Synthesis and antiproliferative activities against Hep-G2 of salicylanide derivatives: potent inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase.

A series of salicylanilide derivatives (compounds 1-- 32) were synthesised by reacting substituted salicylic acids and anilines. The chemical structures of these compounds were determined by ¹H-NMR, electrospray ionisation mass spectrometry (ESI-MS) and elemental analysis. The compounds were assayed for their antiproliferative activities against the Hep-G2 cell line by the 3-(4,5-dimethylthylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Among the compounds tested, 22 and 28 showed the most favouable antiproliferative activities with 50% inhibitory concentration (IC₅₀) values of 1.7 and 1.3 μμM, respectively, which were comparable to the positive control of 5-fluorouracil (IC₅₀ == 1.8 μμM). A solid-phase ELISA assay was also performed to evaluate the ability of compounds 1-- 32 to inhibit the autophosphorylation of the epidermal growth factor receptor tyrosine kinase (EGFR TK). Docking simulations of 22 and 28 were carried out to illustrate the binding mode of the molecule into the EGFR active site, and the result suggested that both compounds 22 and 28 could bind the EGFR kinase well. [ABSTRACT FROM AUTHOR]