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
  • 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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