Synthesis and biological evaluation of 3-substituted 2-oxindole derivatives as new glycogen synthase kinase 3β inhibitors

Natalia A Lozinskaya; Denis A Babkov; Ekaterina V Zaryanova; Elena N Bezsonova; Alexander M Efremov; Michael D Tsymlyakov; Lada V Anikina; Olga Yu Zakharyascheva; Alexander V Borisov; Valentina N Perfilova; Ivan N Tyurenkov; Marina V Proskurnina; Alexander A Spasov

doi:10.1016/j.bmc.2019.03.028

Synthesis and biological evaluation of 3-substituted 2-oxindole derivatives as new glycogen synthase kinase 3β inhibitors

Bioorg Med Chem. 2019 May 1;27(9):1804-1817. doi: 10.1016/j.bmc.2019.03.028. Epub 2019 Mar 15.

Affiliations

¹ Lomonosov Moscow State University, Department of Chemistry, Leninskie gory St., 1, Moscow 119234, Russia; Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severnyi Proezd, Chernogolovka 142432, Russia. Electronic address: [email protected].
² Volgograd State Medical University, Novorossiyskaya St. 39, 400087 Volgograd, Russia.
³ Lomonosov Moscow State University, Department of Chemistry, Leninskie gory St., 1, Moscow 119234, Russia.
⁴ Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severnyi Proezd, Chernogolovka 142432, Russia.
⁵ Lomonosov Moscow State University, Department of Chemistry, Leninskie gory St., 1, Moscow 119234, Russia; Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severnyi Proezd, Chernogolovka 142432, Russia.

PMID: 30902399
DOI: 10.1016/j.bmc.2019.03.028

Abstract

Glycogen synthase kinase 3β (GSK-3β) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus. Inhibition of GSK-3β activity has become an attractive approach for treatment of diabetes and cancer. We report the discovery of novel GSK-3β inhibitors of 3-arylidene-2-oxindole scaffold with promising activity. The most potent compound 3a inhibits GSK-3β with IC₅₀ 4.19 nM. In a cell-based assay 3a shows no significant leucocyte toxicity at 10 µM and is moderately cytotoxic against A549 cells. Compound 3a demonstrated high antidiabetic efficacy in obese streptozotocin-treated rats improving glucose tolerance at a dose of 50 mg/kg body weight thus representing an interesting lead for further optimization.

Keywords: 3-Substituted indolinone; Anticancer; Antidiabetic; GSK3β; Glycogen synthase kinase 3; Indolin-2-one; Oxindole derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Animals
Binding Sites
Catalytic Domain
Cell Survival / drug effects
Diabetes Mellitus, Experimental / chemically induced
Diabetes Mellitus, Experimental / drug therapy
Glucose Tolerance Test
Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
Glycogen Synthase Kinase 3 beta / metabolism
Humans
Inhibitory Concentration 50
Molecular Docking Simulation
Oxindoles / chemistry*
Oxindoles / pharmacology
Oxindoles / therapeutic use
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Rats
Structure-Activity Relationship

Substances

Oxindoles
Protein Kinase Inhibitors
2-oxindole
Glycogen Synthase Kinase 3 beta