Design, Synthesis And Anti-tumor Activity Of Oleanolic Acid Derivatives Based On PI3K Protein Targe

Oleanolic acid（OA）is a pentacyclic triterpene compound,which exists in a variety of animals,plants and microorganisms.It has pharmacological effects such as anti-cancer,liver protection,diuresis and immune regulation.The existing literature shows that OA and its derivatives can inhibit the growth,proliferation and differentiation of various tumor cells to a certain extent,and have a good application prospect in cancer treatment.PI3K signaling pathway is one of the important conduction pathways in vivo,which can regulate a variety of physiological processes.The activation of PI3K pathway is related to cell mitosis,survival,differentiation,migration,invasion and actin cytoskeleton reorganization.Mutation or abnormal activation of PI3K pathway will lead to the occurrence of some tumors.Therefore,by regulating PI3K signaling pathway,it can effectively inhibit the growth and reproduction of tumor cells.The development of PI3K inhibitor antitumor drugs is of great significance.Previous studies have proved that oleanolic acid can promote tumor cell apoptosis and reduce tumor cell proliferation by inhibiting PI3K Signaling pathway.Taking oleanolic acid as the lead compound,20 structural modifications of oleanolic acid were designed and synthesized by using the principle of drug assembly and computer-aided drug design.The I series esterified the C-28 carboxyl benzyl of oleanolic acid,introduced urea group at position C-3 to obtain I_1-10.II series compounds esterified the C-28 carboxyl benzyl of oleanolic acid,introduced aminothiazole group on the A ring,then reacted with different isocyanates with amino group as the connecting arm,and introduced urea group to obtain the target compound II_1-10.The structures were confirmed by ¹H-NMR and ESI-MS（some used HRESIMS）.The cytotoxic activities of K562,MCF-7 and A549 cells were screened by MTT assay.The results showed that the inhibitory activity of oleanolic acid derivatives on three kinds of tumor cells was significantly improved.Among them,compounds I₂(IC₅₀=21.45μM for MCF-7 cells),Ⅱ₂(IC₅₀=13.56μM for MCF-7 cells),Ⅱ₅(IC₅₀=17.49μM for MCF-7 cells,IC₅₀=15.42μM for K562 cells)andⅡ₁₀(IC₅₀=13.56μM for MCF-7 cells)had better antitumor activities.The results showed thatⅡ₂ andⅡ₅ had strong PI3K inhibitory activity,which deserve further study.In this paper,computer molecular docking technology was used to simulate the molecular docking of gedatolisib and PI3K target protein（PBD Code:5JHB）.The results showed that the urea group in gedatolisib structure formed hydrogen bonds with key amino acid residues Asp964,Tyr867 and Asp841.The molecular docking simulation of the designed target compound and PI3K showed that compoundsⅡ₂ andⅡ₅ had strong binding force with PI3K target protein.The analysis showed that the urea group in the target compound can also form hydrogen bonds with the three same key amino acids Asp964,Tyr867 and Asp841 of the target protein,indicating that the urea group may be an important pharmacophore for the interaction between the compound and PI3K target.The paper lays a foundation for the development of oleanolic acid derivative PI3K inhibitors.