Nieddu, Valentina (2015) Biological evaluation of 1,3,4-oxadiazoles bis-substitute derivatives as potential anticancer agents. Doctoral Thesis.
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Cancer is a major health problem and causes substantial morbidity and mortality worldwide.
In order to identify new potent antitumor agents with good specificity and low toxicity, a series of 12 new 1,3,4-oxadiazole bis-substitute molecules were tested on different cancer cell lines as potential antitumor candidates. All the compounds were tested in order to select the molecules with stronger and more selective cell growth inhibitory activity.
The cytotoxic effects were evaluated in vitro and it was found that Molecule 10 had the greatest antitumor activity on cancer cells and it exerted an antiproliferative behavior in a dose-dependent manner. Clonogenic assay revealed a visible reduction of colony formation in all cell lines.
To investigate the effects of the molecule on the cell cycle progression, flow cytometry analysis were performed identifying cell cycle arrest in G2/M phases, therefore immunofluorescence analyses were realized using β-tubulin antibody and abnormal effects were showed on tubulin organization. To understand molecular mechanism involved in cell cycle arrest, western blot analysis were executed identifying a deregulation of p53 levels.
Same experiments were repeated in human fibroblast cells as normal control versus the respective immortalized cell lines. All the fibroblasts were less sensitive and showed a higher IC50 than cancer and immortalized cells, validating that Molecule 10 has low systemic toxicity and a specific activity to cancer cells.
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