The phenolic hydroxy groups of l,l-bis-(4-hydroxyphenyl)-2-phenylbut-1-ene (1) were converted to esters of different chain length and degree of haiogen substitution, and to carbamate, imidoester and ether derivatives. Most of the products maintain the afinity to the estrogen receptor. The acetate 2 has a better antitumor potency than 1.
EinfluB der Derivatisierung der Hydroxygruppen von l,i-Bis-(4-hydroxyphenyl)-2-phenyl-but-1-en auf die Estrogenrezeptoraffinitat und die wachstumshemmende Wirkung am MammacarzinomDie phenolischen OH-Gruppen des l,l-Bis-(4-hydroxyphenyl)-2-phenyl-but-l-ens (1) wurden zu Estern unterschiediicher Kettenlänge und Halogensubstitutionsgrads, zu Carbamaten, Imidoestern und Ethern derivatisiert. Die Afinität zum Estrogenrezeptor blieb bei den meisten Derivaten erhaiten. Das Acetat 2 hat eine bessere Antitumorwirkung als die Ausgangsverbindung 1. 0365-6233/87/0707-O635 S 02.50/0 O VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1987
Schuderer and SchneiderArch. Pharm.
Schuderer and SchneiderArch. Pharm.
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.
A 1,1,2-triphenylbut-1-ene with a 4-OH group at one C-1 phenyl ring and a chlorocarbamate mustard moiety at the second C-1 ring (compound 3) was synthesized in order to obtain a "cytotoxic estrogen" with a specific antitumor effect on estrogen-receptor-containing tumors. This compound was tested in comparison to the carrier (compound 1) and a compound (2) having a carbamate mustard group on both C-1 phenyl rings. The estrogen receptor affinity of compound 3 was only about one-quarter lower than that of compound 1, but much higher than that of compound 2. Compounds 2 and 3 showed only partially irreversible binding to the receptor owing to their relatively low alkylating properties. The growth inhibition of the receptor-positive MCF-7 breast cancer cell line by compound 3, but not by compound 1 or 2, was more pronounced than the inhibition of the receptor-negative line MDA. In vivo the hormone-dependent, transplantable mammary tumor MXT M3.2 of the mouse was much better inhibited by compound 3 than its hormone-resistent line MXT OVEX. Compounds 1-3 had no antiestrogenic properties in the mouse, but estrogenic activity was in the order 1 greater than 3 greater than 2. From these results and because the antitumor activity of compound 3 was superior to that of compounds 1 and 2 in the hormone-dependent tumor models, a selective, receptor-mediated cytotoxic effect of compound 3 on estrogen-receptor-positive tumors in obvious.
Grignard reaction of the ketones (I) with the phenol ether (II) followed by simultaneous acidic elimination and removal of the O‐protecting group forms an E/Z‐mixture of the triarylbutenes (III).
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