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1.
Cancer Lett ; 524: 206-218, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34688842

RESUMO

Phosphatidylinositol 3-kinase (PI3K) δ-specific inhibitors have been approved for the therapy of certain types of B cell lymphoma (BCL). However, their clinical use is limited by the substantial toxicity and lack of efficacy in other types of BCL. Emerging evidence indicates that PI3Kα plays important roles in the progression of B cell lymphoma. In this study, we revealed that PI3Kα was important for the PI3K signaling and proliferation in BCL cells. A novel clinical PI3Kα-selective inhibitor CYH33 possessed superior activity against BCL compared to the marketed PI3Kα-selective inhibitor Alpelisib and PI3Kδ-selective inhibitor Idelalisib. Though CYH33 was able to inhibit PI3K/AKT signaling in tested BCL cells, differential activity against proliferation was observed. Transcriptome profiling revealed that CYH33 down-regulated "MYC-targets" gene set in sensitive but not resistant cells. CYH33 inhibited c-MYC transcription in sensitive cells, which was attributed to a decrease in acetylated H3 bound to the promoter and super-enhancer region of c-MYC. Accordingly, CYH33 treatment resulted in phosphorylation and proteasomal degradation of the histone acetyltransferase p300. An unbiased screening with drugs approved or in clinical trials for the therapy of BCL identified that the clinical BET (Bromodomain and Extra Terminal domain) inhibitor OTX015 significantly potentiated the activity of CYH33 against BCL in vitro and in vivo, which was associated with enhanced inhibition on c-MYC expression and induction of cell cycle arrest and apoptosis. Our findings provide the rationale of combined CYH33 with BET inhibitors for the therapy of B cell lymphoma.

2.
J Med Chem ; 64(18): 13676-13692, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34491054

RESUMO

A series of pyrazole-fused betulinic acid (BA) derivatives were designed and synthesized by replacing the carboxyl group at C-17 with aliphatic amine, amide, and urea groups. The suppressive effects of the compounds on osteoclast (OC) formation and inflammatory cytokine production were evaluated on murine macrophages, RAW264.7 cells, conditioned with receptor activator for nuclear factor-κB ligand (RANKL)/macrophage colony stimulating factor (M-CSF) or lipopolysaccharide (LPS), respectively. Results showed that, compared with betulinic acid, most of these compounds exhibited significant improvements in inhibitory potency. Compound 25 exhibited distinguished activities on inhibiting OC differentiation with an IC50 value of 1.86 µM. Meanwhile, compound 25, displaying the most promising suppression on IL-1ß secretion from RAW264.7 cells, was further found to possess therapeutic effects in the sodium monoiodoacetate (MIA)-induced osteoarthritis rat model. Dose-dependent benefits were observed in MIA-elicited rats with ameliorated joint pain as well as decreased cartilage damage and bone changes after compound 25 treatment.

3.
J Appl Biomater Funct Mater ; 19: 22808000211014724, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34210203

RESUMO

PURPOSE: The effect of flushing at different temperatures on the preparation ability of rotary nickel-titanium files was investigated to provide guideline for clinical application. METHODS: Sixty ProTaper Universal F1 rotary nickel-titanium files were randomly divided into three groups treated by flushing at 6°C, 23°C, and 40°C. Root canal preparation was conducted by step-by-step method on standardized nickel-titanium instrument fracture models. During preparation, the thrust force was set as 10 N, and water was continuously flushed. The motor speed was 350 rpm (rounds per minute), and the torque was 3.0 N cm. When the set torque was reached, the motor automatically rotated in the reverse direction and was pulled out. RESULTS: Root canal preparation was performed using ProTaper Universal F1 rotary nickel-titanium files treated by flushing. The numbers of rotations before the device was fracture were 429.33 ± 214.68, 821.92 ± 410.43, and 1304.92 ± 297.81, respectively. When each root canal was completed, the numbers of instrument rotations were 272.15 ± 88.30, 188.85 ± 34.36, and 163.41 ± 16.18, respectively. Rank sum test and analysis of variance were performed by IBM SPSS Statistics v21.0 software, and both of them were p < 0.01, indicating that the number of cycles to failure (NCF) and the number of instrument rotations for each root tube were statistically different at the three temperatures. CONCLUSIONS: The self-made resin-simulated curved root canal can replace the real root canal to complete the root canal preparation experiment. The group of nickel-titanium files treated by flushing at 23°C can prepare more root canals and prolong the life of nickel-titanium files than at 6°C. When flushing was done at 40°C, the number of root canals prepared by nickel-titanium files was the highest, and it was not easy to damage the instrument, but lateral perforation occurred easily during root canal preparation.


