Synthesis And Preliminary Antitumor Activity Of Oleanolic Acid Derivatives

Oleanolic acid(Oleanolic acid,OA)is a typical five-ring triterpenoids,mainly in the form of free or glycosides in Prunella vulgaris,olive oil,green leaf gall and Ligustrum lucidum and other plants.OA has resistance to Bioactivities such as tumor,anti-HIV,lowering blood sugar and lipid,protecting liver,anti-inflammatory and anti-hypertension.Recent studies have shown that the active sites of OA are mainly concentrated in the A ring,C-2,C-3 hydroxyl and C-28 carboxyl groups.Drugs of vascular endothelial growth factor(VEGF)and its receptor VEGFR can reduce the expression of vascular endothelial growth factor,and inhibit tumor angiogenesis and tumor growth by inhibiting the expression of tumor cell vascular endothelial growth factor.Therefore,the design and development of small molecule inhibitors targeting VEGFR receptors is of great significance.In this paper,computer-assisted drug design is adopted.Through the simulated docking of VEGFR receptors with known active small molecules,the key amino acid residues and the active groups that interact with the target protein are screene d out,and the active groups are combined into the OA.Designed more than 40 ta rget compounds,evaluated the screening results and according to the five principles of drug-like drugs,finally synthesized a total of 12 three types of oleanolic acid a nalogs,They are oleanano[3,2-c]pyrazole-12-ene-28-amide compounds,3-benzoylhydr azino-oleanolane-12-ene-28-amide compounds And oleanano[3,2-c]isoxazole-12-ene-28-amide compounds,whose structure was confirmed by ¹H-NMR spectrum analysis.Using MTT method,Gefitinib and Adriamycin were used as positive control drugs,and human liver cancer cell line(Hep G2)and human breast cancer cell line(MCF-7)were used for preliminary in vitro anti-target compounds.The results of tumor activity determination showed that the obtained compounds have strong inhibitory effects on two kinds of cancer cells.Among them,compounds I₃,II₂and III₄are particularly prominent,with IC₅₀values of 5.06?mol·L^-1and 5.12?mol·L^-1for liver cancer cells,respectively.And 5.56?mol·L^-1,the IC₅₀values for breast cancer are 5.18?mol·L^-1,5.35?mol·L^-1and6.32?mol·L^-1,which are significantly higher than the maternal OA and stronger than the marketed drug Gefitinib.Prove the rationality of the design ideas.This article provides a certain reference for the subsequent structural modification of pentacyclic triterpenoids,especially oleanolic acid.