Synthesis,Cytotoxic Activities And Structure-activity Relationships Of Gypsogenin Derivatives Against Human Cancer Cells

?Objective?Gypsogenin,a natural pentacyclic triterpenoid,have been found widespread in the root of Gypsophila oldhamiana Miq..Moreover,gypsogenin have various biological activities such as antiviral,antitumor and a potent AChE-selective inhibitor.The gypsogenin?1?was obtained by the hydrolysis of the gypsogenin saponin mixtures.In this study,a number of gypsogenin derivatives were synthesized by transforming three functionalities.The anti-cancer activities of the synthesized compounds were studied by an MTT assay using four human cancer cell lines in cell culture.?Methods?The gypsogenin was isolated and purified by silica gel column chromatography,alumina,Sephadex LH-20 column chromatography,ODS column chromatography and preparative HPLC chromatography and recrystallization methods.Gypsogenin derivatives were synthesized by a series of reactions in this study.Their structures were established using IR,¹H NMR,¹³C NMR,and LC-MS spectroscopic data.The synthesized compounds have been screened against four human cancer cell lines,including A549,LOVO,SKOV3 and HepG2,using MTT assay.Moreover,the effect of better active compounds on the cell cycle and apoptosis was further investigated.?Results?Thirty-two gypsogenin derivatives were synthesized in good yield.These compounds were found to be promising lead compounds against the majority of the studied cancer cell lines,exhibiting IC₅₀0 values much lower than that of the parent compound.Among all of these compounds,compounds 4?3?-Hydroxy-23-[?2,4-dinitrophenyl?hydrazono]olean-12-en-28-oic acid?and 7g?N,N-?n-Dibutyl?-?3??-acetyloxy-23-oxoolean-12-en-28-amide?could be considered as possible anti-cancer agents as they were shown to affect the cell cycle,causing cell cycle arrest.In addition,compounds 4 and 7g triggered the apoptotic pathway in cancer cells,showing strong activity in promoting apoptosis.?Conclusions?The structure-activity relationship studies revealed that the introduction of an amide in the 28 position and an acetyl in the 3 position of the target compounds enhanced the anti-cancer activity.Thirty-two gypsogenin derivatives have various biological activities such as anti proliferation,triggered the apoptotic mechanism and arrested cell cycle in S phase.