Assuntos
Níquel , Titânio , Cavidade Pulpar , Desenho de Equipamento , Preparo de Canal Radicular , Temperatura
4.
Polymers (Basel) ; 13(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071349

RESUMO

The long-term mechanical properties of viscoelastic polymers are among their most important aspects. In the present research, a machine learning approach was proposed for creep properties' prediction of polyurethane elastomer considering the effect of creep time, creep temperature, creep stress and the hardness of the material. The approaches are based on multilayer perceptron network, random forest and support vector machine regression, respectively. While the genetic algorithm and k-fold cross-validation were used to tune the hyper-parameters. The results showed that the three models all proposed excellent fitting ability for the training set. Moreover, the three models had different prediction capabilities for the testing set by focusing on various changing factors. The correlation coefficient values between the predicted and experimental strains were larger than 0.913 (mostly larger than 0.998) on the testing set when choosing the reasonable model.

5.
Org Biomol Chem ; 19(24): 5348-5352, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34042936

RESUMO

An efficient and mild synthetic approach for 2-alkyl-substituted chroman-4-ones via zinc-mediated cascade decarboxylative ß-alkylation and dechlorination of 3-chlorochromones was developed. This transformation employed commercially available starting materials and was performed under mild conditions without heat, visible light, peroxide or heavy metals. Moreover, various alkyl NHPI esters with functional groups and differently substituted 3-chlorochromones were tolerated, affording the targeted products with moderate to excellent yields. This protocol could be utilized to construct a diverse library of 2-substituted chroman-4-one derivatives, which could be useful in the discovery of lead compounds for drug discovery in the future.

6.
J Inflamm (Lond) ; 18(1): 18, 2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34022893

RESUMO

BACKGROUND: Anti-vascular endothelial growth factor (VEGF) has been used as a therapeutic drug for the treatment of some human diseases. However, no systematic evidence is performed for assessing the role of VEGF in periodontitis. We carried out a comprehensive analysis to explore the role of VEGF in patients with periodontitis. METHODS: Multiple databases were searched for eligible studies. The pooled standardized mean difference (SMD) and odds ratio (OR) with the corresponding 95% confidence interval (CI) were applied to evaluate the effect sizes. Clinical data validation from microarray analysis was used. Pathway and process enrichment analysis were also investigated. RESULTS: Finally, 16 studies were included in this analysis. Overall, there was a significantly higher level of VEGF expression in periodontitis than in healthy control groups (OR = 16.64, 95% CI = 6.01-46.06, P < 0.001; SMD = 2.25, 95% CI = 1.25-3.24, P < 0.001). Subgroup analysis of ethnicity showed that VEGF expression was still correlated with periodontitis in the Asian and European populations. No correlation was observed between VEGF expression and age, gender, and pathological type. A large clinical sample data (427 periodontitis patients and 136 healthy controls) further validated that VEGF expression was higher in periodontitis than in healthy control groups (P = 0.023). VEGF was involved in many functions such as blood vessel development, response to growth factor, cell proliferation, and cell adhesion. CONCLUSIONS: High levels of VEGF were credible implications for the development of periodontitis. Anti-VEGF therapy may be valuable for the treatment of periodontitis in clinical management.

7.
Signal Transduct Target Ther ; 6(1): 165, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895786

RESUMO

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Simulação por Computador , Reposicionamento de Medicamentos , Modelos Biológicos , SARS-CoV-2/metabolismo , Humanos
8.
Cell Death Dis ; 12(1): 85, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446653

