Synthesis And Antitumor Activity Of 3-trichloroacetoxyprogesterone-20-aminothizone And Steroid Coumarin

Steroids are a kind of natural organic compounds which widely exist in nature and biological tissues.These compounds have good physiological activity,which can be obtained not only from natural products,but also by synthesis.The related research and application of steroids are very extensive in the field of pharmaceutical chemistry.In the study,different methods or means can be used to extract and synthesize the desired target compounds,such as oxidation,reduction,condensation and other reactions to modify the structure,and introduce nitrogen-containing groups.The method of heterocycle group and other active group to obtain the target compound with better biological activity.Since 1950 s,the research of steroids has been paid more and more attention by medical researchers.In the course of related research,some achievements have been made,such as sodium estrostine phosphate,ethemetam,Abitron acetate and 2-methoxyestridiol have become clinical anticancer drugs.Therefore,it is of great significance to modify the structure of steroids in steroid anticancer drugs.The literature shows that coumarin compounds have antibacterial,antioxidant,anti-tumor and other biological activities.Coumarin compounds are often introduced into various fluorescent materials as fluorescent groups because of their strong fluorescence properties.However,coumarin fluorescent materials have also become an important kind of bioluminescence imaging materials,and have been used in cell fluorescence imaging,zebrafish fluorescence imaging,in vivo imaging and other fluorescence imaging experiments.In the previous study of the research group,a series of steroid derivatives were synthesized,and the compounds with good activity were also obtained.Among them,the biological activity of steroid derivatives will be improved after the introduction of nitrogen groups into steroids,such as 20-amine Hydrazone progesterone compounds have good antitumor activity,and 3-trichloroacetoxyprogesterone compounds also have good anti-tumor activity,at the same time,the effect of 3-trichloroacetyloxyprogesterone compounds is also very good.Therefore,in this study,progesterone derivatives were used as raw materials,trichloroacetyloxygen was introduced at 3-position,oxyl group,methoxylamine group or thiourea group containing substituted group was introduced at 20-site.3-trichloroacetyl-20-progesterone amine thizone compound was synthesized.Four cell lines,T24(human bladder cancer cell line),SKOV3(human ovarian cancer cell line),A549(human lung adenocarcinoma cell line)and 293T(human renal epithelial cell line),were selected and their antitumor activities were tested in vitro.The results showed that these steroid derivatives had certain anti-swelling activity against A549(human lung adenocarcinoma cell line),but had no toxicity to 293T(human renal epithelial cell line).Compound 2.2 was selected to test the apoptosis of SKOV3(human ovarian cancer cell line).The results showed that compound 2.2 could induce apoptosis of SKOV3 cancer cells.Coumarin 3-position was synthesized by condensation of diethyl malonate and 4-(diethylamine)salicylaldehyde or 2-hydroxyl-4-methoxybenzaldehyde into cyclic hydrolysis.Another kind of 4-hydroxymethyl coumarin was obtained by hydrolysis of 4-hydroxymethyl coumarin with m-diphenol and ethyl 4-chloroacetoacetate after dehydration into a ring and then hydrolyzed by chlorine atom.Progesterone ketone,cholesterol and goose deoxycholic acid were used as raw materials to react with 3-carboxy-7-(diethylamine)coumarin compound,3-carboxy-7-methoxycoumarin compound,4-hydroxymethyl-7-hydroxycoumarin,respectively.Four novel steroidal coumarin esters and two cholesterol coumarin amides were obtained.T24(human bladder cancer cell line)and SKOV3(human ovarian cancer cell line)were selected to test the antitumor activity of the synthesized compounds in vitro.The results showed that compound 3.11 and compound 3.18 had certain antitumor activity against SKOV3(human ovarian cancer cell line).In addition,the cellular fluorescence imaging of steroids coumarin compounds showed that these steroidal coumarin derivatives could be imaged in cells.In summary,21 compounds were synthesized in this study,of which 9 were 3-trichloroacetoxyprogesterone-20-aminothizone derivatives and 6 were steroids coumarin compounds,all of which had not yet been obtained.The other six are coumarin compounds.The structure analysis and determination of these compounds were measured by infrared spectroscopy,nuclear magnetic resonance carbon and hydrogen spectroscopy and mass spectrometry.The in vitro antitumor activity test and spectral test of the synthesized compounds showed that some compounds had certain antitumor activity,which provided a theoretical basis for the next step of research.At the same time,it also provides certain theoretical support for the study of steroids.