Heterocyclization And Glycosylation Of Epiandrosterone And Dehydroepiandrosterone WithAnti-breast Cancer Activity

Dehydroepiandrosterone (DHEA) is an important endogenous steroid hormone in human peripheral tissues. It is an important precursor in the biosynthesis of the androgen and estrogen steroids. Epiandrosterone (EPI) is a metabolic intermediate of DHEA. DHEA-type compounds have been identified as potential antibacterial, anticancer, antiviral agents and CYP17 inhibitors. In order to obtain high potency antitumor compounds a series of EPI and DHEA derivatives were synthesized by heterocyclization and glycosylation.Novel DHEA and PEI derivatives were obtained by fusing various five or six-membered heterocyclicrings at positions C-16 and C-17 of ring D. Potent active compouds CH12 and CH21 were obtained by screening of these derivatives. More derivatives were obtained by further modification of CH12 and CH21. Results showed that CH33 was the most potent antitumor compound, especially to T47D cell line. Its amazing that the selective index between T47D and human fibroblast cells (HAF) was 362. Further tests discovered that CH33 possessed significant dose-dependently apoptosis and anti-migration on T47D, and had no effect on cell cycle.Upregulation expression of receptor tyrosine kinase EphB3 and phA2 by CH33 may be one of the possible mechanisms.Glycosylated derivatives of CH12 and CH21 were obtained by introducing various monosaccharides at C-3 of ring A. Compouds C-5-1 and C-5-2 showed more antitumor activity than CH12 and CH21 on T47D. In particularly, C-5-1 possessed equivalent potency with CH33 on T47D, the IC50=0.0696uM.