Targeting the estrogen receptor with metal-carbonyl derivatives of estradiol

Abstract

As part of our program to develop new probes for the estrogen receptor binding domain, we prepared and evaluated a novel 17α-(rhenium tricarbonyl bipyridyl) vinyl estradiol complex. Preparation of the final compound was achieved using the Stille coupling between the preformed brominated rhenium tricarbonyl bipyridine complex and the tributylstannyl vinyl estradiol. Competitive receptor binding assays and stimulatory assays demonstrated that the final complex retained affinity and efficacy comparable to the corresponding pyridyl vinyl estradiol analog, but lower than that of the phenyl vinyl estradiol analog.

Figure 1

Relative Binding Affinity (RBA) and Stimulatory Activity (RSA) values for the phenylvinyl, pyridylvinyl and Re(CO)₃-bipyridylvinyl estradiols. RBA = 100 × [E]/[C] where [E] is the concentration of unlabeled estradiol necessary to reduce the specific binding of tritiated estradiol to the ER -HBD by 50% and [C] is the concentration of the competitive ligand necessary to reduce specific binding by 50%. The RBA of estradiol is 100% at 25 °C. Curves for ligand and estradiol had correlation coefficients >95%. RSA = Relative Stimulatory activity compared to E₂ = 100%, in stimulation of alkaline phosphatase (AlkP) in the Ishikawa cell line. EC₅₀ for E₂ = 0.9 ± 0.2 nM.

Scheme 1

Routes to the Re(CO)₃-bipyridyl-vinyl estradiol complexes.