Novel Dehydroepiandrosterone Derivatives with Antiapoptotic, Neuroprotective Activity

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.

BNN27, a 17-Spiroepoxy Steroid Derivative, Interacts With and Activates p75 Neurotrophin Receptor, Rescuing Cerebellar Granule Neurons from Apoptosis

“…BNN27 aims at surpassing the limited clinical value of DHEA and its profile as a non-specific multi-receptor activator and a precursor for the biosynthesis of androgens and estrogens (Calogeropoulou et al, 2009). Indeed, neurosteroids DHEA and DHEA-S, produced within the brain, effectively protect neurons against apoptosis (Charalampopoulos et al, 2004).…”

“…It is of note that recent studies associate DHEA to an increased prevalence of hormone-dependent tumors, particularly to genetically predisposed patients (Fourkala et al, 2012). Thus, BNN27 represents a more specific, with potentially less secondary effects neuroprotective agent, showing specific binding to only TrkA and p75 NTR receptors, and being deprived of estrogenic and androgenic actions, unable to bind to and activate steroid receptors (Calogeropoulou et al, 2009; Pediaditakis et al, 2016). …”

“…Modifications on C17 of BNN27 abolish its susceptibility to metabolic enzymes that convert DHEA to androgens or estrogens. Additionally, BNN27 has been shown to penetrate blood-brain-barrier (Bennett et al, 2016) and to not interact with AR or ERs in in vitro studies (Calogeropoulou et al, 2009; Pediaditakis et al, 2016). …”

Perfluoroalkylsulfonyl fluoride in organic synthesis: a facile synthesis of 17α-hydroxy steroids

“…1 Steroids bearing a 17b hydroxyl group can be easily prepared from 17-oxo steroids via a stereospecific reduction. 2 On the contrary, 17a-hydroxy steroids are much less explored due to synthetic difficulties.…”

Synthetic microneurotrophins in therapeutics of neurodegeneration

“…Our group has recently synthesized and screened a large chemical library of 17-carbon derivatives of DHEA for their ability to protect neurons against apoptosis as well as for their affinity for neurotrophin receptors [6]. BNN27, a BBB-permeable, C17-spiroepoxy steroid derivative, was shown to specifically interact with and activate the TrkA receptor of NGF, inducing phosphorylation of TrkA tyrosine residues and down-stream neuronal survival-related kinase signaling.…”