Design, Modification And Bioactivity Evaluation Of Thiazolyl-pyrazoline Derivatives Containing Benzodioxole

Cancer is a multifactor disease with superfluous and robust biological networks. In recent years, cancer is a deteriorating public health problem because its incidence has increased faster. Therefore, the study of novel anti-cancer compounds attracted more and more attention.Receptor tyrosine kinases (RTKs) and epidermal growth factor receptor (EGFR), activated by ligand-induced dimerization, play very important roles in regulating tumor cell proliferation, differentiation, survival and apoptosis. EGFR and HER-2 are the hottest targets in current cancer research and their over expression or abnormal activation often cause cell malignant transformation. Compounds that inhibit the kinase activity of EGFR and/or HER-2 after binding of its ATP binding site are of potential interest as new therapeutic antitumor agents. Gefitinib (Iressa) and erlotinib (Tarceva) (Fig.1) are the representative drugs for this kind of inhibitors and have been approved by US FDA for treatment of patients with non small-cell-lung cancer (NSCLC).The fact that many compounds containing pyrazole skeleton have broad spectrum biological activities, such as anti-tumor, anti-bacterial, anti-inflammatory and so on, makes them arouse wide attention in chemical, medicinal and pharmaceutical research. Thiazole and their derivatives also have attracted continuing interest over the years because of their varied biological activities, such as anti-tuberculosis, antibacterial and anti-tumor and so on. Especially in the combination with certain reactive groups, pyrazole and thiazole rings can exhibit enhanced biological activity, the specific structure of these groups include benzene ring, oxygen-containing heterocyclic or single-chain structure, such as an amide, sulfonylurea and so on.Herein, in continuation to extend our research on compounds with anti-tumor activity, we reported in the present work the synthesis and structure-activity relationships of a series of thiazolyl-pyrazole derivatives as potential EGFR and HER-2 inhibitor. According to the principle of structure-based design and molecular simulation techniques, a total of 20 new compounds were firstly designed, synthesized and tested their biological activity. The results were summarized below:We synthesized 20 oxygen-containing heterocyclic thiazolyl-pyrazoline derivatives (C1-C20) and measured their EGFR and HER-2 inhibitory activity. Firstly, the compounds were synthesized by a four-step chemical synthesis. Secondly, the structure identify of all compounds were also performed, including 1H NMR, ESI-MS and elemental analysis. Finally, biological activity of this series of compounds were measured, including MCF-7 and B16-F10 proliferation assay, Western blotting and HER-2 inhibition assay. Molecular modeling results show that the binding between amino acid residues of ATP binding site of HER-2 and the compounds C6 is the best (form two hydrogen bonds). Given the combination of molecular modeling and biological activity screening results, we found that compound C6 showed best HER-2 inhibition activity, with IC50 value of 0.18μM, which is equal to the positive control Erlotinib.