Synthesis And Antiproliferative Activity Of Some Steroidal Heterocycle Compounds

Steroidal compounds are a type of important natural organic compounds,widely exist in the biological tissue.Due to their wide-ranging physiological activities,steroidal compounds attract the enough attention of the biologists and chemists.Many compounds with aromatic rings and heterocycles have be used to the biomedical field because of their significant biological activities.In recent years,numerous references reported that the antitumor activities of the steroids connected or fused with aromatic rings or heterocycles were better than their parent compounds.In this paper,combined with the previous studies by our team,using pregnenolone,dehydroepiandrosterone,testosterone and estrone as starting materials,a series of steroids with aromatic heterocycles were synthesized by introducing different aromatic rings or heterocycles.At the same time,the anti-tumor activity of synthesized compounds was assayed in vitro against SGC-7901,HeLa,Bel-7404,Hepg,HT-29,A549 tumor cells and 293T cells by MTT method.First,starting from estrone,estrone-17-hydrazone was prepared by reacting with superfluous hydrazine hydrate.And then reacting with different aromatic rings or heterocycles,9 estrone aromatic heterocycle hydrazones were obtained.The results of antiproliferative activity test in vitro indicated that some of them showed significant inhibition activity against tested cacer cells.For example,compounds 9 and 10showed excellent inhibition activity against Hela cells with IC₅₀ values of 5.0 and<5.0?mol/L respectively,and both of them had not cytotoxicity to normal 293T cells.Secondly,using pregnenolone,testosterone,dehydroepiandrosterone,and estrone as starting materials,by reacting with the bromoacetophenones possessing different substituents,such as-OCH₃,-CF₃,-NO₂,-Cl,or thiosemicarbazide,36 new steroidal compounds with thiazole ring were obtained by one-step microwave reaction.And the reaction conditions had been optimized.Then,under the condition of stannous chloride and concentrated hydrochloric acid,3 amino compounds were synthesized by reduction of NO₂.Furthermore,under the condition of heating,using dehydroepiandrosterone as parent compound,steroidal thiosemicarbazone compounds werepreparedbyreactingwith4-methylthiosemicarbazideand4-phenylthiosemicarbazide respectively,and then 9 dehydroepiandrosterone thiazole were obtained further by reacting with the bromoacetophenone possessing different substituents.By in vitro antiproliferative activity test,we found that compound 31showed good antitumor activity against Hela cells,Hepg cells and A549 cells with IC₅₀ values of 13.2,11.3 and 8.3?mol/L respectively.In addition,using pregnenolone,dehydroepiandrosterone,and estrone as starting materials,3 steroidal thiosemicarbazone compounds were gained by reacting with N,N-dimethylthiosemicarbazide.In conclusion,in this study,we synthesized 50 steroidal compounds,all of them were never reported before.Among them,9 were steroidal aromatic heterocycle hydrazones,36 were steroidal thiazole compounds and 5 were steroidal thiosemicarbazone compounds.The structures of products were characterized by IR,¹H NMR,¹³C NMR and HREIMS.At the same time,the anti-tumor activity of synthesized compounds were assayed in vitro.The results indicated that the synthesized steroidal compounds with aromatic rings and heterocycles showed some inhibition activity against tested cancer cells.Furthermore,for some products having remarkable cytotoxicity,their cell cycle experiment,apoptosis experiment and anti-tumor activity test in vivo will be assayed.The information obtained from our studies may be useful for the design of novel chemotherapeutic drugs for cancer,and promote the development of steroid chemistry.