Design,Synthesis And Biological Activity Evaluation Of Dehydroepiandrosterone Derivatives

Steroidal compounds have unique structures and many modifiable sites,which are hotspots in the field of drug research and development,especially in the field of anti-cancer.Among them,dehydroepiandrosterone（DHEA）is an important steroidal compound,a precursor substance for biosynthesis of various steroid hormones,and it has some antitumor activity.In this study,DHEA was selected as the lead compound to modify its structure in order to obtain compounds with further antitumor activity.In this paper,four series of compounds were designed and described as follows.（1）Amino acid or dipeptide fragments were reacted with DHEA via acylation according to the principle of combination to obtain class A and class B compounds modified at position3,of which 5 class A compounds and 12 class B compounds were obtained;（2）According to the isomers of bioisosteres,substituting the hydroxy group at position 17 of the enolized isomer of DHEA with an aromatic ring to obtained 8 class C compounds;（3）Modifying both of the 3th and 17th positions of DHEA provides 8 class D compounds.A total of 33derivatives were synthesized,of which 32 compounds have not been reported in the literature.The structures were confirmed by ¹HNMR and ¹³CNMR.In the meantime,the synthetic routes of various compounds were studied.The reaction conditions were optimized,and the peptide condensation reaction and the Suzuki coupling reaction were carefully investigated.Through the method of MTT,antitumor activity of synthetic derivatives were evaluated by BGC-823,HCT-116,SK-MEL-1,786-O,and RM-1,PC-3 and B16.The results showed that the derivatives showed different anti-tumor activities on the above cells.Among them,the B,C and D compounds have improved inhibitory effect on the growth of the tested tumor cell lines,better than DHEA and abiraterone and abiraterone acetate.The activity of class D compounds is better than that of other derivatives.At 25μM,compounds D2,D4,and D7 have a strong inhibitory effect on 6 of the above 7 tumor cells,and their IC₅₀ values on tumor cell lines are all reaching the micromolar level.The studies showed that class D compounds have great research potential.