RESUMO

Phosphoinositide-3 kinase alpha-specific inhibitors (PI3Kαi) displayed promising potential for the treatment of esophageal squamous cell carcinoma (ESCC) with frequent activation in PI3K signaling. However, acquired resistance is likely to develop and limit the efficacy of PI3Kαi like other targeted therapies. To identify genomic adaptation to PI3Kαi, we applied whole-genome sequencing and detected gene mutation and amplification in four lines of ESCC cells established with adapted resistance to a novel PI3Kαi CYH33. Particularly, HRASG12S mutation was found in KYSE180C cells. Overexpression of HRASG12S in ESCC parental cells rendered resistance to CYH33. By contrast, down-regulation of HRASG12S restored the sensitivity of KYSE180C1 cells to CYH33, and combination of CYH33 and MEK162 displayed synergistic effect against KYSE180C1 cells and xenografts. Furthermore, elevated mTORC1, mitogen-activated protein kinase (MAPK), and c-Myc signaling pathways were found in resistant cells by RNA sequencing and combination of CYH33 and RAD001, MEK162, or OTX015 overcame the resistance to CYH33, which was accompanied with enhanced inhibition on S6, extracellular signal-regulated kinase 1 (ERK), or c-Myc, respectively. Overall, we characterized the adaptations to PI3Kαi in ESCC cells and identified combinatorial regimens that may circumvent resistance.


Assuntos
Carcinoma de Células Escamosas do Esôfago/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Morfolinas/metabolismo , Oncogenes/genética , Piperazinas/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Transcriptoma , Transfecção
9.
J Appl Biomater Funct Mater ; 19: 2280800020987403, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33509031

RESUMO

OBJECTIVE: To evaluate the effect of synchronous water irrigation on the fatigue resistance of nickel-titanium instrument. METHODS: A standardized cyclic fatigue test models were established, and five types of nickel-titanium instruments (PTU F1, WO, WOG, RE, and M3) were applied. Each instrument was randomly divided into two groups (N = 12). There was synchronous water irrigation in the experimental group, and no water irrigation in the control group. Besides, ProTaper Universal F1 was randomly divided into 10 groups (N = 20). In the static group, nickel-titanium instruments were divided into one control group (no irrigation, N = 20) and six experimental group (irrigation, N = 20) based on different flow rate, angle and position; while in the dynamic group, instruments were divided into one control group (no irrigation, N = 20) and two experimental group (irrigation, N = 20) based on different flow rate. The rotation time (Time to Failure, TtF) of instruments was recorded and analyzed. RESULTS: According to the static experiments, the TtF of instruments in all experimental groups was significantly higher than that in the static control group. Besides, the dynamic tests of PTU F1 showed that the TtF in the experimental group was significantly higher than that in the dynamic control group. Compared with control group, the TtF in the experimental groups increased by at least about 30% and up to 160%. The static and dynamic tests of PTU F1 showed that the TtF of nickel-titanium instrument in all experimental groups was significantly higher than that in the control group. However, there was no significant difference between any two experimental groups. CONCLUSION: Regardless of dynamic or static model, TtF with irrigation was longer than that with non-irrigation, indicating that synchronous irrigation can increase the fatigue resistance of nickel-titanium instrument. However, different irrigation conditions may have the same effect on the fatigue resistance.


Assuntos
Níquel , Titânio , Desenho de Equipamento , Falha de Equipamento , Teste de Materiais , Preparo de Canal Radicular , Rotação , Estresse Mecânico
10.
Eur J Med Chem ; 209: 112913, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33109399

RESUMO

In various human cancers, PI3Ks pathway is ubiquitously dysregulated and thus become a promising anti-cancer target. To discover new potent and selective PI3K inhibitors as potential anticancer drugs, new pyrrolo[2,1-f][1,2,4]triazines were designed, leading to the discovery of compound 37 (CYH33), a selective PI3Kα inhibitor (IC50 = 5.9 nM, ß/α, δ/α,γ/α = 101-, 13-, 38-fold). Western blot analysis confirmed that compound 37 could inhibit phosphorylation of AKT in human cancer cells to modulate the cellular PI3K/AKT/mTOR pathway. And further evaluation in vivo against SKOV-3 xenograft models demonstrated that a dose-dependent antitumor efficacy was achieved.


Assuntos
Inibidores da Angiogênese/síntese química , Antineoplásicos/síntese química , Morfolinas/síntese química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Piperazinas/síntese química , Pirróis/síntese química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosforilação/efeitos dos fármacos , Piperazinas/farmacologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis/farmacologia , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo
11.
Bioorg Med Chem Lett ; 31: 127710, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33246105

RESUMO

A library of new 2-substituted pyrrolo[1,2-b]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CC50s of 340 and 106 nM respectively. The PK property of 15b was also investigated here.


