Synthesis and biological evaluation of new 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles as PI3Kα inhibitors.
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.
Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICIMED-EA 1155, UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44035 Cedex 1, France.
Amélie
A
Bruel
Cédric
C
Logé
Marie-Ludivine de
ML
Tauzia
Myriam
M
Ravache
Rémy
R
Le Guevel
Christiane
C
Guillouzo
Jean-François
JF
Lohier
Jana Sopkova-de
JS
Oliveira Santos
Olivier
O
Lozach
Laurent
L
Meijer
Sandrine
S
Ruchaud
Hélène
H
Bénédetti
Jean-Michel
JM
Robert
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D057075:Enzyme Assays; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
D000970:Antineoplastic Agents; D051360:Cyclin-Dependent Kinase 5; D007211:Indoles; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011724:Pyridazines; D011994:Recombinant Proteins; D000097603:Dyrk Kinases; C495905:CDK5 protein, human