title: Synthesis and in vitro cytotoxicity evaluation of novel naphthindolizinedione derivatives.
abstract: Novel 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxamide derivatives and the corresponding 7,10-dihydroxy analogues were designed in accordance with Moore's and Pindur's theory and synthesized based on the structural similarity with known antitumour agents such as ellipticine, daunorubicin, mitoxantrone and 9-aminoacridine-4 carboxamide derivatives. These compounds, including structural variations of the amide side chain, were evaluated in the NCI panel of human tumour cell lines, from which 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-(2-dimethylamino-ethyl)-12-carboxamide 11a was found to be the most potent agent within the series. It showed good selectivity towards leukaemia, colon and renal cancer cell lines, with significant GI50 values, from lower than 10 nM to 0.2 microM. Moreover, its cytotoxicity against the adriamicine-resistant breast tumour cell line at a concentration lower than 1 microM turned out to be higher than the values using the clinical anticancer agents, daunorubicin and mitoxantrone.
authors.affiliation: Laboratorio di Chimica Bioorganica, Dipartimento di Fisica, Università degli studi di Trento, Trento, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Defant
authors.forename: Graziano
authors.initials: G
authors.lastname: Guella
authors.forename: Ines
authors.initials: I
authors.lastname: Mancini
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007212:Indolizines / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007212:Indolizines; D007364:Intercalating Agents