Human Estrogen Receptor α Antagonists. Part 1: 3-D QSAR-Driven Rational Design of Innovative Coumarin-Related Antiestrogens as Breast Cancer Suppressants through Structure-Based and Ligand-Based Studies

The estrogen receptor alpha (ER alpha) represents a 17 beta-estradiol-inducible transcriptional regulator that initiates the RNA polymerase II-dependent transcriptional machinery, pointed for breast cancer (BC) development via either genomic direct or genomic indirect (i.e., tethered) pathway. To develop innovative ligands, structure-based (SB) three-dimensional (3-D) quantitative structure-activity relationship (QSAR) studies have been undertaken from structural data taken from partial agonists, mixed agonists/antagonists (selective estrogen receptor modulators (SERMs)), and full antagonists (selective ER alpha downregulators (SERDs)) correlated with either wild-type or mutated ER alpha receptors. SB and ligand-based (LB) alignments allow us to rule out guidelines for the SB/LB alignment of untested compounds. 3-D QSAR models for ER alpha ligands, coupled with SB/LB alignment, were revealed to be useful tools to dissect the chemical determinants for ER alpha-based anticancer activity as well as to predict their potency. The herein developed protocol procedure was verified through the design and potency prediction of 12 new coumarin-based SERMs, namely, 3DQ-1a to 3DQ-1e, that upon synthesis turned to be potent ER alpha antagonists by means of either in vitro or in vivo assays (described in the second part of this study).