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.