TY  - THES
T1  - Synthesis and biological activity of multifunctional sensor/effector catalysts
A1  - Shaaban,Saad
Y1  - 2011/02/10
N2  - Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in several types of cancer. This biochemical property of cancer cells might be exploited for therapeutic benefits since it might be possible to preferentially eliminate these cells by pharmacological ROS insults. Compounds able to modulate the intracellular redox state of cells have been developed, which effectively, yet also selectively, appear to kill cancer cells. Among the various agents employed to modulate the intracellular redox state of cells, certain redox catalysts containing quinone and chalcogen moieties have shown considerable promise since they are non-toxic on their own yet develop an effective, often selective cytotoxicity. A simple synthetic method based on the Passerini and Ugi multicomponent reactions has been developed for the synthesis of multifunctional redox catalysts. This method allowed the synthesis of a representative set of agents combining two, three or even four redox centres in one molecule in a good yield.
When incubated with cancer cells these multifunctional agents inhibited cell proliferation and induced both cell cycle delay and apoptotic cell death in low, often sub-micromolar concentrations. The cause was obviously OS, which was reflected by an enhanced ROS level together with a significant decrease in reduced glutathione. Interestingly, some of these redox active compounds showed quite low toxicity with normal human fibroblasts and endothelial cells, supporting the notion that such compounds might have a selective anticancer activity. Chemogenomic assays using a mutant library of Saccharomyces cerevisiae were used to look for chemical-genetic interactions. Analyzing the resulting chemical-genetic interaction profiles afforded a set of sensitive mutants. The corresponding knocked out genes of these mutants play a major role in the antioxidant defence system and are pivotal for the removal of toxic oxidants. Therefore, deletion of the respective genes might cause an OS sensitive phenotype of the mutant. These observations were in excellent agreement with the other cell-based assay performed as a part of this study. Finally, some of these compounds showed a potent antimicrobial activity evaluated against different fungal and bacterial strains.
KW  - Oxidativer Stress
KW  - Eintopfreaktion
KW  - Tumor
CY  - Saarbrücken
PB  - Universitäts- und Landesbibliothek
AD  - Postfach 151141, 66041 Saarbrücken
UR  - http://scidok.sulb.uni-saarland.de/volltexte/2011/3537
ER  -