The Synthesis And Antitumor Activity Of Oleanolic Acid A Ring Combined With Heterocyclic Ring Derivatives

Survivin is a novel anti-apoptotic protein factor of the Inhibitor of Apoptosis Proteins（IAP）.Survivin protein is overexpressed in a variety of tumor tissues.The overexpression of Survivin protein is associated with tumorigenesis,development and induction of anti-cancer drug resistance.However,Survivin protein is almost not expressed in normal terminal differentiated adult tissues and has become a multi-cancer therapy Important target.Therefore,the development of its small molecule inhibitors is of great significance.The antitumor mechanism of pentacyclic triterpenoids has been extensively stu died.Oleanolic acid（OA）is a pentacyclic triterpene which exists in various plants as free radicals and glycosides.It has a wide range of biological activities such a s hepatoprotection,lipid-lowering,antitumor,anti-hypertensive,Anti-inflammatory,an ti-HIV infection.In recent years,the study found that the main active site of OA i n its A ring,C-3 and C-28 position.However,due to its poor water solubility,lo w bioavailability,activity is not high,thus limiting its clinical application.In this paper,oleanolic acid as the raw material.fourteen compounds were desi gned and synthesized.The hydroxyl group of the oleanolic acid C-3 hydroxyl grou p is first oxidized and itsαposition is introduced into the aldehyde group to give the 2-hydroxymethylidene-3-oxo-oleanolic-12-en-28-acid,Hydrazine hydrate（or hydr ochloric acid hydroxyl）reaction,in the A ring parallel pyrazole ring（or isoxazole ring）,followed by oleanolic acid C-28 bit fat,and 14 compounds I₁^I₇ and II₁^II₇were obtained.The reaction was monitored by TLC at the end of the reaction.Th e crude product was separated by column chromatography and purified.The eluent was petroleum ether and ethyl acetate.The melting point of the compound was d etermined by means of a melting point instrument.None of the synthesized compo unds was reported and the structure of the compound was passed MS,1H-NMR sp ectral analysis confirmed.In this paper,the cytotoxic activity of the compounds was determined by MTT assay.The tumor cells were selected from human non-small cell lung cancer cell line（A549）and human gastric cancer cell line（SGC7901）,gefitinib and etoposide（PV-16）as positive controls.The results showed that compounds I₆、I₇ and II₇ showed good inhibitory effect on SGC7901 and A549 cells.The inhibitory rates of I₆、I₇ and II₇ on SGC7901 cells were59.7%、62.11%and 57.8%,respectively.The IC50 values were8.1μmol、6.6μmol and10.4μmol,respectively.The inhibitory rates of A549 cells were 51.9%、58.3%,and 59.1%respectively.The IC₅₀0 values were 12.5μmol、8.7μmol and 16.7μmol respectively.The antitumor activity of I₆,I₇ and II₇ is comparable to that of gefitinib and VP-16.It indicates that the anti-tumor activity of the compounds increases with the extension of the carbon chain,and the anti-tumor activity of the pyrazoles is better than that of the isoxazole compounds.That is,branched-chain compounds have better anti-tumor activity.This article provides the basis for the further study of the structural modification of oleanolic acids and pentacyclic triterpenoids.