6533b835fe1ef96bd129ff7b

RESEARCH PRODUCT

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

Patrizia DianaAnna CarboneVirginia SpanòPaola BarrajaDaniela VedaldiAlessandra MontalbanoBarbara ParrinoM MuscarellaAlessia SalvadorGirolamo Cirrincione

subject

StereochemistryCinnolines; triazinesChemistry PharmaceuticalAntineoplastic AgentsApoptosisHeterocyclic Compounds 2-RingHeterocyclic Compounds 4 or More Ringschemistry.chemical_compoundJurkat CellsCell Line TumorNeoplasmsDrug DiscoverytriazinesHumansCinnolineCell Proliferationchemistry.chemical_classificationReactive oxygen speciesCell DeathChemistryCell growthCell CycleCell MembraneTemperatureDepolarizationCell cycleCaspase InhibitorsMitochondriaEnzyme ActivationCell cultureApoptosisCaspasesCinnolines triazinesCancer cellMolecular MedicineLysosomesReactive Oxygen SpeciesCinnolines

description

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.

yearjournalcountryeditionlanguage
2014-01-01
10.1021/jm501244fhttp://hdl.handle.net/10447/102794