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

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.

Development of Quinazolinone Derivatives as Modulators of Virulence Factors of Pseudomonas aeruginosa Cystic Fibrosis Strains

“…The selected derivatives were drawn in Maestro using the drawing tools of the software and then were prepared employing MacroModel and LigPrep as previously reported [ 40 , 41 , 42 ]. The selected molecules were minimized using a MacroModel with the OPLS3 force field [ 43 ].…”

Identifying Potential Ligand Binding Sites on Glycogen Synthase Kinase 3 Using Atomistic Cosolvent Simulations

“…18 Silva et al 19 employed a number of binding site identification algorithms (Fpocket, Superstar, metaPocket, Sitemap, and PARS) to determine which residues are included to be a part of the pocket 7 by these algorithms. Then, they docked a previously identified allosteric modulator on the four allosteric sites found by Palomo et al 16 Carullo et al 20 synthesized a family of square-amide based compounds and evaluated their potencies as ATP noncompetitive inhibitors of GSK3β. While these are illuminating studies, they are based on a static structure of a protein to identify the binding sites and ligand binding affinities.…”

Development of 1‐(2‐aminophenyl)pyrrole‐based amides acting as human topoisomerase I inhibitors

“…[17] This scaffold has also been encountered in known topoisomerase inhibitors [18] and is sometimes decorated by an amide group. [19] Among the privileged scaffolds, [20][21][22] also indole and quinoline have been used in the past for the development of topoisomerase inhibitors. The natural alkaloid ellipticine 5 and the synthetic quinoline compound 6 (Figure 1) showed good inhibitory properties against topoIB, [7,23,24] fostering the development of new interesting topoIB inhibitors, namely pyrroloquinolines.…”