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Novel dehydroepiandrosterone derivatives with antiapoptotic, neuroprotective activity.

Journal of medicinal chemistry (2009-10-23)
Theodora Calogeropoulou, Nicolaos Avlonitis, Vassilios Minas, Xanthippi Alexi, Athanasia Pantzou, Ioannis Charalampopoulos, Maria Zervou, Varvara Vergou, Efrosini S Katsanou, Iakovos Lazaridis, Michael N Alexis, Achille Gravanis
ABSTRACT

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 17beta-spiro[5-androstene-17,2'-oxiran]-3beta-ol (20), (20S)-3beta,21-dihydroxy-17beta,20-epoxy-5-pregnene (23), and (20R)-3beta,21-dihydroxy-17alpha,20-epoxy-5-pregnene (27) with IC(50) 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 alpha and beta (ERalpha and ERbeta) 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Estradiol, meets USP testing specifications
Sigma-Aldrich
β-Estradiol, BioReagent, powder, suitable for cell culture
Sigma-Aldrich
β-Estradiol, analytical standard
Sigma-Aldrich
β-Estradiol, powder, γ-irradiated, suitable for cell culture
Sigma-Aldrich
trans-Dehydroandrosterone, ≥99%
Sigma-Aldrich
β-Estradiol, ≥98%