Download Estradiol Analogues as Estrogen Receptor Subtype

Design, Synthesis, and Biological Evaluation of D-ring Opened 17-ß
Estradiol Analogues as Estrogen Receptor Subtype-selective Ligands
Sun Young Lee, Yun Seon Song, Minsun Chang and Hee-Doo Kim
College of Pharmacy, Sookmyung Women’s University, Seoul, Korea
Estrogen receptor alpha and beta act as ligand-activated transcription factors mediating many
complex physiological activities in a subtype or tissue-selective manner. ER subtype-selective
ligands could be valuable to manage various pathological conditions such as cancer,
neuropathies, cardiovascular disease, osteoporosis, and metabolic disorders.
In this presentation, we describe the ER subtype-selective ligands with a novel oxime scaffold
that resembles 17ß-estradiol (E2), but with the D-ring opened. Because scaffold hopping is one
of the important approaches in discovering structurally new compounds by starting from
known compounds, we planned to deconstruct the D-ring of E2 to make it jump into different
chemical space of E2-related ER ligands. We also envisioned that conformational flexibility
resulting from the D-ring opening might enhance the ligand’s ability to recognize the slight
difference in the binding cavities between the two receptor subtypes. The biological activities
and the selectivity for the receptor subtype of new oxime analogues as well as their prototype
D-ring opened E2 analogue have been studied by radioligand competitive binding assay and
cell-based transcription assays in which they exerted biological activities at nM concentrations.
Here, we suggest the novel and promising scaffold hopping to develop subtype-selective ER
ligands useful in treating ER and/or estrogen-associated diseases.