Design, Synthesis, Biological Evaluation And SAR Studies Of Sorafenib Derivatives As Potential Antitumor Agents

Recent years, based on the achievement of chemical biology and bioinformatics the rational design of multitarget drugs is being the research direction ofanticancer drugs. Sorafenib, the first oral multikinase inhibitor, can inhibit several kinases involved in tumor proliferation and angiogenesis including Raf, VEGFR, PDGFR, KIT and so on. Due to the advantages of multi-mechanisms, broad-spectrum anticancer potency, and well-tolerated results in combination trials, more and more researchers have focused on the optimization of sorafenib in order to develop novel multi-targeted anticancer drugs.Based on the international current research works, by studying the active sites of sorafenib and using the strategies of rational drug design, we designed and synthesized four series of109targeted sorafenib derivatives, and tested their inhibitory activity against kinase EGFR and ABL1. In vitro anti-phosphorylation of VEGFR and anti-angiogenesis assay of some compounds was also investigated preliminarily. All compounds were evaluated by MTT assay for their in vitro cell cytotoxicity.In this dissertation, based on the strategies of rational drug design, four series of109new diaryl thiourea containing ω-carboxy group sorafenib derivatives, which have not been reported in the literature, were designed and synthesized, and all the structures were identified by ESI-MS, HRMS,1H NMR and13C NMR. The compounds B9n and C9b were characterized by single-crystal X-ray diffraction. The antiproliferative activities of109compounds against human colorectal carcinoma cell line (HCT116), human breast cancer cell line (MDA-MB-231), human prostate cell (PC-3), non-small cell lung cancer (A549), human hepatocellular liver carcinoma cell line(HepG2) and murine melanoma (B16BL6) were evaluated. All compounds exhibited potent antiproliferative activity against HCT116and PC-3cells; some compounds (A9o, A9p, B9p, B9q, B9r, B9s, B9x, B9aa, C9f, C9g, C9r, C9s, D9k, D9o, D9p, D9q, D9r and D9ac) demonstrated competitive antiproliferative activities to sorafenib. The size and shape of the substitutes on the terminal amide may affect the activity and selectivity of these derivatives against cancer cells:In the series A, B and C, the larger substitutes might cause a decrease in cytotoxicity in general, while in D series, the large group may improve the cytotoxicity of the compounds. The effect of the substitutes on the terminal phenyl ring is important to the activity of the compounds, and in the four series:electron-withdrawing groups (such as-CF3) can enhance the cytotoxicity of compounds, while the electron-donating group may reduce the cytotoxicity of compounds.Enzyme test shows that all the target compounds have no inhibitory activity against EGFR, while some compounds can inhibit tyrosine kinase ABL1. Anti-angiogenesis activity was investigated from two aspects:a. the inhibitory activities of some compounds against the phosphorylation of VEGFR were evaluated by western blot; b. the anti-angiogenesis activity of some compounds was investigated by aorta ring assay. Western blot assay showed that compounds A9m, A9o, and A9p could inhibit the phosphorylation of VEGFR-2significantly. All these compounds have the methyl substitute on the terminal amide, and their substitutes in phenyl ring are3-CF3. The results of aorta ring assay showed that compounds D9g and D9p can significantly inhibit blood vessel formation at the concentration of0.1μM; D9r can partly block the formation of blood vessel; while the inhibitory ability of D9q is unconspicuous.Finally, the SAR study of some representative compounds was also investigated by molecular docking:scoring the docking of compounds with B-Raf and VEGFR-2; sketching the figure of interaction mode, and studying the force and connection of compounds with kinases.In summary, we designed and synthesized109new diaryl thiourea sorafenib derivatives in this dissertation. By preliminary bioactivity assay, we found several potential compounds such as compounds B9q、B9r、B9s、B9x、C9r、C9s、D9p、 D9q、D9r�'�D9ac, which need to be further developed in the future. The binding models of these compounds with B-Raf and VEGFR-2were also studied by SYBYL, which would be beneficial for further design and development of novel sorafenib derivatives.