Assuntos
Antineoplásicos/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Piridazinas/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Piridazinas/síntese química , Piridazinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
12.
Org Biomol Chem ; 18(47): 9726, 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33237106

RESUMO

Correction for 'Regioselective synthesis of substituted thiazoles via cascade reactions from 3-chlorochromones and thioamides' by Tianzi Dai et al., Org. Biomol. Chem., 2020, 18, 6162-6170, DOI: .

13.
Org Biomol Chem ; 18(31): 6162-6170, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32716017

RESUMO

A facile and efficient strategy to synthesize substituted thiazoles via a cascade reaction from chromone derivatives and thioamides in an environmentally benign medium was developed. This cascade reaction involves a Michael addition/intramolecular cyclization process and a broad scope of reversed regioselectivity products was prepared in a short reaction time with excellent yields. The reversed regioselectivity was also explained by DFT calculations.

14.
Bioorg Med Chem Lett ; 30(12): 127194, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32317209

RESUMO

A series of 6-aminocarbonyl pyrrolo[2,1-f][1,2,4]triazine derivatives were designed by scaffold hopping strategy. The IC50 values of compound 14a against PI3Ks were measured, showing selective activity against p110α and p110δ with IC50s of 122 nM and 119 nM respectively. All the synthesized compounds were evaluated for their antiproliferative activity against human cancer cells by SRB assay. Compounds 14a, 14p and 14q exhibited potent antiproliferative activity against five types of human cancer cells and the PK property of 14q was also investigated here.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Triazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química
15.
BMC Oral Health ; 20(1): 127, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345292

RESUMO

BACKGROUND: In the current study, we aimed to evaluate the accuracy of indirect bonding by either three-dimensional (3D) printing guides or double-layer guide plates. The results may serve as a clinical reference for bracket placements. METHODS: In total, 140 teeth were collected and arranged into five pairs of full dentition. The marking points were labeled on the buccal/labial surface of the crown in these orthodontic study models. (1) 3D printing guide: A digital profile was generated using an intraoral scanner. Two types of indirect bonding guide, namely the whole denture type and the single tooth type, were designed with the 3Shape TRIOS® Standard intraoral scanner and fabricated using 3D printing technology. (2) Double-layer guide plate: A working model was obtained by replicating the experimental models, and the double-layer guide plate was then made of the inner layer soft film (1.0 mm thickness) and the outer layer hard film (0.6 mm or 0.8 mm thickness). Brackets were transferred from working models to study models by the indirect bonding trays. We measured and analyzed the distance between marking points and bracket placement. Statistical analysis was done using SPSS 20.0 software. The accuracy of indirect bonding between 3D printing guide and double-layer guide plate was compared using paired t-test. RESULTS: According to our data, there was a significant difference between the 0.6 mm group and 0.8 mm group when the brackets were indirectly adhered using double-layer guide plates (p = 0.036). However, no statistical significance in bracket positioning accuracy was revealed between two types of 3D printing guide (p = 0.078), as well as between the 3D printing guide group and the 0.6 mm double-layer guide plate group (p = 0.069). CONCLUSIONS: When applying double-layer guide plates for indirect bonding, the 0.6 mm group is more accurate than the 0.8 mm group. When utilizing 3D printing guides for indirect bonding, whole denture type is more accessible than single tooth type but with no significant difference in accuracy. The accuracy of indirect bonding is comparable when using 3D printing guides (whole denture type) and double-layer guide plates (0.6 mm).


Assuntos
Colagem Dentária , Braquetes Ortodônticos , Impressão Tridimensional , Modelos Dentários , Coroa do Dente
17.
Molecules ; 24(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434258

RESUMO

Herein, a direct strategy to synthesize 3-(2-hydroxybenzoyl)-1-aza-anthraquinones with excellent efficiency, mild conditions, and benign functional group compatibility was reported. A variety of 3-formylchromone compounds were employed as compatible substrates and this protocol gave the 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives in good to excellent yields without inert gas and expensive transition metal catalysts. Some compounds displayed good anti-proliferative activities.


