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: Barbara Parrino, Anna Carbone, Marina Muscarella, Virginia Spanò, Alessandra Montalbano, Paola Barraja, Alessia Salvador, Daniela Vedaldi, Girolamo Cirrincione, Patrizia Diana
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 22 Pg. 9495-511 (Nov 26 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25317694 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Caspase Inhibitors
• Heterocyclic Compounds, 2-Ring
• Heterocyclic Compounds, 4 or More Rings
• Reactive Oxygen Species
• Triazines
• Caspases
• cinnoline

Topics

• Antineoplastic Agents (chemistry)
• Apoptosis
• Caspase Inhibitors (chemistry)
• Caspases (chemistry)
• Cell Cycle
• Cell Death
• Cell Line, Tumor
• Cell Membrane (enzymology)
• Cell Proliferation
• Chemistry, Pharmaceutical (methods)
• Enzyme Activation
• Heterocyclic Compounds, 2-Ring (chemistry)
• Heterocyclic Compounds, 4 or More Rings (chemistry)
• Humans
• Jurkat Cells
• Lysosomes (enzymology)
• Mitochondria (enzymology)
• Neoplasms (drug therapy)
• Reactive Oxygen Species
• Temperature
• Triazines (chemistry)