RESUMO
VEGFR-2 is an attractive target for the development of anti-tumor drugs and plays a crucial role in tumor angiogenesis. This study reports a series of novel thiophene-3-carboxamide derivatives based on PAN-90806 as VEGFR-2 inhibitors, among which compound 14d exhibits excellent anti-proliferative activity against HCT116, MCF7, PC3, and A549 cell lines, and has effective VEGFR-2 inhibitory activity with an IC50 value of 191.1 nM. Additionally, CETSA results indicated that VEGFR-2 was a relevant target of compound 14d in the cell lines, and compound 14d could also inhibit VEGFR-2 protein phosphorylation in A549 cell line. Furthermore, compound 14d inhibited colony formation, cell migration, and HUVECs tube formation in a dose-dependent manner. The mechanism by which 14d induced cancer cell death involves blocking the cell cycle, increasing ROS production, inducing apoptosis, and dose-dependently reducing the levels of phosphorylated ERK and MEK. Molecular docking and molecular dynamics simulations had shown that compound 14d could stably bind to the active site of VEGFR-2. These results confirmed that compound 14d might be a promising lead compound for anti-angiogenesis.
Assuntos
Inibidores da Angiogênese , Antineoplásicos , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases , Tiofenos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Tiofenos/farmacologia , Tiofenos/química , Tiofenos/síntese química , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Estrutura Molecular , Descoberta de Drogas , Movimento Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Simulação de Acoplamento Molecular , Linhagem Celular TumoralRESUMO
PURPOSE: To investigate the retinal vascular network alterations in highly myopic eyes. METHODS: Thirty-three highly myopic eyes from 21 subjects and 47 mildly myopic or emmetropic eyes from 24 healthy control subjects were enrolled. Optical coherence tomography angiography (OCTA) was used to image the superficial, deep, and whole retinal vascular plexuses at the macular region. Highly myopic eye images were analyzed after adjusting the ocular magnification using Bennett's formula. Fractal analysis (box counting method, Dbox) representing vessel density was performed in different annular and quadrantile zones of both large vessels and microvessels. Correlations between the vascular density, axial length, and spherical equivalent refractive error were analyzed. RESULTS: The average density (Dbox) of the superficial retinal annular zone (0.6-2.5 mm) microvessels was 1.741 ± 0.018 in highly myopic eyes and was shown to be significantly lower than that of the controls (1.773 ± 0.010, P < 0.001). Individual annular zone (bandwidth of 0.16 mm) analysis of highly myopic eyes revealed a significant level of microvessel alteration in all zones compared with the same zones in control eyes (P < 0.001). Furthermore, in the highly myopic group, the microvessel density was significantly correlated with axial length elongation in all three layers (r = -0.38 to -0.48; P < 0.05). CONCLUSIONS: This study reveals retinal microvascular network alterations in highly myopic eyes, which correlates with axial length elongation. Fractal analysis of the microvasculature by OCTA images may help to characterize the underlying pathophysiological mechanisms involved in high myopia.