura Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Eur J Med Chem ; 200: 112424, 2020 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-32447197

RESUMEN

Specific inhibition of CDK9 is considered a promising strategy for developing effective anticancer therapeutics. However, most of the reported CDK9 inhibitors are still at an early stage of development and lack selectivity against other CDKs. Herein, we discovered coumarin derivative 30i as a potent CDK9 inhibitor with high selectivity (8300-fold over CDK7). Binding mode analysis illustrated that the substituent coumarin moiety is a critical group for CDK9 selectivity by occupying a flexible hinge/αD region, which is sterically hindered in other CDKs. Compound 30i showed excellent cellular antiproliferative activity, moderate pharmacokinetic property and low hERG inhibition. Moreover, 30i significantly induced tumour growth inhibition in a dose-dependent manner without causing an obvious loss of body weight in an MV4-11 xenograft mice model. Altogether, these results suggest that 30i may serve as a potential acute myeloid leukaemia (AML) therapeutics by selectively targeting CDK9.


Asunto(s)
Antineoplásicos/farmacología , Cumarinas/farmacología , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Cumarinas/síntesis química , Cumarinas/química , Quinasa 9 Dependiente de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad
7.
J Med Chem ; 63(13): 6748-6773, 2020 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-32479083

RESUMEN

A series of N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives with NF-κB inducing kinase (NIK) inhibitory activity were obtained through structure-based drug design and synthetic chemistry. Among them, 4-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-morpholinophenyl)-2-(thiazol-2-yl)but-3-yn-2-ol (12f) was identified as a highly potent NIK inhibitor, along with satisfactory selectivity. The pharmacokinetics of 12f and its ability to inhibit interleukin 6 secretion in BEAS-2B cells were better than compound 1 developed by Amgen. Oral administration of different doses of 12f in an imiquimod-induced psoriasis mouse model showed effective alleviation of psoriasis, including invasive erythema, swelling, skin thickening, and scales. The underlying pathological mechanism involved attenuation of proinflammatory cytokine and chemokine gene expression, and the infiltration of macrophages after the treatment of 12f. This work provides a foundation for the development of NIK inhibitors, highlighting the potential of developing NIK inhibitors as a new strategy for the treatment of psoriasis.


Asunto(s)
Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Psoriasis/tratamiento farmacológico , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Animales , Perros , Diseño de Fármacos , Humanos , Modelos Moleculares , Conformación Proteica , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/química , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Quinasa de Factor Nuclear kappa B
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