Novel steroidal pure antiestrogens

doi:10.1016/0039-128X(89)90076-7

Steroids

Volume 54, Issue 1, July 1989, Pages 71-99

https://doi.org/10.1016/0039-128X(89)90076-7 Get rights and content

Abstract

A series of steroidal estrogen antagonists with no intrinsic estrogenicity in rat uterotrophic-antiuterotrophic tests has been discovered. The compounds are derivatives of estradiol containing amidoalkyl side chains at the 7α-position. The most potent compounds are N-n-butyl-N-methyl-11-(3,17β-dihydroxyestra-1, 3,5(10)-trien-7α-yl)undecanamide and N-2,2,3,3, 4,4,4-heptafluorobutyl-N-methyl-11-(3,17β-dihydroxyestra-1,3, 5(10)-trien-7α-yl)undecanamide. Structure activity relationships are discussed.

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Conversely, SERMs block the AF-2 activity with H12 relocating into the coactivator-binding cleft (Nettles and Greene, 2005; Paul et al., 2003; Pike et al., 2001). Moreover, the binding of pure antagonists results in the complete destabilization of H12 because of their bulky alkyl chains (Bowler et al., 1989; Pike et al., 2001; Wakeling et al., 1991). The MD simulations show the conformation changes of hERα in the apo state when binding the different PAEs-type ligands (Figs. S1–S3).
Phthalate esters (PAEs), as widely used plasticizers, have been concerned for their possible disruption of estrogen functions via binding to and activating the transcription of estrogen receptors (ERs). Nevertheless, the computational interpretation of the mechanism of ERs activities modulated by PAEs at the molecular level is still insufficient, which hinders the reliable screening of the ERs-active PAEs with high speed and high throughput. To bridge the gap, the in silico simulations considering the effects of coactivators were accomplished to explore the molecular mechanism of action for the purpose of predicting the estrogenic potencies of PAEs. The transcriptional activation functions of human ERα (hERα) modulated by PAEs is predicted via the simulations including binding interaction of PAEs and hERα, conformational changes of PAEs-hERα complexes and recruitment of coactivators. Molecular insight into the diverse estrogen mechanism of action among PAEs with regard to hERα agonists and selective estrogen receptor modulators (SERMs) is provided. Agonist-modulated conformational change of hERα leads to the optimal exposure of its Activation Function 2 (AF-2) surface which, in turn, facilitates the recruitment of coactivators, therefore promoting the transcriptional activation functions of hERα. Conversely, binding interaction of hERα with SERMs among PAEs leads to the conformational change with blocked AF-2 surface, thus preventing the recruitment of coactivators and consequently inhibiting the AF-2 activity. The two-hybrid recombinant yeast is experimentally used for verification. The established in silico evaluation methodology exhibits great promise to speed up the prediction of chemicals which work as hERα agonist or SERMs.
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Estrogen receptor-positive (ER⁺) breast cancers frequently remain dependent on ER signaling even after acquiring resistance to endocrine agents, prompting the development of optimized ER antagonists. Fulvestrant is unique among approved ER therapeutics due to its capacity for full ER antagonism, thought to be achieved through ER degradation. The clinical potential of fulvestrant is limited by poor physicochemical features, spurring attempts to generate ER degraders with improved drug-like properties. We show that optimization of ER degradation does not guarantee full ER antagonism in breast cancer cells; ER “degraders” exhibit a spectrum of transcriptional activities and anti-proliferative potential. Mechanistically, we find that fulvestrant-like antagonists suppress ER transcriptional activity not by ER elimination, but by markedly slowing the intra-nuclear mobility of ER. Increased ER turnover occurs as a consequence of ER immobilization. These findings provide proof-of-concept that small molecule perturbation of transcription factor mobility may enable therapeutic targeting of this challenging target class.
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It was observed that pure antiestrogenicity resulted from compounds whose chain lengths at the 7α position were anywhere between 15–19 atoms, long enough to interact with the coactivator binding groove. Side chains with 13–14 carbon atoms either resulted in agonist or SERM activity (Bowler, Lilley, Pittam, & Wakeling, 1989; Hilmi et al., 2012; Traboulsi, El Ezzy, Gleason, & Mader, 2017). The side chain of ICI 164,384 was shown to abolish the association between H12 and the rest of the LBD, preventing the receptor from adopting an agonist or an antagonistic conformation highlighting the unique mode of action of pure antiestrogens (Pike et al., 2001).
Breast cancer is the most frequently diagnosed cancer in women, with estrogen receptor positive (ER+) breast cancer making up approximately 75% of all breast cancers diagnosed. Given the dependence on active ER signaling in these tumors, the predominant treatment strategy has been to inhibit various aspects of this pathway including directly antagonizing ER with the use of selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). Interestingly, the dependence on ER for breast cancer growth is often retained even after progression through several lines of antiestrogen therapy, making ER a bonafide biomarker for this cancer subtype and driving the continued research and development of novel ER-targeted therapeutics to treat this patient population. This, combined with the continuous discovery of mechanisms underlying endocrine resistance, is resulting in a continually evolving treatment landscape for ER+ breast cancer. This review discusses various ER antagonists investigated for the treatment of breast cancer, outlining their pharmacological and tissue-specific mechanisms of action as well as their specified use within the ER+ breast cancer setting. In addition, mechanisms of resistance to SERMs and SERDs, the use of ER antagonists in combination therapy strategies, and the ongoing development of novel drugs are also reviewed in the context of the changing clinical landscape of ER+ breast cancer. Lastly, the role of SERMs and SERDs in non-breast cancer indications is also discussed.
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Several lines of evidence suggest that 7α-substituted estradiol derivatives bind to the estrogen receptor (ER). In line with this hypothesis, we designed and synthesized ¹⁸F-labeled 7α-fluoroalkylestradiol (Cn-7α-[¹⁸F]FES) derivatives as molecular probes for visualizing ERs. Previously, we successfully synthesized 7α-(3-[¹⁸F]fluoropropyl)estradiol (C3-7α-[¹⁸F]FES) and showed promising results for quantification of ER density in vivo, although extensive metabolism was observed in rodents. Therefore, optimization of the alkyl side chain length is needed to obtain suitable radioligands based on Cn-7α-substituted estradiol pharmacophores.
We synthesized fluoromethyl (23; C1-7α-[¹⁸F]FES) to fluorohexyl (26; C6-7α-[¹⁸F]FES) derivatives, except fluoropropyl (C3-7α-[¹⁸F]FES) and fluoropentyl derivatives (C5-7α-[¹⁸F]FES), which have been previously synthesized. In vitro binding to the α-subtype (ERα) isoform of ERs and in vivo biodistribution studies in mature female mice were carried out.
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