Structure-activity relationships of estrogenic ligands: synthesis and evaluation of (17.alpha.,20E)- and (17.alpha.,20Z)-21-halo-19-norpregna-1,3,5(10),20-tetraene-3,17.beta.-diols

Abstract

As part our program to probe the molecular requirement for estrogen-receptor binding we undertook the synthesis and evaluation of the 17 alpha,E and 17 alpha,Z halovinyl estradiols. By use of an improved variation of the existing synthetic strategy, the targeted compounds were prepared stereospecifically and in 92-98% yields from the corresponding 17 alpha,E or 17 alpha,Z [(tri-n-butylstannyl)vinyl]estradiol 3-acetates. The novel estradiol derivatives were evaluated for their relative binding affinity (RBA) for the estrogen receptor with use of a rat uterine preparation. The results demonstrated a marked difference between the E and Z isomers and among the halogen employed. The Z isomers possessed significantly higher RBA values and the larger halogens (I, Br) were more effective than the smaller Cl substituent. These results modify the previous interpretations of estrogen-receptor binding for steroidal ligands. As a result, our design of (radio)halogenated ligands will incorporate this concern for Z vs E stereochemistry.

Synthesis of Auger Electron-Emitting Radiopharmaceuticals

“…Because both approaches utilized the destannylation methodology for introduction of the Auger emitting radiohalides, the challenges were primarily associated with the synthesis of the precursor trialkylvinylstannanes. Previous studies [11] had demonstrated that the 17α-Z-halovinyl estradiols had higher affinity than the corresponding 17α-E-isomers. Small lipophilic substituents at the 11β-position provided an additional enhancement of relative binding affinity (RBA) [12].…”

Steroid Receptor Ligands for Breast Cancer Targeting: An Insight into Their Potential Role As Pet Imaging Agents

“…Thus, the Z-isomer showed much higher binding affinity than the E isomers, with bulky substituents enhancing affinity at this position. The opposite pattern was observed in the E series [206]. The behaviour of the related phenyl, phenylthio, and phenylseleno vinyl estradiols has been shown to follow the same pattern suggesting that the orientation of the substituent on the vinyl group towards the receptor differs considerably depending on the Eand Z-configuration of the double bond [208,214].…”

“…The behaviour of the related phenyl, phenylthio, and phenylseleno vinyl estradiols has been shown to follow the same pattern suggesting that the orientation of the substituent on the vinyl group towards the receptor differs considerably depending on the Eand Z-configuration of the double bond [208,214]. The lower affinity of the 17 -E-vinyl isomers has been explained as being attributable to their structural similarity to the 17 -ethynyl series that is sensitive to small changes in molecular volume [206]. For the E isomers and 17 -iodoethynyl derivatives the iodo-group is oriented in a similar way, outward from below the -face of the steroid and qualitatively similar binding affinities are observed.…”

“…The 17iodoethynyl estradiol, despite of the larger volume of the iodine relative to a proton, shows quite favourable binding, probably due to the greater polarizability of the iodine [203,204]. 17 -vinyl estradiols have also been investigated in considerable detail [205][206][207][208][209][210]. The presence of the iodovinyl group does not significantly alter the ER binding affinity [211][212][213].…”

Synthesis and evaluation of 17α-E-20-(heteroaryl)norpregn-1,3,5(10),20 tetraene-3,17β-diols [17α-(heteroaryl)vinyl estradiols] as ligands for the estrogen receptor-α ligand binding domain (ERα-LBD)

“…16–23 Such structural probes permit enhanced insight into the influence of physicochemical properties in modulating receptor affinity, selectivity and efficacy. Most of our initial work has focused on the 17α-position through the use of modifications of the phenylvinyl moiety.…”