Journal of Medicinal Chemistry p. 192 - 197 (1989)
Update date:2022-08-03
Topics:
Ruenitz, Peter C.
Arrendale, Richard F.
Schmidt, Walter F.
Thompson, Carolyn B.
Nanavati, Nitin T.
The triarylethylene antiestrogen clomiphene (1) was previously shown to undergo biotransformation to an active metabolite, 4-hydroxyclomiphene (2), and to 3-methoxy-4-hydroxyclomiphene (3) plus the respective regioisomers of these, 4 and 5.We now report the synthesis and further chemical and biochemical studies on 3-5.Coupling of 4-<2-(diethylamino)ethoxy>benzophenone (10) with either 4-(benzyloxy)benzaldehyde (11a) or its 3-methoxy analogue 11b in the presence of titanium, followed by chlorination and deprotection of the intermediate triarylethylenes, gave 4 and 5, resp ectively .Condensation of benzylmagnesium chloride with the (2-methoxyethoxy)methyl (MEM) ether of 4-<2-(diethylamino)ethoxy>-3'-methoxy-4'-hydroxybenzophenone (8), followed by mild acid treatment, afforded deschloro 3 due to facile MEM ether hydrolysis.Acetylation of this, followed by chlorination and deacetylation, gave 3.Compounds 4 and 5 reacted readily with nucleophiles.In particular, 2-mercaptoethanol reacted with 4 to afford deschloro vinyl thioether 13 as suggested by NMR spectral studies, a result that implicated allene-quinone 14 as the electrophilic species produced in solution from 4.Antiestrogen binding sites and estrogen receptors from MCF 7 human breast cancer cells interacted with 3 and 5 with affinities comparable to those of tamoxifen and 1, respectively; 5 was shown not to bind irreversibly with these sites.Inhibition of MCF 7 cells proliferation by 3-5 at 5 μM concentration (76percent, 57percent, and 49percent, respectively, relative to drug-free controls) compared favorably to that observed with 5 μM 1 (80percent).These results suggest that 3-5 as well as 2 may contribute to the antiestrogenic effects of 1.
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