Synthesis of 2-Phenylbenzofuran Derivatives and Selective Binding Activities on Estrogen Receptor

Zhang, Ping; Yang, Yan; Zheng, Xiaoliang; Huang, Wenhai; Ma, Zhen; Shen, Zhengrong

doi:10.1248/cpb.60.270

Cited by 11 publications

(7 citation statements)

References 23 publications

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“…When docking to ERβ, however, a significant increase of the docking energy could be observed (ΔG AH =∑11.49 kcal/mol, ΔG AG =43.89 kcal/mol). As we reported before, 37) the binding cavity size of ERβ is slightly smaller than that of ERα. Since AH is a small molecule with 19 heavy atoms (molecule weight=299), the increase of the docking energy might be due to the loss of the hydrogen bonds compared to ERα.…”

Section: Resultssupporting

confidence: 73%

Discovery of Novel Selective ERα/ERβ Ligands by Multi-pharmacophore Modeling and Virtual Screening

Huang

Wei

Yang

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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Estrogen receptor α (ERα) and estrogen receptor β (ERβ) regulate different sets of gene expression, and have different ligand responses, which make the estrogen tissue-specific. Thus, the estrogen receptor (ER) subtype-selective ligands can improve the target-site selectivity and decrease the off-target effect. In order to discover the selective ER subtype ligands with novel scaffolds, in this work three-dimensional (3D) pharmacophore models of the ERα ligands (Hypo 1) and the ERβ ligands (Hypo 2) were established (correlation coefficients were 0.959 and 0.966) and validated (R 0.936 and 0.879; enrichment factors (EFs) at 2% were 16.2 and 8.4; areas under the concentration-time curve (AUC) of the receiver operating curve (ROC) were 0.88 and 0.91) using the Discovery Studio 4.0 software package. Hypo 1 and Hypo 2 were then employed for virtual screening and ten hits were found as potential candidate leads. Based on their ERα/ERβ binding affinity results by fluorescence polarization technology, two of these leads, AH-262/34334025 (AH) and AG-670/08803023 (AG) with novel scaffolds were identified as selective ERα ligands. A molecular docking study was also performed, which provided the explanation for the ER subtype preferences for AH and AG.Key words estrogen receptor ligand; pharmacophore model; virtual screening Estrogen exerts its cascade of biochemical events through estrogen receptors (ERs).1-3) Mainly, there are two ER subtypes, estrogen receptor α (ERα) and estrogen receptor β (ERβ). ERα predominates in the uterus and the mammary gland, thus being mostly responsible for the female reproductive functions, whereas ERβ plays roles in many other body compartments, such as the central nervous, urogenital and immune systems. 4,5) ERα and ERβ regulate different sets of gene expression, and have different ligand responses, which make the estrogen tissue-specific. For instance, since estrogen can promote growth in breast cancers via the activation of ERα, ERα antagonists can be used for treating breast cancer. An ERβ-selective ligand may promote ER activity in the bone without promoting tumorigenesis in the breast. Furthermore, ER subtype ligands could present opposite effect in ovarian. ERα antagonist could suppress the cell growth in ovarian cancer cell lines SKOV3 and OV2008, whereas ERβ antagonist could significantly enhance cell growth.6) Therefore, subtypeselective ligands can improve the target-site selectivity and decrease the off-target effect.Until now, many ER ligands have been reported. Most of them (such as 1, 3, 5, 8, 48 in Fig. 1) have the similar scaffold of diphenylethene or diphenylpropylene. In this work, we focused on discovering the lead compound with new scaffold. Pharmacophore model-based virtual screening is a common fast way to find the lead compounds. Therefore, pharmacophore models of the ERα and ERβ ligands were built and employed for discovering selective ER subtype ligands (Fig. 2). ExperimentalData Preparation Sixty-nine positives with binding affinities (range from 0.3 to 7980 nmol) o...

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Section: Resultssupporting

confidence: 73%

Discovery of Novel Selective ERα/ERβ Ligands by Multi-pharmacophore Modeling and Virtual Screening

Huang

Wei

Yang

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The molecular docking study was performed as reported . Briefly, the Discovery Studio 2.5/flexible docking protocol with published crystal structure of E2/ERα complex (PDB ID:1A52) or E2/ERβ complex (PDB ID: 3OLS) was used, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The molecular docking study was performed as reported. [15] Briefly, the Discovery Studio 2.5/flexible docking protocol with published crystal structure of E2/ERa complex (PDB ID:1A52) or E2/ERb complex (PDB ID: 3OLS) was used, respectively. Based on methods within CHARMm to sample side chain and ligand conformations, the side chains of amino acids in the LBD were allowed to move during docking in an induced fit model.…”

Section: Dockingmentioning

confidence: 99%

“…Recently, we compared the structures of pre‐ or postclinic SERMs in the literatures and found that most compounds have a similar scaffold of diphenylethene and a common basic ether side chain . Previously, we showed the compounds with a conjugated diphenylethene skeleton, such as 2‐phenylbenzofuran derivatives, had a high ER binding affinity and subtype‐selective activity . Cyclopropyl group is a common pharmacophore in many biologically active molecules, and more importantly, this group is considered as an ethylene bioisostere .…”

Section: Introductionmentioning

confidence: 99%

“…[14] Previously, we showed the compounds with a conjugated diphenylethene skeleton, such as 2-phenylbenzofuran derivatives, had a high ER binding affinity and subtype-selective activity. [15] Cyclopropyl group is a common pharmacophore in many biologically active molecules, [16] and more importantly, this group is considered as an ethylene bioisostere. [17,18] Many cyclopropyl derivatives were designed and synthesized as ligands for ERs.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and biological evaluation of novel cyclopropyl derivatives as subtype-selective ligands for estrogen receptor

Wang

Yang

Zheng

et al. 2018

Journal of Pharmacy and Pharmacology

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Palladium‐Catalyzed Synthesis of Benzofurans and Coumarins from Phenols and Olefins

et al. 2013

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Synthesis of 2-Phenylbenzofuran Derivatives and Selective Binding Activities on Estrogen Receptor

Cited by 11 publications

References 23 publications

Discovery of Novel Selective ERα/ERβ Ligands by Multi-pharmacophore Modeling and Virtual Screening

Discovery of Novel Selective ERα/ERβ Ligands by Multi-pharmacophore Modeling and Virtual Screening

Synthesis and biological evaluation of novel cyclopropyl derivatives as subtype-selective ligands for estrogen receptor

Palladium‐Catalyzed Synthesis of Benzofurans and Coumarins from Phenols and Olefins

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