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Genet Test Mol Biomarkers ; 24(4): 204-211, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32213082


Background: Atherosclerosis is one of the leading causes of morbidity and mortality worldwide. A variety of long noncoding RNAs (lncRNAs) have been reported to be significantly involved in vascular smooth muscle cell (VSMC) proliferation, which is an essential process for atherosclerotic plaque formation. The aim of this study was to investigate the mechanism of lncRNA urothelial cancer associated 1 (UCA1) involvement in atherosclerosis. Method: The effects of oxidized low-density lipoprotein (oxLDL) and UCA1 on VSMC proliferation and colony-forming ability was measured by 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyl-2H-tetrazolium bromide (MTT) assays, real-time polymerase chain reaction (PCR), and western blots, as well as to determine the effect that oxLDL has on UCA1 expression, and the effect of oxLDL and UCA1 on the expression of cyclin-dependent kinase 2 (CDK2). Results: oxLDL treatment increased the proliferation rate of VSMCs in a concentration-dependent manner. Importantly, UCA1 apparently increased the viability of VSMCs as the VSMCs exhibited a significantly reduced growth rate when UCA1 expression was knocked down by specific small interfering RNAs (siRNAs). In conjunction with increasing cell viability, oxLDL also enhanced the colony-forming ability of VSMCs while UCA1 siRNA decreased the colony-forming ability of VSMCs. Furthermore, UCA1 significantly decreased the percentage of VSMCs in G1 phase, while increasing their percentage in S phase. In contract siRNA knockdown of UCA1 caused an increased percentage of cell in G1 phase, and a reduction in the percentage of cells in S phase. Using real-time PCR and western blot assays, we showed that oxLDL significantly increased the expression levels of UCA1 and CDK2. Furthermore, UCA1 siRNA and CDK2 siRNA almost abolished the positive effect of oxLDL on CDK2 expression. Finally, overexpression of UCA1 induced an increase in CDK2 levels, and knockdown of UCA1 caused inhibition of CDK2 expression. Conclusion: Upregulation of UCA1 enhances abnormal proliferation of VSMC by promoting G1/S transition through modulating the expression of CDK2.

J Asian Nat Prod Res ; 19(9): 890-902, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27809606


A new series of resveratrol heterocyclic analogs (4a-m) were designed and synthesized, and their inhibitiory effects on MCF-7 cells were evaluated to investigate structure-activity relationship. The effects of these analogs on human breast cancer MCF-7 cells were also determined. Results showed that MCF-7 cells could be inhibited more potently by these analogs than by resveratrol (IC50 = 80.0 µM). Among the analogs, compounds 4c, 4e, and 4k showed a significantly higher activity (IC50 = 42.7, 48.1, and 43.4 µM) than resveratrol. Furthermore, the derivatives without additional heterocyclic structure in the 4'-OH position exhibited a more potent activity than that with addition heterocyclic structure. In addition, docking simulation was performed to adequately position compound 4c in a human F1-ATPase active site to determine a probable binding model. These heterocyclic analogs could be effective candidates for the chemoprevention of human breast cancer.

Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Desenho de Fármacos , Estilbenos/síntese química , Estilbenos/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Resveratrol , Estilbenos/química , Relação Estrutura-Atividade
Bioorg Med Chem ; 24(12): 2739-53, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27166573


In the present study, a series of unreported fluorinated dabigatran analogues, which were based on the structural scaffold of dabigatran, were designed by computer-aided simulation. Fifteen fluorinated dabigatran analogues were screened and synthesized. All target compounds were characterized by (1)H NMR, (13)C NMR, (19)F NMR and HRMS. According to the preliminary screening results of inhibition ratio, eleven analogues (inhibition ratio >90%) were evaluated for antithrombin activity in vitro (IC50). The test results expressed that all the analogues showed effective inhibitory activities against thrombin. Especially, compounds 8f, 8k and 8o, with IC50 values of 1.81, 3.21 and 2.16nM, respectively, showed remarkable anticoagulant activities which were in the range of reference drug dabigatran (IC50=1.23nM). Moreover, compounds 8k and 8o were developed to investigate their anticoagulant activities in vivo. In those part, compound 8o exhibited a fairly strong inhibitory action for arteriovenous thrombosis with inhibition ratio of 84.66%, which was comparable with that of dabigatran (85.07%). Docking simulations demonstrated that these compounds could act as candidates for further development of novel anticoagulant drugs.

Anticoagulantes/química , Anticoagulantes/uso terapêutico , Dabigatrana/análogos & derivados , Dabigatrana/uso terapêutico , Trombose/tratamento farmacológico , Animais , Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Antitrombinas/síntese química , Antitrombinas/química , Antitrombinas/farmacologia , Antitrombinas/uso terapêutico , Dabigatrana/síntese química , Dabigatrana/farmacologia , Desenho de Fármacos , Halogenação , Humanos , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Trombina/antagonistas & inibidores
Bioorg Med Chem ; 24(2): 73-84, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26690913


In this work, 48 thrombin inhibitors based on the structural scaffold of dabigatran were analyzed using a combination of molecular modeling techniques. We generated three-dimensional quantitative structure-activity relationship (3D-QSAR) models based on three alignments for both comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to highlight the structural requirements for thrombin protein inhibition. In addition to the 3D-QSAR study, Topomer CoMFA model also was established with a higher leave-one-out cross-validation q(2) and a non-cross-validation r(2), which suggest that the three models have good predictive ability. The results indicated that the steric, hydrophobic and electrostatic fields play key roles in QSAR model. Furthermore, we employed molecular docking and re-docking simulation explored the binding relationship of the ligand and the receptor protein in detail. Molecular docking simulations identified several key interactions that were also indicated through 3D-QSAR analysis. On the basis of the obtained results, two compounds were designed and predicted by three models, the biological evaluation in vitro (IC50) demonstrated that these molecular models were effective for the development of novel potent thrombin inhibitors.

Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Dabigatrana/análogos & derivados , Modelos Moleculares , Trombina/antagonistas & inibidores , Anticoagulantes/química , Dabigatrana/química , Dabigatrana/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Trombina/metabolismo
Eur J Med Chem ; 96: 122-38, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25874337


Twenty-one fluorinated dabigatran derivatives were designed based on the bioisosteric principle. All derivatives were synthesised and evaluated for their thrombin inhibitory activity in vitro. Among these compounds, 14h, 14m, 14s and 14t were potent and the activity was in the range of reference drug, dabigatran. Three structural changes were introduced in these 21 compounds to elucidate the structure-activity relationship of the drugs. In addition, prodrugs of compounds 14h and 14s were developed to investigate their anticoagulant activities in vivo. In these experiments, compound 16 showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and demonstrated potent activity for inhibiting arteriovenous thrombosis with an inhibition rate of (73 ± 6) %, which was comparable to that of dabigatran etexilate (76 ± 2) %. Moreover, molecular docking studies were performed to understand the binding interactions of active compounds 14h, 14s and 14t with thrombin protein (PDB ID:1KTS). Contour maps obtained from the 3D-QSAR model are meaningful in designing more active molecules to act as direct inhibitors of thrombin.

Anticoagulantes/farmacologia , Antitrombinas/farmacologia , Dabigatrana/farmacologia , Desenho de Fármacos , Hidrocarbonetos Fluorados/farmacologia , Trombina/antagonistas & inibidores , Animais , Anticoagulantes/síntese química , Anticoagulantes/química , Antitrombinas/síntese química , Antitrombinas/química , Coagulação Sanguínea/efeitos dos fármacos , Dabigatrana/química , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Estrutura Molecular , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Trombina/metabolismo