Design And Synthesis Of Amido Derivatives Derived From C-3 Position Of Oleanolic Acid

Cancer has become the major threat to human health today.According to studies and scientific experiments that have been mastered,the growth and proliferation of cancer cells depend on specific growth factors and signaling pathways.Inhibition of such growth factors or targeted regulation of specific signaling pathways can effectively prevent angiogenesis of tumor cells.Proliferates and promotes apoptosis.Drug-specific actions on specific targets have become the main measures for the treatment of cancer.The Ras/Raf/MEK/ERK signaling cascade is a mitogen-activated protein kinase(MAPK)pathway in which MEK subcellular proteins act as extracellular regulatory protein kinases of ERK(extracellular regulated protein kinases)cells.The upstream kinases have been shown to be closely related to the occurrence and progression of many malignant cancers.For example,malignant melanoma,advanced differentiated thyroid cancer,and advanced renal cancer are all related to this pathway.Among the currently available drugs,anticancer drugs such as seletinib,sorafenib,and trimetinib are MEK inhibitors in this signaling pathway.MEK has become a popular target for many cancer treatments.Oleanolic acid(abbreviation OA)is a pentacyclic triterpene compound that is abundant in natural plants.OA has a wide range of biological activities,such as anti-tumor,anti-bacterial,anti-inflammatory,anti-HIV,control platelet aggregation,hypoglycemic and liver protection liver and other effects.Oleanolic acid has low toxic and side effects and rarely produces malignant adverse reactions.Therefore,it is considered to be a lead compound drug with extremely potential for development.The marketed drug sorafenib is a mitogen-activated extracellular signal-regulated kinase 1/2 reversible inhibitor,which mainly inhibits MEK subcellular proteins in the signaling pathway through ERK,thereby affecting the MAPK pathway and inhibiting cancer Cell proliferation is mainly used to treat hepatocellular carcinoma that cannot undergo surgery or distant metastasis.Using computer-assisted docking simulation testing of drug molecules,it was confirmed that sorafenib can have stronger and more stable binding force with MEK target,and has better targeting ability.The amide moiety in the structure is hydrogen-bonded to amino acid residues in the MEK target,suggesting that the drug and the MEK target protein can produce a strong binding force.Based on this,it has been speculated that amide groups are important pharmacophores that Sorafenib exerts a targeted antitumor activity on MEK.OA itself has a certain activity of inhibiting angiogenesis of tumor cells and has a certain anti-cancer activity.Our group used computer-aided simulation screening technology to further transform the OA structure and introduce amide fragments to increase the specific binding of MEK targets,thereby enhancing anti-tumor activity.The selected small molecule inhibitors were synthesized and optimized,and preliminary anti-tumor activity screening was performed.In this paper,OA was used as the lead compound.Eight products containing amide fragments were synthesized through esterification,oxidation,addition,reduction,and condensation reactions.TLC was used to detect the end point of the reaction and the product was separated by column chromatography.Means were processed and the target product structure was confirmed by 1H-NMR and 13 C NMR.In this study,the pharmacological evaluation of in vitro cytotoxicity of oleanolic acid derivatives using human lung cancer cells(A549),human gastric cancer cells(SGC7901)and human hepatocellular carcinoma cells(BEL7402)was performed using MTT assay.Sorafenib was positive.Controls.The results showed that the IC50 values of the tested compounds were significantly better than that of maternal OA and had better antitumor activity.It proved the rationality of the design idea.In this study,novel small molecule MEK inhibitors of oleanolic acid with novel structure and outstanding biological activity were obtained,which provided new ideas and new methods for molecular targeted therapy of tumors,and developed a new generation of small molecule inhibitors and anticancer drugs.