Novel Dehydroepiandrosterone Derivatives with Antiapoptotic, Neuroprotective Activity

• DOI: 10.1021/jm900468p
• Publication Date: 2009-11-05T06:43:08Z
• Authors: Theodora Calogero...; Nicolaos Avlonitis; Vassilios Minas; Xanthippi Alexi; Athanasia Pantzou; Ioannis Charalamp...; Maria Zervou; Varvara Vergou; Efrosini S. Katsanou; Iakovos Lazaridis; Michael N. Alexis; Achille Gravanis
• Keywords: Models, Molecular; 0301 basic medicine; Neurons/cytology/drug effects; Estrogen Receptor alpha/agonists/biosynthesis; Estrogen Receptor beta/agonists/biosynthesis; Molecular Conformation; Apoptosis; Cell Proliferation/drug effects; Structure-Activity Relationship; 03 medical and health sciences; Cell Line, Tumor; Animals; Estrogen Receptor beta; Humans; Cell Proliferation; Neurons; Estrogen Receptor alpha; Dehydroepiandrosterone; Apoptosis/*drug effects; Neuroprotective Agents/adverse effects/*chemical synthesis/pharmacology; Rats; 3. Good health; Neuroprotective Agents; synthesis/pharmacology; Dehydroepiandrosterone/adverse effects/*analogs & derivatives/*chemical

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.