1‐[4‐(N,N‐Bis‐β‐chloroethylcarbamoyloxy)‐phenyl]‐1,2‐bis‐(hydroxyphenyl)‐but‐1‐enes: Drugs Specifically Targeted against Estrogen Receptor Positive Mammary Tumors

1‐[4‐N,N‐bis‐2‐chloroethylcarbamoyloxy)‐phenyl]‐1‐(4‐hydroxyphenyl) ‐2‐phenylbut‐1‐ene ( 1 ) is a cytotoxic estrogen with a selective antitumor effect only on estrogen receptor (ER) containing tumors. In order to improve the ER affinity and thereby the antitumor activity of 1 a second OH‐group in position 3 or 4 was introduced into the phenyl ring at C‐atom 2 ( 8 and 9 ) and the respective acetates 10 and 11 were prepared. These modifications caused an enhanced ER affinity of 8 – 11 as compared to 1 . The estrogenic properties were only slightly increased. In vitro, an enhanced antitumor effect on the ER positive MCF‐7 mammary tumor cell line was determined for 8 – 11 as compared to 1 leading to inhibitions up to 90%. In vivo, 8 – 11 caused a pronounced growth inhibition of the hormone‐dependent MXT M3.2 mammary tumor of the mouse though these effects were not better than those caused by 1 except the acetate 10 , which inhibited tumor growth by 88%. These data show that the introduction of a second OH‐group into 1 not only increased ER affinity, but also the antitumor activity in vitro and to a lesser extent in vivo in ER positive tumors. As none of these compounds had any significant effect on ER negative tumor models, 8 – 11 can be regarded as cytotoxic estrogens with a specific ER‐mediated effect selectively on ER positive tumors.