In our continuing effort devoted at developing agents targeting the EphA2 receptor by means of protein-protein interaction (PPI) inhibitors, we report here the design and synthesis of a new class of L-β-homotryptophan conjugates of 3-β-hydroxy-Δ5-cholenic acid bearing a set of arylsulfonyl substituents at the indole nitrogen atom. An extensive structure-activity relationship (SAR) analysis indicates that the presence of a bulky lipophilic moiety at the indole nitrogen is fundamental for improving potency on the EphA2 receptor, while abrogating activity on the EphB1-EphB3 receptor subtypes. A rational exploration, guided by the combined application of an experimental design on σp and π physicochemical descriptors and docking simulations, led to the discovery of UniPR1454, a 1-(4-(trifluoromethyl)phenyl)sulfonyl derivative acting as potent and competitive EphA2 antagonist able to inhibit ephrin-A1 dependent signals and to reduce proliferation of glioblastoma (U251) cell line at micromolar concentration.
Discovery of a new 1-(phenylsulfonyl)-1H-indole derivative targeting the EphA2 receptor with antiproliferative activity on U251 glioblastoma cell line / Guidetti, Lorenzo; Castelli, Riccardo; Zappia, Alfonso; Ferrari, Francesca Romana; Giorgio, Carmine; Barocelli, Elisabetta; Pagliaro, Luca; Vento, Federica; Roti, Giovanni; Scalvini, Laura; Vacondio, Federica; Rivara, Silvia; Mor, Marco; Lodola, Alessio; Tognolini, Massimiliano. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 276:(2024). [10.1016/j.ejmech.2024.116681]
Discovery of a new 1-(phenylsulfonyl)-1H-indole derivative targeting the EphA2 receptor with antiproliferative activity on U251 glioblastoma cell line
Guidetti, Lorenzo;Castelli, Riccardo;Zappia, Alfonso;Ferrari, Francesca Romana;Giorgio, Carmine;Barocelli, Elisabetta;Pagliaro, Luca;Vento, Federica;Roti, Giovanni;Scalvini, Laura;Vacondio, Federica;Rivara, Silvia;Mor, Marco;Lodola, Alessio
;Tognolini, Massimiliano
2024-01-01
Abstract
In our continuing effort devoted at developing agents targeting the EphA2 receptor by means of protein-protein interaction (PPI) inhibitors, we report here the design and synthesis of a new class of L-β-homotryptophan conjugates of 3-β-hydroxy-Δ5-cholenic acid bearing a set of arylsulfonyl substituents at the indole nitrogen atom. An extensive structure-activity relationship (SAR) analysis indicates that the presence of a bulky lipophilic moiety at the indole nitrogen is fundamental for improving potency on the EphA2 receptor, while abrogating activity on the EphB1-EphB3 receptor subtypes. A rational exploration, guided by the combined application of an experimental design on σp and π physicochemical descriptors and docking simulations, led to the discovery of UniPR1454, a 1-(4-(trifluoromethyl)phenyl)sulfonyl derivative acting as potent and competitive EphA2 antagonist able to inhibit ephrin-A1 dependent signals and to reduce proliferation of glioblastoma (U251) cell line at micromolar concentration.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.