Assuntos
Antraquinonas/síntese química , Antineoplásicos/síntese química , Antraquinonas/química , Antraquinonas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Células HeLa , Humanos , Metais , Estrutura Molecular
18.
J Med Chem ; 62(11): 5370-5381, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31082234

RESUMO

Targeting RANKL/RANK offers the possibility of developing novel therapeutic approaches to treat bone metabolic diseases. Multiple efforts have been made to inhibit RANKL. For example, marketed monoclonal antibody drug Denosumab could inhibit the maturation of osteoclasts by binding to RANKL. This study is an original approach aimed at discovering small-molecule inhibitors impeding RANKL/RANK protein interaction. We identified compound 34 as a potent and selective RANKL/RANK inhibitor by performing structure-based virtual screening and hit optimization. Disruption of the RANKL/RANK interaction by 34 effectively inhibits RANKL-induced osteoclastogenesis and bone resorption. The expression of osteoclast marker genes was also suppressed by treatment of 34. Furthermore, 34 markedly blocked the NFATc1/c-fos pathway. Thus, our current work demonstrates that the chemical tractability of the difficult PPI (RANKL/RANK) target by a small-molecule compound 34 offers a potential lead compound to facilitate the development of new medications for bone-related diseases.


Assuntos
Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Reabsorção Óssea , Avaliação Pré-Clínica de Medicamentos , Simulação de Acoplamento Molecular , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Ligação Proteica/efeitos dos fármacos , Conformação Proteica , Ligante RANK/química , Bibliotecas de Moléculas Pequenas/metabolismo , Interface Usuário-Computador
19.
Cancer Biol Med ; 16(1): 66-83, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31119047

RESUMO

Objective: Activating KRAS mutations are the most common drivers in the development of non-small cell lung cancer (NSCLC). However, unsuccess of treatment by direct inhibition of KRAS has been proven. Deregulation of PI3K signaling plays an important role in tumorigenesis and drug resistance in NSCLC. The activity of PI3Kα-selective inhibition against KRAS-mutated NSCLC remains largely unknown. Methods: Cell proliferation was detected by sulforhodamine B assay. Cell cycle distribution and apoptosis were measured by flow cytometry. Cell signaling was assessed by Western blot and immunohistochemistry. RNA interference was used to down-regulate the expression of cyclin D1. Human NSCLC xenografts were employed to detect therapeutic efficacy in vivo. Results: CYH33 possessed variable activity against a panel of KRAS-mutated NSCLC cell lines. Although CYH33 blocked AKT phosphorylation in all tested cells, Rb phosphorylation decreased in CYH33-sensitive, but not in CYH33-resistant cells, which was consistent with G1 phase arrest in sensitive cells. Combined treatment with the CDK4/6 inhibitor, PD0332991, and CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and CYH33-resistant cells, which was accompanied by enhanced G1-phase arrest. Moreover, down-regulation of cyclin D1 sensitized NSCLC cells to CYH33. Reciprocally, CYH33 abrogated the PD0332991-induced up-regulation of cyclin D1 and phosphorylation of AKT in A549 cells. Co-treatment with these two drugs demonstrated synergistic activity against A549 and H23 xenografts, with enhanced inhibition of Rb phosphorylation. Conclusions: Simultaneous inhibition of PI3Kα and CDK4/6 displayed synergistic activity against KRAS-mutated NSCLC. These data provide a mechanistic rationale for the combination of a PI3Kα inhibitor and a CDK4/6 inhibitor for the treatment of KRAS-mutated NSCLC.

20.
Molecules ; 24(5)2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30857232

RESUMO

Bisindolyl alkaloids represent a large family of natural and synthetic products that display various biological activities. Among the bisindole compounds, 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b']diindoles have received little attention. Only two methods have been developed for the construction of the 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b']diindole scaffold thus far, including the classical Fischer indole synthesis conducted by reacting indole-fused cycloheptanone and hydrazines, and the condensation reaction to build the seven-membered ring. Here, we report for the first time a new route to synthesize 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b']diindoles through intramolecular oxidative coupling of 1,3-di(1H-indol-3-yl)propanes in the presence of PIFA, DDQ and TMSCl with moderate to excellent yields.


Assuntos
Indóis/química , Iodo/química , Indicadores e Reagentes/química , Iodetos/química , Iodobenzenos/química , Estrutura Molecular , Ácido Trifluoracético/química
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