Synthesis of Unsymmetrical Squaramides as Allosteric GSK-3β Inhibitors Promoting β-Catenin-Mediated Transcription of TCF/LEF in Retinal Pigment Epithelial Cells.

Autor: Carullo G; Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy., Bottoni L; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy., Pasquini S; Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy., Papa A; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy., Contri C; Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy., Brogi S; Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy., Calderone V; Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy., Orlandini M; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy., Gemma S; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy., Varani K; Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy., Butini S; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy., Galvagni F; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy., Vincenzi F; Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy., Campiani G; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2022 Dec 16; Vol. 17 (24), pp. e202200456. Date of Electronic Publication: 2022 Oct 27.
DOI: 10.1002/cmdc.202200456
Abstrakt: The glycogen synthase kinase 3β (GSK-3β) is a ubiquitous enzyme that is a validated target for the development of potential therapeutics useful in several diseases including retinal degeneration. Aiming at developing an innovative class of allosteric inhibitors of GSK-3β potentially useful for retinal degeneration, we explored the class of squaramides. The developed compounds (6 a-l) were obtained through a nontoxic one-pot synthetic protocol, which employs low-cost goods and avoids any purification step. Ethanol was used as the reaction solvent, simultaneously allowing the pure reaction products' recovery (by precipitation). Out of this set of squaramides, 6 j stood out, from computational and enzymatic converging data, as an ATP non-competitive inhibitor of GSK-3β of micromolar potency. When engaged in cellular studies using retinal pigment epithelial cells (ARPE-19) transfected with a luciferase reporter gene under the control of T-cell factor/lymphoid enhancer factor (TCF/LEF) binding sites, 6 j was able to dose-dependently induce β-catenin nuclear accumulation, as shown by the increased luciferase activity at a concentration of 2.5 μM.
(© 2022 Wiley-VCH GmbH.)
Databáze: MEDLINE
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