Anion-Triggered Substituent-Dependent Conformational Switching of Salicylanilides. New Hints for Understanding the Inhibitory Mechanism of Salicylanilides

摘要

A series of salicylanilides (la—h) bearing varied substituents at the 3'- or 4'-position of the anilino moiety (substituent = p-OCH_3, p-CH_3, m-CH_3, H, p-Cl, m-Cl, p-CO_2CH_3, and p-CN) were synthesized. In acetonitrile all of the substituted salicylanilides la—h predominantly adopt the "closed-ring" conformation facilitated by a strong intramolecular OH…O=C hydrogen bond. In the presence of H_2PO_4, the conformation of la—h was found to be modulated by the substituent. With our proposed proton-transfer fluorescence probing method, we were able to show that the conformation of la—f bearing a not highly electron-withdrawing substituent was switched to the "open-ring" form by H_2PO_4~-, whereas lh bearing a highly electron-withdrawing substituent, p-CN, remained in the "closed-ring" conformation. The significance of these findings for understanding, from a molecular structural point of view, the mechanism of salicylanilide-based inhibitors for inhibiting the protein tyrosine kinase epidermal growth factor receptor was discussed.