期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 52, 期 21, 页码 6569-6587出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm900468p
关键词
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资金
- Greek General Secretariat for Research and Technology [PENED 2001 ED258]
- Bionature EA Ltd.
- EmergoMed Co
DHEA analogues with modifications at positions C3 or 07 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 17 beta-spiro[5-androstene-17, 2'-oxiran]-3 beta-ol (20), (20S)-3 beta,21-dihydroxy-17 beta,20-epoxy-5-pregnene (23), and (20R)-3 beta,21-dihydroxy-17 alpha,20-epoxy-5-pregnene (27) with IG(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 (ER alpha and ER beta) 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.
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