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 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.
Calogeropoulou
Theodora
T
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue 11635, Athens, Greece. tcalog@eie.gr
Avlonitis
Nicolaos
N
Minas
Vassilios
V
Alexi
Xanthippi
X
Pantzou
Athanasia
A
Charalampopoulos
Ioannis
I
Zervou
Maria
M
Vergou
Varvara
V
Katsanou
Efrosini S
ES
Lazaridis
Iakovos
I
Alexis
Michael N
MN
Gravanis
Achille
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000096:biosynthesis; D047629:Estrogen Receptor beta / Q000819:agonists / Q000096:biosynthesis; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018696:Neuroprotective Agents; D003687:Dehydroepiandrosterone