RESUMEN
A novel approach to the synthesis of pH-sensitive prodrugs has been proposed: thiourea drug modification. Resulting prodrugs can release the cytotoxic agent and the biologically active 2-thiohydantoin in the acidic environment of tumor cells. The concept of acid-catalyzed cyclization of thioureas to 2-thiohydantoins has been proven using a FRET model. Dual prodrugs of model azidothymidine, cytotoxic doxorubicin, and 2-thiohydantoin albutoin were obtained, which release the corresponding drugs in the acidic environment. The resulting doxorubicin prodrug was tested on prostate cancer cells and showed that the thiourea-modified prodrug is less cytotoxic (average IC50 ranging from 0.5584 to 0.9885 µM) than doxorubicin (IC50 ranging from 0.01258 to 0.02559 µM) in neutral pH 7.6 and has similar toxicity (average IC50 ranging from 0.4970 to 0.7994 µM) to doxorubicin (IC50 ranging from 0.2303 to 0.8110 µM) under mildly acidic conditions of cancer cells. Cellular and nuclear accumulation in PC3 tumor cells of Dox prodrug is much higher than accumulation of free doxorubicin.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Concentración de Iones de Hidrógeno , Profármacos/farmacología , Tiourea/química , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Doxorrubicina/química , Fluoresceína/química , Transferencia Resonante de Energía de Fluorescencia , Humanos , Masculino , Naftalenos/química , Profármacos/química , Neoplasias de la Próstata/patologíaRESUMEN
A series of 73 ligands and 73 of their Cu+2 and Cu+1 copper complexes with different geometries, oxidation states of the metal, and redox activities were synthesized and characterized. The aim of the study was to establish the structure-activity relationship within a series of analogues with different substituents at the N(3) position, which govern the redox potentials of the Cu+2/Cu+1 redox couples, ROS generation ability, and intracellular accumulation. Possible cytotoxicity mechanisms, such as DNA damage, DNA intercalation, telomerase inhibition, and apoptosis induction, have been investigated. ROS formation in MCF-7 cells and three-dimensional (3D) spheroids was proven using the Pt-nanoelectrode. Drug accumulation and ROS formation at 40-60 µm spheroid depths were found to be the key factors for the drug efficacy in the 3D tumor model, governed by the Cu+2/Cu+1 redox potential. A nontoxic in vivo single-dose evaluation for two binuclear mixed-valence Cu+1/Cu+2 redox-active coordination compounds, 72k and 61k, was conducted.
Asunto(s)
Complejos de Coordinación/química , Cobre/química , Imidazoles/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacología , Cristalografía por Rayos X , Daño del ADN/efectos de los fármacos , Humanos , Ligandos , Células MCF-7 , Modelos Biológicos , Conformación Molecular , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo , Esferoides Celulares/efectos de los fármacos , Relación Estructura-Actividad , Telomerasa/antagonistas & inhibidores , Telomerasa/metabolismoRESUMEN
We have synthesized and characterized a panel of new binuclear mixed valence Cu(I,II) complexes containing substituted 2-alkylthio-5-arylmethylene-4H-imidazolin-4-ones with unusual structure. These complexes are shown to be cytotoxic for various cell lines. We have found that these compounds did not intercalate DNA, inhibited number of polymerases (telomerase predominantly), accumulated in the cell nucleus, and caused DNA degradation. Preliminary studies revealed that lead compound inhibited human breast adenocarcinoma growth in mice model.