1. 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
- Author
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Patrizia Diana, Anna Carbone, Virginia Spanò, Paola Barraja, Daniela Vedaldi, Alessandra Montalbano, Barbara Parrino, M Muscarella, Alessia Salvador, Girolamo Cirrincione, Parrino, B, Carbone, A, Muscarella, M, Spanò, V, Montalbano, A, Barraja, P, Salvador, A, Vedaldi, D, Cirrincione, G, and Diana, P
- Subjects
Stereochemistry ,Cinnolines ,triazines ,Chemistry, Pharmaceutical ,Antineoplastic Agents ,Apoptosis ,Heterocyclic Compounds, 2-Ring ,Heterocyclic Compounds, 4 or More Rings ,chemistry.chemical_compound ,Jurkat Cells ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Humans ,Cinnoline ,Cell Proliferation ,chemistry.chemical_classification ,Reactive oxygen species ,Cell Death ,Chemistry ,Cell growth ,Cell Cycle ,Cell Membrane ,Temperature ,Depolarization ,Cell cycle ,Caspase Inhibitors ,Mitochondria ,Enzyme Activation ,Cell culture ,Caspases ,Cinnolines, triazines ,Cancer cell ,Molecular Medicine ,Lysosomes ,Reactive Oxygen Species - 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.
- Published
- 2014