Designed,Synthesized And Antitumor Activity Studied Of The Multi-Targrted Salicylanitide Derivaties

With the continuous improvement of science and technology, medical researchers acquire a deep understanding of the pathogenesis of malignant neoplasma. The development of anti-tumor drug has from cytotoxic drugs to targeted therapy drug. The advantages of the drugs used for cancer target therapy are worthy of further research. However, the pathogenesis of multiple target diseases is a complex project. The single-targeted drug is not effective for the treatment of these diseases, but also a cause of tumor resistance. Looking for more effective multitarget anticancer drug is an effective method for cancer therapy, but also an important way to solve the single target drug resistance.Based on the background, 12 novel salicylanilide ether derivatives and 5 salicylanilide ester derivatives were synthesized. Their anti-proliferative activities were also evaluated by MTT. Some magnificent biological results have been obtained and the compound 23 b has been showed most effective both against A549 and A431, the IC50 of them are 0.42±0.43 μM and 0.57±0.43 μM, respectively, while the IC50 of gefitinib were 4.28±3.93 μM and 15.56±3.93 μM. Compounds 29 b and 29 e displayed the potent inhibitory activity comparable to the positive control gefitinib for Heb-3 cell. The date demonstrated that ether derivatives showed good activity with anti-proliferative activity. The enzyme inhibitory activity against EGFR of ether derivatives were carried out, which had almost the same trend as the anti-proliferation activities. The excellent anti-proliferation activity of compounds 23 a and 23 b proved the positive impact of the 3-Cl, 4-F aniline moieties.The representative compounds 23 a and 23 b are influenced the STAT3 expression in the immunofluorescence test, and we also evaluated the effect of the representative compounds 23 a and 23 b on JAK2/Stat3 signaling pathway by Western blot. The immunofluorescence test showed that compound 23 a and 23 b could through inhibition of the expression of STAT-3 protein in the tumor cell, and this may play some roles in the anti-tumor. Western-blot test showed that compound 23 b significant inhibition of STAT3 protein phosphorylation and JAK2 phosphorylation, with time proportional. Compound 23 a showed significant inhibition to STAT3 protein phosphorylation, but no inhibitory activity to JAK2 phosphorylation.The date showed that the compound 23 b exert double antitumor effects on anti-EGRF and JAK2/ Stat3.