Synthesis of Chimeric 7α-Substituted Estradiol Derivatives Linked to Cholesterol and Cholesterylamine

Abstract

We report the synthesis of 7r-substituted β-estradiol derivatives bearing side chains terminated with cholesterol and 3β-cholesterylamine. These chimeric compounds were designed to exhibit high affinity for estrogen receptors (ERs) and cellular plasma membranes to potentially enable regulated uptake of ERs by mammalian cells. Evaluation with recombinant yeast reporting compound-mediated ER dimerization revealed potencies similar to the antiestrogen ICI 182780. Compounds that efficiently deliver dominant negative ERs into cells may provide novel therapeutics against breast cancers.

Design and synthesis of a crosslinker for studying intracellular steroid trafficking pathways

“…As reported previously, 30 cholesterol was O -alkylated to give the t -butyl acetate derivative 10 (see also 2 in Figure 7). Allylic oxidation afforded enone 11 , which was subjected to catalytic hydrogenation to give saturated ketone 12 .…”

“…30 The synthesis of Cholesterol Unit 1 was more demanding due to the need of a steroid as a starting material lacking the terminal portion of the cholesterol tail. Commercially available hyodeoxycholic acid served this purpose but required considerable modification of the functional group pattern of the A and B rings of its core in a manner similar to previous work of Zhou, et al .…”

“…1 H NMR (CDCl 3 ) δ 5.37 (m, 1H), 4.01 (s, 2H), 3.24 (m, 1H), 2.43–1.50 (m, 13H), 1.48 (s, 9H), 1.44–1.04 (m, 14H), 1.01 (s, 3H), 0.92 (d, 3H, J= 6.5 Hz), 0.87 (app dd, 6H, J=5.5, 1.1 Hz), 0.68 (s, 3H) (lit. 30 1 H NMR).…”

Homologation of Estrone or Estradiol. Appending a Carbon Substituent Into the 3-hydroxyestra-1,3,5-triene Skeleton

“…An improved two-step procedure for the 70 72 conversion was published by Tedesco et al in 1995 [33], avoiding the use of heavy metals (Scheme 5.1). This protocol was applied by Hussey et al for the synthesis of estradiol derivatives coupled to cholesterol, such as 75 [34]. A midway procedure (borate/H 2 O 2 , then PCC) was also used by Katzenellenbogen and coworkers for the introduction of a 7-mercapto or benzylthio substituent [35].…”

Quaternary Alkylammonium Conjugates of Steroids: Synthesis, Molecular Structure, and Biological Studies

“…This aminosterol is a novel broad-spectrum antibiotic and exhibits a biocidal activity against Gram-positive and Gram-negative bacteria, fungi, protozoa, and viruses [15][16][17][18][19][20][21][22][23]. The antimicrobial activity of the squalamine has inspired work to design and synthesize new derivatives of steroidal-polyamine conjugates [24][25][26][27][28][29][30][31][32]. …”