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.
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue 11635, Athens, Greece. tcalog@eie.gr
Theodora
T
Calogeropoulou
Nicolaos
N
Avlonitis
Vassilios
V
Minas
Xanthippi
X
Alexi
Athanasia
A
Pantzou
Ioannis
I
Charalampopoulos
Maria
M
Zervou
Varvara
V
Vergou
Efrosini S
ES
Katsanou
Iakovos
I
Lazaridis
Michael N
MN
Alexis
Achille
A
Gravanis
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