1. Synthesis and biological evaluation of new 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles as PI3Kα inhibitors.
- Author
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Bruel A, Logé C, Tauzia ML, Ravache M, Le Guevel R, Guillouzo C, Lohier JF, Oliveira Santos JS, Lozach O, Meijer L, Ruchaud S, Bénédetti H, and Robert JM
- Subjects
- Animals, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Survival drug effects, Crystallography, X-Ray, Cyclin-Dependent Kinase 5 antagonists & inhibitors, Cyclin-Dependent Kinase 5 chemistry, Cyclin-Dependent Kinase 5 metabolism, Enzyme Assays, Escherichia coli genetics, Humans, Indoles pharmacology, Isoenzymes antagonists & inhibitors, Isoenzymes chemistry, Isoenzymes metabolism, Molecular Docking Simulation, Phosphatidylinositol 3-Kinases chemistry, Phosphatidylinositol 3-Kinases metabolism, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases chemistry, Protein Serine-Threonine Kinases metabolism, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases chemistry, Protein-Tyrosine Kinases metabolism, Pyridazines pharmacology, Rats, Recombinant Proteins antagonists & inhibitors, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Structure-Activity Relationship, Dyrk Kinases, Antineoplastic Agents chemical synthesis, Indoles chemical synthesis, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors chemical synthesis, Pyridazines chemical synthesis
- Abstract
A series of novel 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles was synthesized through a newly developed approach. All these compounds were evaluated against DYRK1A, CDK5 and PI3Kα and showed promising inhibitory activities against PI3Kα with most IC(50) values in the micromolar range. Among them, compound 18 was strongly considered as the most interesting compound with an IC(50) value of 0.091 μM. This series exhibited also significant anti-proliferative effects in various human cancer cell lines including those resulting in activation of the PI3K pathway., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)
- Published
- 2012
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