Synthesis And In Vitro Antiproliferative Evaluation Of Some Steroidal Lactone Compounds And Some Ring B Abeo-sterols

Steroids represent an important type of natural products.With the deepening of the research on steroid chemistry,the applications of steroidal drugs were expanded continually in the medical field.The introduction of heteroatom or replacement of one or more carbon atoms in steroidal molecule by a heteroatom may affect the chemical properties of the steroidal molecule and often results in alterations of its biological activities.In order to evaluate the anti-tumor activity of new steroidal derivatives,two new types of steroidal compounds,including steroidal lactone compounds and ring B abeo-sterols with novel skeleton of[6-5-6-5]-fused rings,were designed and synthesized.Some different functional groups,such as hydroxyl,hydroximino and hydrazone,were introduced into the 3-position or 6-positon of the steroid nuclei,or side chain of the steroid molecule,respectively.The antiproliferative activities of these synthesized compounds against HeLa(human cervical carcinoma),SMMC 7404(human liver carcinoma)and MGC 7901(human gastric carcinoma)cells were investigated.Firstly,using cholesterol as starting material,two B-ring lactone isomers with 7-ox a and 6-oxa structures were synthesized by oxidation,reduction,Baeyer-Villiger reaction and condensation reaction.Then 3 steroidal lactones containing nitrogen were prepared by the functional group transformation of the isomers.On the other side,some abeo-sterols compounds with[6-5-6-5]-fused rings were obtained by using cholesterol,?-sitosterol,dehydro is oandrosterone or pregnenolone as starting materials via acetylation,ozonolysis and aldol condensation reactions.Afterward,by various chemical reactions and functional group transformation methods,hydroxyl,hydroxyimino,or thiosemicarbazone groups were introduced into different positions of the steroid nuclei or the side chain.Finally,54 steroidal compounds with[6-5-5-5]-fused rings were prepared and 52 of them were reported firstly.The structures of these products were characterized by IR,1H NMR,13C NMR and Mass Spectra.The in vitro anti-tumor activities of these synthesized compounds were assayed against HeLa(human cervical carcinoma),SMMC 7404(human liver carcinoma)and MGC 7901(human gastric carcinoma)cell lines by MTT method.The results indicated that the B-homo-cholestane lactone compounds with a hydroxyl or a thiosemicarbazone at the C-3 position of steroidal nucleus displayed a distinct antiproliferative activity.For example,the compound 8 had a similar cytotoxicity to cisplatin's against MGC 7901,SMMC 7404 and HeLa cells.The corresponding IC50 values of compound 8 were 10.0?M,8.9?M,7.0?M,respectively.Meanwhile,the antiproliferative activities of B-abeo-sterols with[6-5-6-5]-fused ring were investigated.The results revealed that some compounds,such as 21?27?53?55?73 and 75,showed obvious cytotoxicities when a cholesterol-type side chain,a hydroximino or a thiosemicarbazone at the C-6 position of steroidal nucleus was existed.Nevertheless,the cytotoxicity of compound was decreased significantly when the side chain was substituted by polar groups.In particularly,the compounds,which have a cholesterol-type or a sitosterol-type side chain,and a hydroxyimino or a thiosemicarbazone group at 6-position of steroidal nucleus,have similar cytotoxic capability as cisplatin does.Based on the research of structure-activity relationship,we can conclude that:1.The antiproliferative activities is obvious for the B-homo-cholestane lactone derivatives with 3-hydroxyl or 3-thiosemicarbazone group.Compared with its precursor,the cytotoxicity of 3-hydroxyimino-B-homo-cholestane decreased significantly.On the contrary,the cytotoxicity of the 3-thiosemicarbazone-B-homo-cholestane increased dramatically compared with its precursor.2.The antiproliferative activities of 3,5-dihydroxyl steroid compounds possing[6-5-6-5]-fused ring were evaluated by using MTT method.The results showed that:(1)The inhibitory activity is the best while the side chain is alky group.(2)The inhibitory activities of compounds decreased while the side chain is polar groups.However,the inhibitory activities of the compound increased when the 3-hydroxyl was esterified.(3)When the compounds have different polar group in the side chain,the hydroxyl group,hydroxyimino group or thiosemicarbazone group was better than other groups for the antiproliferative activities.In conclusion,we have synthesized a series of novel nitrogen-contained steroidal lactone compounds and steroidal compounds with[6-5-6-5]-fused ring the antiproliferative activity of these compounds against HeLa,SMMC 7404 and MGC 7901 cells was investigated.The results showed that cholesterol lactone compounds with 3-hydroxy or 3-thiosemicarbazone could exhibit a distinct cytotoxicity to tumor cell line tested.Among the steroids with[6-5-6-5]-fused ring,the compounds with alkyl side chain had super antiproliferative activities.The ICso values of these compounds were all around 10?M.Our findings could provide new evidences showing the relationship between the chemical structure and biological activity,which could be helpful in designing more potent anti-cancer agents for therapeutic use.