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

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.
Natalia A Lozinskaya 1,  Denis A Babkov 2,  Ekaterina V Zaryanova 3,  Elena N Bezsonova 3,  Alexander M Efremov 3,  Michael D Tsymlyakov 3,  Lada V Anikina 4,  Olga Yu Zakharyascheva 2,  Alexander V Borisov 2,  Valentina N Perfilova 2,  Ivan N Tyurenkov 2,  Marina V Proskurnina 5,  Alexander A Spasov 2
Affiliations

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.

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