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Novel dehydroepiandrosterone derivatives with antiapoptotic, neuroprotective activity
- Publication Year :
- 2009
-
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. J Med Chem
- Subjects :
- Models, Molecular
medicine.medical_specialty
Neurons/cytology/drug effects
Estrogen Receptor alpha/agonists/biosynthesis
Estrogen Receptor beta/agonists/biosynthesis
Molecular Conformation
Estrogen receptor
Dehydroepiandrosterone
Apoptosis
Neuroprotection
Cell Proliferation/drug effects
Structure-Activity Relationship
Internal medicine
Cell Line, Tumor
Drug Discovery
LNCaP
medicine
Estrogen Receptor beta
Animals
Humans
Cell Proliferation
Neurons
Chemistry
Estrogen Receptor alpha
Biological activity
Apoptosis/*drug effects
Neuroprotective Agents/adverse effects/*chemical synthesis/pharmacology
Rats
Antiapoptotic Agent
Endocrinology
Neuroprotective Agents
Cell culture
Molecular Medicine
synthesis/pharmacology
Dehydroepiandrosterone/adverse effects/*analogs & derivatives/*chemical
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....5b96f3371209c61c584f02710b5c1cd3