title: Anticancer properties of new synthetic hybrid molecules combining naphtho[2,3-b]furan-4,9-dione or benzo[f]indole-4,9-dione motif with phosphonate subunit.
abstract: In this paper we report an efficient and general synthesis of substituted 3-diethoxyphosphorylnaphtho [2,3-b]furan-4,9-diones and 3-diethoxyphosphorylbenzo [f]indole-4,9-diones which integrate the natural 1,4-naphtalenedione scaffold, present in several anticancer agents with the phosphonate moiety. The cytotoxicity of such hybrid molecules was tested against two leukemia cell lines, HL-60 and NALM-6 and against a breast adenocarcinoma MCF-7 cell line. Selected compounds were also tested on normal human cells: HUVEC and MCF-10A. In general, naphthofuran-4,9-diones showed much higher cytotoxic activity (IC50 values below 10 μM) than benzoindole-4,9-diones. The most promising 2-(2-chlorophenyl)-3-diethoxyphosphorylnaphtho [2,3-b]furan-4,9-dione, with the highest cytotoxic activity in the MTT test, was chosen for further evaluation of its anticancer potential. This compound, tested on HL-60 and MCF-7 cells inhibited cell proliferation, generated DNA damage and induced apoptosis. The suggested mechanism of its cytotoxic activity was the generation of intracellular reactive oxygen species and the induction of mitochondrial membrane potential dissipation.
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gach
authors.affiliation: Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Modranka
authors.affiliation: Central Scientific Laboratory, Division of Public Health, Faculty of Health Sciences, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Szymański
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Pomorska
authors.affiliation: Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, Muszynskiego 1, 90-151, Lodz, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Krajewska
authors.affiliation: Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, Muszynskiego 1, 90-151, Lodz, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Mirowski
authors.affiliation: Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland. Electronic address: tomasz.janecki@p.lodz.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Janecki
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland. Electronic address: anna.janecka@umed.lodz.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D063065:Organophosphonates
keywords: Apoptosis; Cytotoxicity; Hybrid molecules; Naphthofurandiones; Phosphonate moiety