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Atropisomerism and Conformational Equilibria: Impact on PI3Kδ Inhibition of 2‑((6-Amino‑9H‑purin-9-yl)methyl)-5-methyl-3‑(o‑tolyl)quinazolin-4(3H)‑one (IC87114) and Its Conformationally Restricted Analogs

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posted on 10.05.2017, 00:00 by Alessio Lodola, Serena Bertolini, Matteo Biagetti, Silvia Capacchi, Fabrizio Facchinetti, Paola Maria Gallo, Alice Pappani, Marco Mor, Daniele Pala, Silvia Rivara, Filippo Visentini, Mauro Corsi, Anna Maria Capelli
IC87114 [compound 1, (2-((6-amino-9H-purin-9-yl)­methyl)-5-methyl-3-(o-tolyl)­quinazolin-4­(3H)-one)] is a potent PI3K inhibitor selective for the δ isoform. As predicted by molecular modeling calculations, rotation around the bond connecting the quinazolin-4­(3H)-one nucleus to the o-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e., atropisomers). After verifying that the aS and aR isomers of compound 1 do not interconvert in solution, we investigated how biological activity is influenced by axial chirality and conformational equilibrium. The aS and aR atropisomers of 1 were equally active in the PI3Kδ assay. Conversely, the introduction of a methyl group at the methylene hinge connecting the 6-amino-9H-purin-9-yl pendant to the quinazolin-4­(3H)-one nucleus of both aS and aR isomers of 1 had a critical effect on the inhibitory activity, indicating that modulation of the conformational space accessible for the two bonds departing from the central methylene considerably affects the binding of compound 1 analogues to PI3Kδ enzyme.

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