title: Synthesis and Evaluation of New Naphthalene and Naphthoquinone Derivatives as Anticancer Agents.
abstract: DNA topoisomerase I inhibitors, both synthetic and of natural origin, are receiving increasing consideration primarily as drugs against refractory tumors. Alkannin and shikonin, two enantiomeric dyes from Alkanna tinctoria and Lithospermum erythrorhizon, have been known over many centuries as dyestuff, wound healing, anti-inflammatory, antibacterial and antitumor substances. Although multiple mechanisms appear to be implicated, their potency is associated with the inhibition of topoisomerase I and with the redox properties of the naphthazarin scaffold. Here, the synthesis of new naphthalene and naphthoquinone derivatives inspired by alkannin and shikonin is described and their structural and biological properties were examined. Different oxidation states of the naphthalene nucleus were examined to observe the effect of this parameter on cytotoxicity. Antiproliferative activities against a panel of human cancer cell lines were evaluated and the implication of topoisomerase I was assessed.
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Beretta
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ribaudo
authors.affiliation: Department of Chemical Sciences, University of Padova, Padova, Italy.
authors.forename: Ileana
authors.initials: I
authors.lastname: Menegazzo
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Supino
authors.affiliation: "G. Moruzzi" Department of Biochemistry, University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Capranico
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zagotto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009281:Naphthalenes; D009285:Naphthoquinones; D059004:Topoisomerase I Inhibitors; C031721:naphthalene; D005978:Glutathione; D019803:Glutathione Disulfide
keywords: Alkannin; Anticancer; Camptothecin; Naphthoquinones; Topoisomerase