Multifaceted properties of 1,4-dimethylcarbazoles: Focus on trimethoxybenzamide and trimethoxyphenylurea derivatives as novel human topoisomerase II inhibitors

Publication date: 1 January 2017
Source:European Journal of Pharmaceutical Sciences, Volume 96
Author(s): Domenico Iacopetta, Camillo Rosano, Francesco Puoci, Ortensia Ilaria Parisi, Carmela Saturnino, Anna Caruso, Pasquale Longo, Jessica Ceramella, Aurélie Malzert-Fréon, Patrick Dallemagne, Sylvain Rault, Maria Stefania Sinicropi
Natural or synthetic carbazole derivatives have recently attracted the attention of the scientific world because of their multiple biological activity, leading to an increase of designed, synthesized and studied analogues. In this paper, four 1,4-dimethylcarbazole derivatives, analogues of Ellipticine, have been investigated for their ability to block cancer cells growth, with low effects on the proliferation of normal cells. DNA topoisomerases inhibition assays, docking simulations, stability studies and effects on a membrane model are reported. Particularly, compounds 2 and 3 have been found thermally stable and able to inhibit, strongly and selectively, the human DNA topoisomerase II. These properties confer a good and broad antitumoral activity in vitro, with very low cytotoxic effect on the proliferation of normal cell lines and without damaging, in contrast with Ellipticine, the cell membrane model. The presented outcomes set the most active compounds as good candidates for pre-clinical studies useful in cancer treatment.

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