Cytotoxic esters of 1,1-bis-(4-hydroxyphenyl)-2-phenyl-but-1-ene with selective antitumor activity against estrogen receptor-containing mammary tumors.

Both hydroxy groups of 1,1-bis-(4-hydroxyphenyl)-2-phenyl-but-1-ene (1) were esterified with the beta-chloropropionate (2), beta-bromopropionate (3) and acrylate functions (4). Linkage of these cytotoxic moieties reduced the estrogen receptor affinities of these compounds, especially in the case of the beta-haloesters only slightly compared with the affinity of the unsubstituted carrier molecule 1. The estrogenic potencies of the derivatives 2-4 and of 1 were nearly identical. The alkylating activities increased in the order 2, 3, and 4. Because of their alkylating activities, all cytotoxic esters showed an irreversible mode of binding to the estrogen receptor. In vitro, 3 in particular, exerted better growth inhibition of the hormone-dependent MCF-7 cell line than of the hormone-independent MDA cell line. In vivo, all cytotoxic derivatives caused almost complete inhibition of the growth of the hormone-dependent MXT M3.2 mouse mammary tumor, whereas growth of the hormone-independent MXT-Ovex tumor was much less inhibited. In all tumor models, the antitumor effect of the cytotoxic esters was better than that of the unsubstituted carrier. Therefore, the antitumor activity of these esters could be due not only to their improved pharmacokinetic properties compared to 1, but also to a selective estrogen receptor-mediated cytotoxic action.