RESUMO
In this work, screening studies of the cytotoxic effect of chlorins with fragments of di-, tri-, and pentaethylene glycol at the macrocycle periphery in relation to HeLa, A549, and HT29 cells were performed. It is shown that, despite different hydrophobicity, all the compounds studied have a comparable photodynamic effect. The conjugate of chlorin e6 with pentaethylene glycol, which has the lowest tendency to association among the studied compounds with tropism for low density lipoproteins and the best characteristics of the formation of molecular complexes with Tween 80, has a significant difference in dark and photoinduced toxicity (ratio IC50(dark)/IC50(photo) approximately 2 orders of magnitude for all cell lines), which allows to hope for a sufficiently large "therapeutic window". A study of the interaction of this compound with HeLa cells shows that the substance penetrates the cell and, after red light irradiation induces ROS appearance inside the cell, associated, apparently, with the photogeneration of singlet oxygen. These data indicate that photoinduced toxic effects are caused by damage to intracellular structures as a result of oxidative stress. Programmed type of cell death characterized with caspase-3 induction is prevailing. So, the conjugate of chlorin e6 with pentaethylene glycol is a promising antitumor PS that can be successfully solubilized with Tween 80, which makes it suitable for further in vivo studies.
Assuntos
Fotoquimioterapia , Polietilenoglicóis , Porfirinas , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Clorofila A , Células HeLa , Polissorbatos , Porfirinas/farmacologia , Porfirinas/química , Interações Hidrofóbicas e Hidrofílicas , Clorofila/químicaRESUMO
Two diastereomers of methylpheophorbide a 13(2)-N-n-octyl-N-(2-hydroxy-3-isobornyl-5-methylbenzyl)amide were obtained from (+)- and (-)-enantiomers of 2-isobornyl-4-methylphenol. Evaluation of membrane protective and antioxidant activity of individual diastereomers on the model of H2O2-induced hemolysis of blood erythrocytes showed that the stereochemistry of isobornyl substituent in the synthesized conjugates has no effect on their biological activity.
Assuntos
Canfanos/química , Clorofila/análogos & derivados , Membranas/efeitos dos fármacos , Substâncias Protetoras/química , Animais , Clorofila/síntese química , Clorofila/química , Clorofila/farmacologia , Cromatografia Líquida de Alta Pressão , Cresóis/química , Eritrócitos/efeitos dos fármacos , Peróxido de Hidrogênio/química , Camundongos , Estrutura Molecular , Substâncias Protetoras/síntese química , Substâncias Protetoras/farmacologia , EstereoisomerismoRESUMO
A series of terpenophenol-chlorin conjugates where terpenophenolic fragment has amide bond with macrocycle of methylpheophorbide a, formed by amidation of 13(2)-ester group were obtained by interaction of methylpheophorbide a and ortho-aminomethyl derivatives of 2-isobornyl-4-methylphenol. The substances investigated ability to interact with the cell membrane was shown in blood erythrocytes surface structure with scanning electron microscope. The conjugates studied were established to have antioxidant and membrane protective properties resulted from inhibiting H2O2-induced erythrocytes hemolysis and decrease of lipid peroxidation secondary product accumulation.
