Synthesis and evaluation of 17α-(dimethylphenyl)vinyl estradiols as probes of the estrogen receptor-α ligand binding domain

Abstract

As part of our program to explore the influence of small structural modifications on the biological response of the estrogen receptor-α (ERα), we prepared and evaluated a series of mono-and di-substituted phenyl vinyl estradiols. The target compounds were prepared in 45-80% yields using the Stille coupling reaction and evaluated using competitive binding analysis with the ERα-ligand binding domain (hERα-LBD) and estrogenic activity (induction of alkaline phosphatase in Ishikawa cells). Results indicated that the 2,4- and 2,5-dimethyl derivatives, 5b and 5c, had the highest relative binding affinity (RBA=20.5 and 37.3%) and relative stimulatory activity (RSA=101.0% and 12.3%) of the di-methyl series.

Figure 1

Superimposition of 17α-(di-methylphenyl)vinyl estradiol isomers 5a-f within ligand binding pocket (LBP) of ERα. As with the mono-substituted phenyl vinyl estradiols, the terminal phenyl ring is bounded by three methionines and one phenylalanine. Only slight side chain or steroidal adaptations are required to accommodate the ligands within the LBP.

Scheme 1

Synthesis of mono- and di-substituted phenylvinyl estradiols.