10.1006/bioo.1996.0009
The research focused on the synthesis and chiral separation of four Z-isomers of 1,1-dichloro-2,2,3-triarylcyclopropane (DTACs), which are potent antitumor agents designed to target hormone-dependent breast cancer. The purpose of the study was to develop pure antiestrogens that lack estrogen agonist activity, potentially offering more effective treatment for breast cancer patients, especially those resistant to tamoxifen. The researchers synthesized the DTACs through a series of reactions involving Grignard reagents, dehydration of intermediate carbinols, and dichlorocyclopropanation. Key chemicals used in the process included benzyl-4-benzyloxyphenyl ketone, 4-bromoanisole, magnesium turnings, anhydrous THF, and various other reagents for the Grignard reaction and subsequent steps. The study concluded with the successful synthesis of the Z-isomers and their enantiomeric separation using chiral chromatography with amylose tris-3,5-dimethylphenyl carbamate as the chiral stationary phase. The enantiomers were characterized by high-resolution NMR, and their optical rotations were determined, providing a foundation for further biological evaluation of their antitumor activity.
10.1021/jm00174a020
The research focuses on the structure-activity relationship of antiestrogens, specifically phenolic analogues of 2,3-diaryl-2H-1-benzopyrans (DABP). The purpose of the study was to synthesize and evaluate these compounds for their potential as antiestrogens, with the aim of understanding the molecular origins of their partial agonist-antagonist character. The conclusions drawn from the research indicated that the incorporation of hydroxyl groups at certain positions in the benzopyran structure significantly improved receptor affinity and antagonist activity without affecting estrogen agonist activity. Notably, the monophenol 19 and the diphenol 25 emerged as potent antiestrogens, exhibiting marked antiestrogenic activity and being more effective than tamoxifen, trioxifen, and LY-117018.
10.1016/j.bmcl.2011.11.086
The study explores the development of compounds that can selectively degrade estrogen receptor alpha (ERα) in breast cancer cells. The researchers designed and synthesized three hybrid molecules, designated as compounds 5, 6, and 7, which are composed of a tamoxifen derivative and bestatin (BS), an inhibitor of the cellular inhibitor of apoptosis protein 1 (cIAP1). These molecules are engineered to cross-link ERα and cIAP1, thereby inducing ubiquitylation and subsequent proteasomal degradation of ERα. The tamoxifen derivative serves as a ligand to bind specifically to ERα, while the BS moiety binds to cIAP1 to facilitate the degradation process. The study demonstrates that compounds 5, 6, and 7 effectively reduce ERα levels in MCF-7 breast cancer cells in a dose-dependent manner, with their activity being inhibited by the proteasome inhibitor MG132, confirming the proteasomal degradation pathway. These findings suggest that these molecules could serve as potential therapeutic agents for breast cancer by selectively degrading ERα, a protein often overexpressed in breast cancer tissues.
10.1002/jlcr.2580340810
The research aimed to investigate the mechanism of tamoxifen-induced hepatic DNA adduct formation by synthesizing a tamoxifen derivative with a fully deuterated ethyl group, known as [D5-ethyl]-tamoxifen. The purpose was to probe the mechanism by which tamoxifen forms covalent DNA adducts, which is believed to be a consequence of liver cancer in rats and has implications for its use as a breast cancer preventative agent. The researchers hypothesized that cytochrome P-450 mediated α-oxidation of the ethyl group in tamoxifen is the key step in forming electrophilic alkylating agents capable of DNA adduct formation. The synthesis involved several chemicals, including 1-[4-(2-chloroethoxy)phenyl]-2-phenylethanone, sodium hydride, [D5]-iodoethane, phenyllithium, and dimethylamine, among others. The study concluded with the successful preparation of [D5-ethyl]-tamoxifen, which allows for the measurement of DNA adducts through 32P-postlabelling experiments, providing a tool to further understand the metabolic pathways and potential carcinogenic effects of tamoxifen.
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