title: Multifaceted properties of 1,4-dimethylcarbazoles: Focus on trimethoxybenzamide and trimethoxyphenylurea derivatives as novel human topoisomerase II inhibitors.
abstract: 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.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Iacopetta
authors.affiliation: UOS Proteomics IRCCS AOU San Martino-IST National Institute for Cancer Research, Largo R. Benzi 10, Genoa, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Puoci
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy.
authors.forename: Ortensia Ilaria
authors.initials: OI
authors.lastname: Parisi
authors.affiliation: Department of Pharmacy, University of Salerno, 84084 Fisciano, Salerno, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Saturnino
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caruso
authors.affiliation: Department of Chemistry and Biology, University of Salerno, 84084 Fisciano, Salerno, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Longo
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ceramella
authors.affiliation: Normandie Université, UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), Caen, France. Electronic address: aurelie.malzert-freon@unicaen.fr.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Malzert-Fréon
authors.affiliation: Normandie Université, UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), Caen, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Dallemagne
authors.affiliation: Normandie Université, UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), Caen, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy. Electronic address: s.sinicropi@unical.it.
authors.forename: Maria Stefania
authors.initials: MS
authors.lastname: Sinicropi
mesh_terms: D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D002227:Carbazoles / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D001549:Benzamides; D002227:Carbazoles; D010671:Phenylurea Compounds; D059005:Topoisomerase II Inhibitors; C037689:benzamide
keywords: Antitumor; Docking simulation; Human topoisomerases I/II; Large unilamellar vesicles; Thermal stability