Search

Among nonsteroidal antiandrogens, mostly compounds of the Flutamide-type are described. For the development of new compounds with affinity to androgen receptors and antiandrogenic activity five new hydroxy-substituted phenyltetralines were prepared and tested. Synthesis was achieved by reaction of the respective 1-tetralones with phenyl magnesium bromides, dehydration of the carbinols, hydrogenation and ether cleavage. In addition to the expected affinity to estrogen receptors, especially the 6-OH, 4'-OH-substituted compound 11 showed an affinity to androgen receptors, too. Whereas none of the tested compounds had a marked estrogenicity, 11 and 15 (6-OH, 3'-OH) exerted antiestrogenic effects. Androgenic properties were not given. In the adult, intact mouse, 11 and 15 exhibited a pronounced inhibition of seminal vesicle weights concomitant with a reduction of the testosterone level. Since in castrated, androgen-substituted animals only relatively weak direct antiandrogenic effects were demonstrable, the antiandrogenic activity of these new phenyltetralines is more due to an inhibition of testosterone biosynthesis than to a direct, receptor-mediated effect.

1,1,2-Triphenylbut-1-enes (26-35), which are substituted with one or two 3,4-diacetoxy groups or with one 3,4-diacetoxy and one 3- or 4-acetoxy group in two aromatic rings, were synthesized. The occurring E and Z isomers were isolated, and their identity was established by 1H NMR spectroscopy. A study on structure-activity relationship was carried out with regard to estradiol receptor affinity in vitro, estrogenic and antiestrogenic properties in the immature mouse, and inhibition of the hormone-dependent MXT mammary tumor of the mouse in vivo. Among the tested compounds, most of the 1,1-disubstituted 1,1,2-triphenylbut-1-enes (29, Z-30, Z,E-31) and (E)-1-(3-acetoxyphenyl)-1-phenyl-2-(3,4-diacetoxyphenyl)but- 1-ene (E-35) as well as its respective Z isomer (Z-35) exerted antiestrogenic properties. Compounds Z-30, Z,E-31, Z-35, and E-35 inhibited the growth of the hormone-dependent MXT tumor. The best antitumor effect without estrogenic side effects during therapy was shown by E-35.

Three 1,2-diaminoethane-dichloro-platinum(II) complexes linked to 5-hydroxy-2-(4-hydroxyphenyl)-3-methylindole by spacer groups of varying length were evaluated for cytostatic activity in estrogen receptor (ER) positive and negative tumor cells. In vitro, only the growth of ER positive MCF-7 mammary tumor cells was inhibited whereas hormone independent MDA-MB 231 cells did not respond. In vivo, a strong inhibitory effect was only observed in ER positive MXT mammary tumors of the mouse. The complex with a hexyl group as spacer reduced the tumor weight by 89% after 6 weeks of treatment. The R 3327 Dunning prostatic tumor of the rat, which also contains ER was inhibited, too. Generally, the effect in ER negative tumors was weak. These findings can be rationalized by the high binding affinities of the complexes for ER. By the mouse uterine weight test it was shown that the endocrine activity of the complexes is very low. Therefore, a mode of action different from that exerted by estrogens or antiestrogens has to be assumed.