title: Simple avarone mimetics as selective agents against multidrug resistant cancer cells.
abstract: In this work, synthesis of alkylamino and aralkylamino derivatives of sesquiterpene quinone avarone and its model compound tert-butylquinone was described. For all obtained derivatives biological activity was studied. Cytotoxic activity of the synthesized derivatives towards multidrug resistant MDR human non-small cell lung carcinoma NCI-H460/R cells, their sensitive counterpart NCI-H460 and human normal keratinocytes (HaCaT) as well as detection of cell death superoxide anion generation were investigated. Antimicrobial activity towards Gram positive and Gram negative bacteria and fungal cultures was determined. The results showed that strong cytotoxic activity toward cancer cells was improved with simple avarone mimetics. Some derivatives were selective towards MDR cancer cells. The most active derivatives induced apoptosis in both cancer cell lines, but not in normal cells. Superoxide production was induced by 2,6-disubstituted compounds in MDR cancer cells and not by less active 2,5-disubstituted compounds and was accompanied by the collapse of the mitochondrial transmembrane potential. Two tert-butylquinone derivatives were particularly selective towards MDR cancer cells. Some tert-butylquinone derivatives exhibited a strong antimicrobial activity.
authors.affiliation: Innovation Center of Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia. Electronic address: mjeremic@chem.bg.ac.rs.
authors.forename: Marko
authors.initials: M
authors.lastname: Jeremić
authors.affiliation: Institute for Biological Research "Siniša Stanković", University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia. Electronic address: camala@ibiss.bg.ac.rs.
authors.forename: Milica
authors.initials: M
authors.lastname: Pešić
authors.affiliation: Institute for Biological Research "Siniša Stanković", University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia. Electronic address: jelena.dinic@ibiss.bg.ac.rs.
authors.forename: Jelena
authors.initials: J
authors.lastname: Dinić
authors.affiliation: Institute for Biological Research "Siniša Stanković", University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia. Electronic address: jasnam@ibiss.bg.ac.rs.
authors.forename: Jasna
authors.initials: J
authors.lastname: Banković
authors.affiliation: Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Center for Chemistry, Njegoševa 12, 11000 Belgrade, Serbia. Electronic address: irenan@chem.bg.ac.rs.
authors.forename: Irena
authors.initials: I
authors.lastname: Novaković
authors.affiliation: Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia. Electronic address: segand@chem.bg.ac.rs.
authors.forename: Dejan
authors.initials: D
authors.lastname: Šegan
authors.affiliation: Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia. Electronic address: dsladic@chem.bg.ac.rs.
authors.forename: Dušan
authors.initials: D
authors.lastname: Sladić
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000737:chemistry; D045744:Cell Line, Tumor; D053138:Cyclohexenes / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D006873:Hydroquinones / Q000737:chemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D016227:Benzoquinones; D053138:Cyclohexenes; D006873:Hydroquinones; D012717:Sesquiterpenes; C004532:quinone; C046374:avarone; C031927:hydroquinone
keywords: Anticancer activity; Apoptosis; Mitochondrial potential; Multidrug resistant; Quinones; ROS generation