title: 1-[4-(N,N-bis-beta-chloroethylcarbamoyloxy)-phenyl]-1,2-bis- (hydroxyphenyl)-but-1-enes: drugs specifically targeted against estrogen receptor positive mammary tumors.
abstract: 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.
authors.affiliation: Sonderforschungsbereich 234, Institut für Pharmazie, Universität Regensburg, F.R.G.
authors.forename: M R
authors.initials: MR
authors.lastname: Schneider
authors.forename: M L
authors.initials: ML
authors.lastname: Schuderer
mesh_terms: D000475:Alkenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000475:Alkenes; D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D011960:Receptors, Estrogen; C058082:1-(4-(N,N-bis-2-chloroethylcarbamoyloxy)phenyl)-1-(4-hydroxyphenyl)-2-phenylbut-1-ene