Anion-triggered substituent-dependent conformational switching of salicylanilides. New hints for understanding the inhibitory mechanism of salicylanilides.
A series of salicylanilides (1a-h) bearing varied substituents at the 3'- or 4'-position of the anilino moiety (substituent = p-OCH3, p-CH3, m-CH3, H, p-Cl, m-Cl, p-CO2CH3, and p-CN) were synthesized. In acetonitrile all of the substituted salicylanilides 1a-h predominantly adopt the "closed-ring" conformation facilitated by a strong intramolecular OH...O=C hydrogen bond. In the presence of H2PO4-, the conformation of 1a-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 1a-f bearing a not highly electron-withdrawing substituent was switched to the "open-ring" form by H2PO4-, whereas 1h 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.
Guo
Lin
L
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
Wang
Qiang-Li
QL
Jiang
Qian-Qian
QQ
Jiang
Qiu-Ju
QJ
Jiang
Yun-Bao
YB
D000097:Acetonitriles / Q000737:chemistry; D000838:Anions / Q000737:chemistry; D001667:Binding, Competitive / Q000187:drug effects; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008968:Molecular Conformation; D015394:Molecular Structure; D010756:Phosphoric Acids / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012458:Salicylanilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000097:Acetonitriles; D000838:Anions; D010756:Phosphoric Acids; D047428:Protein Kinase Inhibitors; D012458:Salicylanilides; C030242:phosphoric acid