Design, Synthesis And Bioactivity Study Of Tyrosine Kinase Inhibitors Containing Saccharide Moieties And Purine Cyclo-compounds Containing Fragment Of Glucuronic Acid

This dissertation aims at finding small molecules with high anticancer activity, more active targeting and low toxicity with EGFR tyrosine kinase and DNA as the target respectively. Series of compounds with saccharide moieties were designed and synthesized. The structures of the synthesized compounds were all characterized and preliminary biological activities evaluations were well done. The content of this dissertation was divided into two parts which were as follows:1. Design, synthesis and biological activity evaluation of tyrosine kinase inhibitors containing saccharide moieties.In the past decade, research about small molecule inhibitors toward tyrosine kinase has been made considerable progress. More recently, researchers pay more attention to the modification of 4-(phenylamino)quinazoline. Finding new quinazoline derivatives with high anticancer activity and good water solubility are the aims of chemical researchers. Previous research demonstrated that glycosylation of lead compounds could improve the activities, low the toxicity, improve the water solubility and so on. Based on the important biological functions of saccharides, comprehensive investigation about the glycosylation of 4-(phenylamino)quinazoline were completed in this research. Ten series of quinazoline glycosides derivatives were designed and synthesized. The inhibition activities in vitro of the synthesized compounds were determined. Most compounds showed good inhibitory activity, of which compound C13 was found to show good inhibitory activity toward MDA-231 cell lines (87.1% inhibition rate at the concentration of 10μM). Compound C62 showed the highest activity toward EGFR in vitro with the IC₅₀ 0.14 nM and compound C43 was found to show the highest inhibitory activity toward A431 cell lines with the IC₅₀ 0.765μM. Six quinazoline glycoside derivatives in all showed satisfactory inhibition activity toward EGFR in vitro with the IC₅₀ < 1 nM and their preliminary activity evaluations were better than Gefitinib.Based on the good EGFR tyrosine kinase inhibitory activity of the symmetrical bis(phenylamino)isoindoline-1,3-dione, four series of symmetrical quinazoline glycoside dimmers were designed and synthesized. Preliminary bioactivity screening results demonstrated that most quinazoline glycoside dimmer showed moderate inhibitory activity, of which compound 149 showed better EGFR inhibitory activity than Gefitinib at the concentration of 10μM and 1μM.Based on the important bioactivity of benzoxazinone compounds and the structure simililarities with quinazoline ring, series of novel benzoxazinone compounds were designed and synthesized using the strategy of bioisosterism. Preliminary activity evaluation demonstrated that all target compounds showed moderate inhibitory activity toward EGFR in vitro. The glycoside derivatives showed better activities than other series of compounds. The inhibition rate of compound 234 was 55% at the cocentration of 10μM.Using the strategy of computer aided drug design, molecular docking between the selective target compounds and the EGFR binding pocket were completed. The results showed that the hydroxys of glycoside ring could form hydrogen bonds with EGFR which could strengthen the interaction between the molecule and EGFR binding pocket. Other series of novel compounds could also form hydrogen bonds with EGFR binding pocket in a different way.2. Design, synthesis and DNA interaction study of novel cyclo-compound containing saccharide moieties and purines.Researchers are focusing on the discovery of non-covalent interaction anticancer drugs considering the serious toxicity of covalent interaction drugs targeting DNA. Finding small molecules with good DNA intercalating activities are the mainstream of drug development. After searching of the literature in this field, we found that research about DNA intercalators mainly contained the modification of original molecules and optimization the natural products. Design and synthesize novel cyclo-compounds by changing the aromatic rings and selecting the flexible side chain with variable conformations have important meaning in the field of finding DNA intercalators. In this research, purine ring which have some similarities with DNA base pairs was selected as the aromatic ring and glucuronic acid fragment was used as the skeleton of side chain. In the end, three different sizes of cylo-compounds were synthesized using ethanediamine or 1,3-propanediamine as the connecting bridge. The structures of the synthesized compounds were all characterized by 1^H NMR, (13)^C NMR and HRMS (ESI). The interactions between the target cyclo-compounds and calf thymus CT-DNA were also investigated using fluorescence spectroscopy and EB competitive displacement analysis. Preliminary results showed that the target cylo-compounds could interact with CT-DNA.The research in this dissertation not only enriched the content of medicinal chemistry but also supply valuable ideas for the design and synthesis of anticancer drug candidates with high anticancer activity, more active targeting, low toxicity, better physical and chemical properties.