This study prepared a series that consisted of substituted benzoylbenzamide derivatives of 17-E-vinyl estradiol 6a-i and 7a-d in good overall yields from the corresponding novel iodinated benzoylbenzamide precursors using Pd(0)-catalyzed Stille coupling.
Biological evaluation using competitive binding assays indicated that all compounds were effective ligands for the ERa- and ERB-LBD (RBA=0.5-10.0 percent of estradiol). Most of the compounds expressed lower stimulatory (agonist) potency (RSA <0.2-0.5 percent) compared to their binding affinity, however, the meta-substituted isomer 6h demonstrated a level of efficacy (RSA=5.7 percent) comparable to its affinity (RBA=9.5 percent). Docking studies of 6b, 6h, and 6i with the 2YAT crystal structure suggested that higher affinity and efficacy of 6h are due to an effective set of interactions with exposed receptor sidechains not observed with the ortho- and para- isomers. In this binding model, the terminal ring of the ligand is exposed to the solvent space, which would explain both the small variation in RBA values and the narrow SAR for the diverse structural features. (publisher abstract modified)