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.

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

Pasquini S.;Contri C.;Varani K.;Vincenzi F.
Penultimo
;
2022

Abstract

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
Carullo, G.; Bottoni, L.; Pasquini, S.; Papa, A.; Contri, C.; Brogi, S.; Calderone, V.; Orlandini, M.; Gemma, S.; Varani, K.; Butini, S.; Galvagni, F.; Vincenzi, F.; Campiani, G.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2501734
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