Synthesis and biological evaluation of new 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles as PI3Kα inhibitors

• Published in: European journal of medicinal chemistry Vol. 57; pp. 225 - 233
• Main Authors: Bruel, Amélie, Logé, Cédric, Tauzia, Marie-Ludivine de, Ravache, Myriam, Le Guevel, Rémy, Guillouzo, Christiane, Lohier, Jean-François, Oliveira Santos, Jana Sopkova-de, Lozach, Olivier, Meijer, Laurent, Ruchaud, Sandrine, Bénédetti, Hélène, Robert, Jean-Michel
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.11.2012; Elsevier
• Subjects: 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles; Animals; Anti-proliferative effects; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Crystallography, X-Ray; Cyclin-Dependent Kinase 5 - antagonists & inhibitors; Cyclin-Dependent Kinase 5 - chemistry; Cyclin-Dependent Kinase 5 - metabolism; Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); Dyrk Kinases; Enzyme Assays; Escherichia coli - genetics; Humans; Indoles - chemical synthesis; Indoles - pharmacology; Isoenzymes - antagonists & inhibitors; Isoenzymes - chemistry; Isoenzymes - metabolism; Kinase inhibitors; Life Sciences & Biomedicine; Medical sciences; Miscellaneous; Molecular Docking Simulation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - chemistry; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide 3-kinase (PI3K); Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors - chemical synthesis; 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 - chemical synthesis; Pyridazines - pharmacology; Rats; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Science & Technology; Structure-Activity Relationship; Phosphoinositide 3-kinase (PI3K); Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles; Anti-proliferative effects; Kinase inhibitors; KINASE; VALIDATION; DERIVATIVES; 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b] indoles
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.09.001

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 IC50 values in the micromolar range. Among them, compound 18 was strongly considered as the most interesting compound with an IC50 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. [Display omitted] A series of novel 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles was prepared and screened against DYRK1A, CDK5, PI3Kα and various human cancer cell lines. Compound 18 exhibited the best inhibitory activity against PI3Kα. ► Novel 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles were synthesized. ► Structure was confirmed by a single-crystal X-ray diffraction. ► These compounds showed promising in vitro inhibitory activities against PI3Kα. ► This series exhibited significant anti-proliferative effects in various human cancer cell lines.