The Prototypical Inhibitor of Cholesterol Esterification, Sah 58-035 [3-[Decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide], Is an Agonist of Estrogen Receptors

Abstract

We have shown recently that estrogen receptor (ER) ligands share a diphenyl ethane pharmacophore with Sah 58-035 [3- [decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide], a prototypical inhibitor of the acyl-cholesterolacyl-transferase (ACAT), which enabled us to establish that ER ligands were potent inhibitors of ACAT and blocked the formation of foam cells. In the present study, we have tested whether this structural similarity means that Sah 58-035 is an ER modulator. We report that Sah 58-035 bound to ER␣ and ER␤ with an IC 50 of 2.9 and 3.1 M, respectively. Docking studies using molecular modeling of Sah 58-035 with the X-ray structure of the ER showed that Sah 58-035 fits well into the ligand binding site known for 4-hydroxy-tamoxifen. Despite having high threedimensional structural similarities with the pure antiestrogen ICI 164,384 [(N-n-butyl-N-methyl-11-[3,17␤-di-hydroxyestra-1,3, 5(10)-trien-7␣-yl]-undecanamide], we showed that Sah 58-035 is an agonist of ER for transcription and cellular proliferation. These data showed that Sah 58-035 was an estrogen receptor agonist and that the size and the chemical nature of the side chain were critical for agonist versus antagonist activity on ER. This new molecular mechanism of action for Sah 58-035 has to be taken into account in understanding better its pharmacological activities. Moreover, these data give new structural insights into the understanding of agonist versus antagonist activities of ER ligands and also for the conception of new drugs with a dual ACAT inhibition and ER modulation potential and their evaluation in different pathologies where both targets are involved, such as atherosclerosis, Alzheimer's disease, and cancer.We have reported recently that the prototypical acyl-cholesterol-acyl-transferase (ACAT) inhibitor Sah 58-035 and estrogen receptor (ER) ligands shared a common pharmacophore that caused the ER ligands to inhibit ACAT (de Medina et al., 2004b), a new important target for the antiestrogen tamoxifen that may explain its antiatherogenicity in mammals. This pharmacophore for ACAT inhibition is the diphenylethane (DPE) moiety of Sah 58-035. It has been known since the pioneering work of Dodds et al. (1938), showing that diethylstilbestrol (DES) acts as a potent estrogen, that the DPE moiety could mimic the hexahydrophenanthrene motif of 17␤-estradiol (E 2 ). This observation led to the subsequent development of DPE derivatives that were at the origin of nonsteroidal estrogens and antiestrogens (Anstead et al., 1997;Jordan, 2003a). Crystallographic analysis of E 2 -S.S.-P. is in charge of research for the Centre National de la Recherche Scientifique.

Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties

“…We therefore examined whether DDA could function as an ER modulator using MELN cells, which are MCF-7 cells stably transfected with a plasmid that encodes an oestrogen-responsive promoter fused to the luciferase gene32. As shown in Fig.…”

“…All culture media contained penicillin and streptomycin (50 U ml −1 each) and 1.2 mM glutamine (3.2 mM glutamine for B16F10). MELN32 and MCF-7 cells were grown in RPMI supplemented with 5% FBS. TS/A, A549, SK-N-SH, SH-SY5Y, SW620, HCT-8, HT29, SK-Mel-2, SK-Mel-28, U937 and NB4 cells were grown in RPMI 1640 supplemented with 10% FBS (FBS was heat-inactivated for SK-Mel-28 cells).…”

Avasimibe Encapsulated in Human Serum Albumin Blocks Cholesterol Esterification for Selective Cancer Treatment

“…12 Blocking ACAT-1 activity by inhibitors reduced levels of cholesteryl esters in cancer cells and suppressed cancer proliferation with no obvious negative effects to normal cells. 13–16 These results show great potential of targeting ACAT-1 for cancer-selective therapy. Notably, a number of ACAT-1 inhibitors have been developed as hypolipidemic and anti-atherosclerotic drugs.…”

Scavenger receptor class B type I regulates cellular cholesterol metabolism and cell signaling associated with breast cancer development

“…Consistent with this hypothesis, increasing cellular esterified cholesterol levels have been shown to induce cellular proliferation and enhance invasiveness of tumor cell lines [50]. Conversely, the inhibition of cholesterol esterification has been shown to have the reverse effect [51,52]. …”