title: Synthesis and in vitro and in vivo antitumor activity of 2-phenylpyrroloquinolin-4-ones.
abstract: In our search for potential new anticancer drugs, we designed and synthesized a series of tricyclic compounds containing the antimitotic 2-phenylazaflavone chromophore fused to a pyrrole ring in a pyrroloquinoline structure. Compounds 8, 18, 19, 22, 23, 25 and 26, when tested against a panel of fourteen human tumor cell lines, showed poor in vitro cytotoxic activity, whereas 20, 21 and 24 showed significant activity (IC(50) 0.7 to 50 microM). Steroid hormone-sensitive ovary, liver, breast and adrenal gland adenocarcinoma cell lines displayed the highest sensitivity (IC(50) 0.7 to 8 microM). Compound 24 blocked cells in the G(2)/M phase of the cell cycle and induced a significant increase in apoptotis. Compounds 20, 21 and 24 proved to alter microtubule assembly and stability, displaying a cytoplasmic microtubule network similar to that caused by Vincristine. In vivo, administration of compound 24 to Balb/c mice inhibited the growth of a syngenic hepatocellular carcinoma.
authors.affiliation: Department of Pharmaceutical Sciences, and Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Italy. mariagrazia.ferlin@ unipd.it
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Ferlin
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Chiarelotto
authors.forename: Venusia
authors.initials: V
authors.lastname: Gasparotto
authors.forename: Lisa
authors.initials: L
authors.lastname: Dalla Via
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pezzi
authors.forename: Luisa
authors.initials: L
authors.lastname: Barzon
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.forename: Ignazio
authors.initials: I
authors.lastname: Castagliuolo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D047072:Aromatase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D011758:Pyrroles; D011804:Quinolines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors