Synthesis And Antitumor Activity Of Dehydroepiandrosterone Derivatives

Dehydroepiandrosterone(DHEA)is one of major adrenal hormones.It is a precursor in many body steroid hormone biosynthesis.DHEA can inhibit excessive mitochondria and 5-ribophosphate esters,thereby inhibiting and preventing tumor growth.DHEA has significant anti-cancer activity.As an important intermediate for the synthesis of various steroid hormone drugs,the antitumor activity of DHEA and its derivatives has received more and more attention in recent years.In this dissertation,in order to further improve the antitumor activity and selectivity of DHEA,DHEA was used as raw material to carry out a series of structural modifications to DHEA’s structure.In this study,DHEA was used as a raw material,and three series of novel derivatives were synthesized and modified.(1)C3-OH Six compounds were synthesized via ester condensation with the aromatic triazole carboxylic acid;(2)C-16 25 compounds were synthesized by aldol condensation with the aromatic triazole aldehyde;(3)C-16 Six compounds were synthesized by aldol condensation with benzaldehyde intermediates substituted different nitrogen-containing heterocycles(hexahydropyridine,imidazole,etc.).The synthesized derivatives were characterized by 1H-NMR,13C-NMR and HRMS.Through the method of MTT,the antitumor activity of synthetic derivatives was studied by HeLa,HepG2),A549,BEL-7402,HCT 116,MCF-7 and L-02.The cell cycle and apoptosis of compound g14 were detected by flow cytometry.The results showed that most of the modified derivatives exhibited different antitumor activities and the activities were superior to those of DHEA.Among them,the inhibition of growth and proliferation of the tested tumor cell lines of 16-(E)-1-(4-iodophenyl)-1H-1,2,3-triazol-4-vinyl-dehydroepiandrosterone(g14)is the most obvious and has obvious selectivity.The IC50 values for individual tumor cells are as follows:HepG2 is 9.10 μM,HCT is 31.04 μM,MCF-7 is 9.18 μM.However,antitumor activity of L-02 did not show significant inhibition,IC50>100 μM.Compound g14 induced cell cycle arrest and apoptosis.The results showed that compound g14 induced cell cycle arrest in G2 phase and induced HepG2 cell apoptosis.Other derivatives also exhibited varying degrees of inhibitory activity,even the activity and selectivity of other derivatives were exceeding the reference drug 5-fluorouracil.From this study,it can be concluded that the activity of the target obtained in the esterification reaction of C3-OH in DHEA is close to that of DHEA;the activity of the target of C-16 connected to different nitrogen-containing heterocyclic substituted benzaldehyde is not obvious,16-(E)-1-(4-ethylpiperazine)pheny 1-4-vinyl-dehydroepiandrosterone(j6)was excepted;This study has shown that C-16 modification of DHEA can increase anti-tumor activity.This study lays the foundation for screening candidates of anti-tumor drug.