title: 11H-Pyrido[3',2':4,5]pyrrolo[3,2-c]cinnoline and pyrido[3',2':4,5]pyrrolo[1,2-c][1,2,3]benzotriazine: two new ring systems with antitumor activity.
abstract: Derivatives of new ring systems 11H-pyrido[3',2':4,5]pyrrolo[3,2-c]cinnoline and pyrido[3',2':4,5]pyrrolo[1,2-c][1,2,3]benzotriazine have been prepared from the key intermediates 2-(1H-pyrrolo[2,3-b]pyridin-2-yl)anilines in excellent yields (94-99%) and screened by the National Cancer Institute (Bethesda, MD) on about 60 human tumor cell lines derived from nine cancer cell types. The tested compounds exhibited antiproliferative activity against all the human cell lines, showing comparable MG_MID (mean graph midpoint) values in the range of 0.74-1.15 μM. A particular efficacy was observed against the leukemia subpanel (GI50 = 0.73-0.0090 μM). Flow cytometric analysis of the cell cycle demonstrated an increase in the percentage of cells in the G2/M phase. The compounds caused apoptosis of the cells, mitochondrial depolarization, generation of reactive oxygen species, and activation of caspase-3, caspase-8, and caspase-9. Moreover, they acted as topoisomerase I inhibitors.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo , Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Parrino
authors.forename: Anna
authors.initials: A
authors.lastname: Carbone
authors.forename: Marina
authors.initials: M
authors.lastname: Muscarella
authors.forename: Virginia
authors.initials: V
authors.lastname: Spanò
authors.forename: Alessandra
authors.initials: A
authors.lastname: Montalbano
authors.forename: Paola
authors.initials: P
authors.lastname: Barraja
authors.forename: Alessia
authors.initials: A
authors.lastname: Salvador
authors.forename: Daniela
authors.initials: D
authors.lastname: Vedaldi
authors.forename: Girolamo
authors.initials: G
authors.lastname: Cirrincione
authors.forename: Patrizia
authors.initials: P
authors.lastname: Diana
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D061945:Caspase Inhibitors / Q000737:chemistry; D020169:Caspases / Q000737:chemistry; D002453:Cell Cycle; D016923:Cell Death; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004789:Enzyme Activation; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry*; D006801:Humans; D019169:Jurkat Cells; D008247:Lysosomes / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology; D009369:Neoplasms / Q000188:drug therapy*; D017382:Reactive Oxygen Species; D013696:Temperature; D014227:Triazines / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D006576:Heterocyclic Compounds, 4 or More Rings; D017382:Reactive Oxygen Species; D014227:Triazines; D020169:Caspases; C476282:cinnoline