Novel dehydroepiandrosterone derivatives with antiapoptotic, neuroprotective activity.

DHEA analogues with modifications at positions C3 or C17 were synthesized and evaluated for neuroprotective activity against the neural-crest-derived PC12 cell model of serum deprivation-induced apoptosis. The most potent compounds were the spiro-epoxy derivatives 17β-spiro[5-androstene-17,2′-oxiran]-3β-ol (20), (20S)-3β,21-dihydroxy-17β,20-epoxy-5-pregnene (23), and (20R)-3β,21-dihydroxy-17α,20-epoxy-5-pregnene (27) with IC50 values of 0.19 ± 0.01, 99.0 ± 4.6, and 6.4 ± 0.3 nM, respectively. Analogues 20, 23, and 27, up to the micromolar range of concentrations, were unable to activate estrogen receptor α and β (ERα and ERβ) or to interfere with ER-dependent gene expression significantly. In addition, they were unable to stimulate the growth of Ishikawa, MCF-7, and LNCaP cells. Our results suggest that the spiro-epoxyneurosteroid derivatives 20, 23, and 27 may prove to be lead molecules for the synthesis of novel neuroprotective agents.