RESUMO
DNA polymorphism exerts a fascination on a large scientific community. Without crystallographic structural data, clarification of the binding modes between G-quadruplex (G4) and ligand (complex) is a challenging job. In the present work, three porphyrin compounds with different flexible carbon chains (arms) were designed, synthesized and characterized. Their binding, folding and stabilizing abilities to human telomeric G4 DNA structures were comparatively researched. Positive charges at the end of the flexible carbon chains seem to be favorable for the DNA-porphyrin interactions, which were evidenced by the spectral results and further confirmed by the molecular docking calculations. Biological function analysis demonstrated that these porphyrins show no substantial inhibition to Hela, A549 and BEL 7402 cancer cell lines under dark while exhibit broad inhibition under visible light. This significantly enhanced photocytotoxicity relative to the dark control is an essential property of photochemotherapeutic agents. The feature of the flexible arms emerges as critical influencing factors in the cell photocytotoxicity. Moreover, an ROS-mediated mitochondrial dysfunction pathway was suggested for the cell apoptosis induced by these flexible-armed porphyrins. It is found that the porphyrins with positive charges located at the end of the flexible arms represent an exciting opportunity for photochemotherapeutic anti-cancer drug design.
Assuntos
Apoptose/efeitos dos fármacos , Quadruplex G/efeitos dos fármacos , Porfirinas/toxicidade , Telômero/genética , Células A549 , Apoptose/efeitos da radiação , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Dicroísmo Circular , Quadruplex G/efeitos da radiação , Células HeLa , Humanos , Luz , Microscopia de Fluorescência , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Porfirinas/química , Porfirinas/metabolismo , Oxigênio Singlete/análiseRESUMO
The clinical use of daunomycin is restricted by dose-dependent toxicity and low specificity against cancer cells. In the present study, modified superparamagnetic iron oxide nanoparticles were employed to load daunomycin and the drug-loaded nanospheres exhibited satisfactory size and smart pH-responsive release. The cellular uptake efficiency, targeted cell accumulation, and cell cytotoxicity experimental results proved that the superparamagnetic iron oxide nanoparticle-loading process brings high drug targeting without decreasing the cytotoxicity of daunomycin. Moreover, a new concern for the evaluation of nanophase drug delivery's effects was considered, with monitoring the interactions between human serum albumin and the drug-loaded nanospheres. Results from the multispectroscopic techniques and molecular modeling calculation elucidate that the drug delivery has detectable deleterious effects on the frame conformation of protein, which may affect its physiological function.