Design, Synthesis And Bioactivity Of STAT3 And FABP4 Small Molecule Inhibitors

The first part of this thesis is the design, synthesis and biological activity of STAT3small molecule inhibitors.The signal transducer and activator of transcription3(STAT3) is a kind of important signal transduction protein in cells. Since this protein is closely related with the occurrence and development of the tumors, inhibiting its over-expression can be used to fight against tumors. Recently, Many Studies concerning STAT3inhibitors and their anti-tumor activity has been reported, some of these compounds have entered clinical research, which has brought new opportunities for the study of new anticancer drugs.We used computer-aided high-throughout screening technology to screening STAT3pathway small molecule inhibitors with DOCK4and Glide from Specs library. Luciferase report was used to test compounds on STAT3signaling pathway inhibition and three hits were found (32,17, and55). These three compounds have2.4-4fold selectivity over STAT1and NF-κB. Next, a similarity search was performed to find analogs of55and32. We summarized the preliminary structure-activity relationship within the32analogs and investigated the mechanism of action with western blot experiments. Besides, we got compound55-2with better activity.Compound55was chosen as the lead compound and we conducted the structure optimization. A total of57new target compounds in four series were designed and synthesized through rational drug design. After4rounds of structural optimization, the compound inhibitory activity was greatly increased, the most active compound5e inhibited STAT3signaling pathway with an ICso of1.6μM.The second part of this thesis is the design, synthesis and biological activity of FABP4small molecule inhibitors.Fatty acid binding protein4(FABP4) can modulate inflammatory and metabolic response, and it is expressed in adipocytes and macrophage. The inhibitors can improve insulin sensitivity and resistance to the development of atherosclerosis, and is a potential target for the treatment of type2diabetes. Up to now a series of potent small molecule inhibitors of FABP4which are potential to prevent and treat metabolic diseases such as atherosclerosis and type2diabetes have been identified and found. Based on the previous work of our group, we employed the principle of bioisostere and rational drug design with the help of computer docking simulations to design the first series of8compounds. Subsequently, we used the scaffold hopping principle to design and synthesis of the second series of9compounds in order to reduce the loss of entropy when the compound binds to the receptor.We carried out the biological evalutions of the compounds. The results indicated that the substitution with naphthalene ring significantly increased the activity and the methoxy at4’ position possessed the best activity. In series2, substituted benzoic acid could improve the activity of the compound, which is consistent with our expectations. In addition, we co-crystallized the active compound5with FABP4protein. The results showed that the mode of action is similar to fatty acid. It formed of a number of van der Waals interactions and hydrogen bonding interactions with the receptor, which directly proved the reasonableness of the design of this project.