A Michael addition-driven four-component reaction (4-CR) with four Ugi inputs was developed and utilized for the synthesis of chromone derivatives and tetrazole substituted chromones under mild reaction conditions.
BackgroundRecent studies showed that benzimidazoleisoquinolinone derivatives exhibit anticancer activity against human cancer cell lines. The aim of this study is to evaluate the anti-tumor effects and mechanisms of benzimidazoleisoquinolinones in isocitrate dehydrogenase-wildtype subtype of human glioblastoma (GBM) cells.MethodsHuman U87 and LN229 cell lines were used to perform the experiments. MTT was applied to screen the effective small molecular inhibitors suppressing growth of GBM cells. Colony formation and BrdU staining assays were performed to assess the inhibition effect of compound-1H on the proliferation of GBM cells. The cell cycle and apoptosis were measured by flow cytometry and western blot to analyze the changes of the relative protein expressions and their signal pathways.ResultsCompound-1H could suppress GBM cells in a time- and dose-dependent manner. Treatment of compound-1H could arrest cell cycle in S phase through up-regulating P21 and P53, and down-regulating cyclin A and E in a dose-dependent manner. Compound-1H also induced mitochondrial-dependent apoptosis by increasing Bax, cleaved caspase-3, cleaved caspase-9 and poly ADP-ribose polymerase expression, and decreasing Bcl-2 expression. Moreover, phosphorylated (p)-AKT and p-ERK levels relating to cell proliferation were dramatically decreased in U87 and LN229 cells.ConclusionsOur results suggest that it is the first time to report the compound-1H with benzimidazoleisoquinolinone core playing antitumor activity in human glioblastoma cells by inhibiting Raf/MEK/ERK and PI3K/AKT signaling pathways, and it could be as a lead compound for the further development of targeted glioblastoma cancer therapy.
Structurally
unique 2,2-disubstituted indolin-3-ones with a quaternary
carbon center have been constructed through a novel C–C bond
formation at the C3 position of Ugi N-acylamino amide
adducts employing an organic base-mediated Dieckmann condensation.
This facile, flexible protocol can be fine-tuned to construct drug-like
pyrazino[1,2-a]indole fragments with the same quaternary
carbon center only through the variation of the acid part in Ugi input.
This novel and expeditious methodology has a broad scope and can rapidly
generate the drug-like indolin-3-one core.
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