Synthesis And Biological Activities Of Steroidal Selenium

Steroid was a kind of compounds with mother nucleus of cyclopentanoperhy drophenanthrene.With the research and development of advanced technology such as molecular level,reports on the synthesis of steroids have been emerging continually.The researchers took steroid structure as the mother nucleu,introducing different heteroatoms and functional groups,different heterocyclic groups into the steroid ring,or modified the structure of steroid nuclei and branched chains.The result shows that the compounds exhibite different physiological activities and even exceed intrinsic activity.Spironolactone as an antagonist of mineralocorticoid has been used in combination therapy for congestive heart failure and hypertension.As a new generation of steroid androgen inhibitors,Abiraterone has been used in the treatment of advanced metastatic prostate cancer(m CRPC).Steroid has been widely used in clinic,and became the most productive drugs after antibiotics.Therefore,further research on steroids has become a new important way for current researchers to explore tumor and immune diseases.The research was focused on steroids containing selenium functional groups,introducing three pharmacophore group into steroids,such as organoselenocyanate,1,2,3-selenadiazoles,benzisoselenazolone,and studing the synthetic methods of the selenium steroid compounds.Meanwhile,the inhibitive effect of these compounds against human gastric cancer cells(803),human prostate cancer cells(PC3),human breast cancer cell(MCF-7),human ovarian cancer cells(SKOV3),ductal cancer cells(T47D),human liver cancer cells(7404),human nasopharyngeal carcinoma cell line(CNE-2),human lung cancer cells(A549)and lung cancer cells(H460)was also evaluated by MTT assay.The antibacterial activity of some compounds was tested by disc diffusion method in vitro.Firstly,the method of introducing selenocyanato into steroids was studied.In this study we discovered a new simple and easy method to introducte selenocyanato into organic substrates that were susceptible to attack by electrophiles.Using sodium nitrite,10% hydrochloric acid solution and potassium thiocyanate as reagents,a selenocyanato can be easily intruduced into the organic substrates.In this way,using pregnenolone as a raw material,some 21-seleniumcyano pregnenolone and17-seleniumcyano pregnenolone were geted.Furtherly,by reacted with different chloride in the pyridine solution,eight 3-acyloxy-21-selenidecyanide derivatives and two 3-acyloxy-17-selenidecyanide derivatives were obtained.All compounds werecharacterized by IR,NMR and HRMS.The antiproliferative activity of synthetic compounds was tested in vitro and the results showed that some compounds showed distinct inhibitory activity on the tumor cells,such as compound 1 b and 3 b with17-selenocyanato substitution,their IC50 against PC3 cells were 7.32 ± 0.32μM and21.10 ± 0.64μM,IC50 against SKOV3 cells were 13.13 ± 0.97μM and 24.77 ± 0.20μMμM and IC50 against T47 D cells were 16.22 ± 0.19 and 5.86 ± 0.28 μM respectively.The antibacterial activity of the synthesized compounds in vitro was tested by disc diffusion method,and the results showed that some compounds containing selenocyanato showed certain antibacterial activity.Among them,the inhibitory ring diameter of compound 1b for pseudomonas aeruginosa was 13.02 mm,while the inhibitory ring diameter of streptomycin sulfate was 13.86 mm.It is similar to that of streptomycin sulfate.Secondly,using the pregnenolone as raw materials,3-acyloxyl pregnenolones were obtained by the reaction of 3-hydroxyl group of pregnenolone with different chloride in the pyridine solution.Then 3-acyloxyl pregnenolone semicarbazones were yieled by reacted with semicarbazone.Furtherly,by 3-acyloxyl pregnenolone semicarbazones reacted with selenium dioxide,we got ten3-acyloxy-17-pregnenolone selenodiazole compounds.All the compounds were characterized by IR,NMR and HRMS.The further antitumor activity test results showed that steroid selenodiazole compound 7i displayed obvious antiproliferative activity against PC3 and SKOV3 cells with IC50 values of 21.40 ± 0.37μM and 18.26± 0.49 μM.The IC50 value of the compound 7h to PC3 cells was 18.56 ± 0.82 μM.Finally,using the dehydroepiandrosterone as the raw material,through the oximation of 17–carbonyl group and the reduction of the oxime group using sodium cyanide borohydride as reductant in the presence of molybdenum pentaoxide,some17-aminodehydroepiandrosterone compounds were gotten.Further reacted with different structures of 2-chloroselenyl benzoyl chloride,ten of dehydroepiandrosterone benzisoselenazolone derivatives were yielded.On the other hand,using naturally occurring cholesterol as the raw material,some B-norcolesterol benzisoselenazolone compounds were obtained by ozonation,cyclization,oximation,reduction and reacted with different structures of 2-chloroselenyl benzoyl chloride.All compounds were characterized by IR,NMR and HRMS.At the same time,the antitumor activity of the compounds in vitro was tested and the results showed that these steroidal benzisoselenazolone derivatives showed a significant inhibitoryactivity against the tumor cells tested.For example,compound 14 b has obvious inhibitory effect on human ovarian cancer cell SKOV3 with the IC50 value of 10.41 ±0.37 μM.The IC50 value of 14 e to human breast duct carcinoma cells SKOV3 is 6.49± 0.59μM;The inhibition effect of the compound 19 g on SKOV3 cells was 8.72 ±0.21μM in IC50.The IC50 value of 19 g to T47 D cells was 10.70 ± 0.63μM μM.To sum up,68 of steroidal selenium compounds with different structural characteristics were synthesized in this paper,including 41 of target products and 27 of intermediate products.60 of these organic selenium compounds have not been reported in the literatur.All the synthesized products were characterized by IR,1H-NMR,13C-NMR and high resolution mass spectrometry.In addition,all target compounds were tested for their anti-tumor activity in vitro.The results showed that after introduced selenocyanato or selenium heterocyclic functional groups into the parent nucleus or branched chain of steroid compounds,some compounds showed a good inhibitory effect on the proliferation of tumor cells,and moreover some compounds also showed certain antibacterial activity in vitro.Our results provide a theoretical basis for the synthesis of selenium steroids and the application of antineoplastic agents,and further enriched the content of rganic selenium chemistry.