Design, Synthesis And Antitumor Activity Of 2-aminothiazoles With VEGFR/PI3K As A Dual Target

Cancer is a serious disease threating to human health, its incidence has increased year after year and it was estimated that nearly 15 million new cases become by 2020all over the world. With the development of biological science and technology and the deeper understanding of the biological characteristics of the tumor, some key enzymes involved in tumor cell differentiation and proliferation can be used as the targets of drug and the protein tyrisine kinases (PTKS) are just good target. PTKS are key proteins which play important roles in cellular singnaling pathways. Overexpression of PTKS can activate it’s downstream signaling and lead to cell transformation,proliferation, antiapoptosis and promotion of cell survival, eventually the tumor cell occurrence. Tyrosine kinase has become one of the main targets for antitumor drug and by blocking the PTKS can destroy signaling pathways of tumor cells, to achieve the purpose of the antitumor. Finding selective new anticancer drugs with high efficiency, low toxicity, high specific for these specific target has become the main direction of drug research.VEGFR as one kind of PTKS combind with VEGF to stimulate endothelial cell proliferation, migration, promoting and had a close relationship with the incidence of many common tumors and tumor metastasis. Five VEGFR antineoplastic drugs already on the market: Sorafeinib, Sunitinib, Pazopanib, Vandetanib and Axitinib.PI3K is a kind of phosphatidylinositol kinase, can regulate cell division,differentiation, and apoptosis. So far, none drugs for PI3K kinase are approved by FDA. Reported in the literature that "inhibiting PI3K might restore the sensitivity of tumor cells to anti-angiogenic treatment and improve its efficacy". So, in this paper,we virtually screened the Chemspider and MDDR database aiming at searching VEGFR and PI3K dual-inhibitors using SVM (Support Vector Machine) as screening model and the 51 hits were get and further evaluated by "Lipinski’s rule of 5”,molecular docking and the synthesis accessibility. Eventually found one hit compound 1 containing imidazo[2,1 -b]thiazole core with potential anticancer activity and designed and synthesized 16 novel imidazo[2,1-b]thiazol acetamides derivatives.Follow-up of this compound, we designed and synthesized 38 novel 2-amino thiazole acetamides derivatives.To assess the antitumor activities of the synthesized compounds, expriments with"MTT assay" was performed in vitro in human HepG-2(Human Liver Cancer) andMDA-MB-231 (Human Breast Cancer) cancer cell lines. The results demonstrated that these compounds could inhibit the two cell lines. To investigate the potential of these compounds, compounds 1, 12, 31, 46, 48 and 49 were selected for VEGFR and PI3K kinase inhibition. The results showed that these series of compounds could inhibit these two kinase.So far, there were no VEGFR and PI3K dual-inhibitors reported. Compound 1 as the lead compound, is expected to design a more innovative structure, active, more selective of VEGFR and PI3K dual inhibitors, and we hope to provide a reference for follow-up study.