Affiliation: | 1. Industrial and Applied Organic Chemistry Research Unit, Department of Inorganic and Organic Chemistry, Universidad de Barcelona, Martí Franquès 1-11, 08028 Barcelona, Spain;2. Institute of Biotechnology and Biomedicine Vicent Villar Palasí, Universidad Autónoma de Barcelona, Bellaterra, 08193 Barcelona, Spain;3. Consolidated Research Group of Proteins Engineering and Proteomics, Universidad Autónoma de Barcelona, Bellaterra, 08193 Barcelona, Spain |
Abstract: | This article describes the design, synthesis and biological evaluation of a new family of antitumor agents having the 1,7-epoxycyclononane framework. We have developed a versatile synthetic methodology that allows the preparation of a chemical library with structural diversity and in good yield. The synthetic methodology has been scaled up to the multigram level and can be developed in an enantioselective fashion. The study in vitro of a model compound, in front of the cancer cell lines HL-60 and MCF-7, showed a growth inhibitory effect better than that of cisplatin. The observation of cancer cells by fluorescence microscopy showed the presence of apoptotic bodies and a degradation of microtubules. The study of cell cycle and mechanism of death of cancer cells by flow cytometry indicates that the cell cycle arrested at the G0/G1 phase and that the cells died by apoptosis preferably over necrosis. A high percentage of apoptotic cells at the subG0/G1 level was observed. This indicates that our model compound does not behave as an antimitotic agent like nocodazole, used as a reference, which arrests the cell cycle at G2/M phase. The interaction of anticancer agents with DNA molecules was evaluated by atomic force microscopy, circular dichroism and electrophoresis on agarose gel. The results indicate that the model compound has not DNA as a target molecule. The in silico study of the model compound showed a potential good oral bioavailability. |