Synthesis and biological evaluation of 3-substituted 2-oxindole derivatives as new glycogen synthase kinase 3β inhibitors. Issue 9 (1st May 2019)

• Record Type: Journal Article
• Authors: Lozinskaya, Natalia A.; Babkov, Denis A.; Zaryanova, Ekaterina V.; Bezsonova, Elena N.; Efremov, Alexander M.; Tsymlyakov, Michael D.; Anikina, Lada V.; Zakharyascheva, Olga Yu.; Borisov, Alexander V.; Perfilova, Valentina N.; Tyurenkov, Ivan N.; Proskurnina, Marina V.; Spasov, Alexander A.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 9(2019)
• Page Start: 1804
• Page End: 1817
• Publication Date: 2019-05-01
• Subjects: Oxindole derivatives -- Indolin-2-one -- GSK3β -- Glycogen synthase kinase 3 -- Antidiabetic -- 3-Substituted indolinone -- Anticancer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.03.028
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 compound3a inhibits GSK-3β with IC50 4.19 nM. In a cell-based assay3a shows no significant leucocyte toxicity at 10 µM and is moderately cytotoxic against A549 cells. Compound3a 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.