Design and synthesis of carborane-containing estrogen receptor-beta (ERβ)-selective ligands

Ohta, Kiminori; Ogawa, Tokuo; Oda, Akifumi; Kaise, Asako; Endo, Yasuyuki

doi:10.1016/j.bmcl.2015.08.007

Cited by 19 publications

(6 citation statements)

References 35 publications

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“…The binding affinities of the synthesized bisphenols (compounds 4a – 4c and 5a – 5c ) toward ERα were evaluated by means of a competitive binding assay using [6,7- 3 H] 17β-estradiol and human recombinant ERα [27,28,29]. Figure 2A,B shows dose-response curves for competitive binding of the synthesized compounds 4a – 4c and 5a – 5c to ERα, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Next, estrogenic and antiestrogenic activities of compounds 4a – 4d and 5a – 5d , except for 4b and 5b (poor binding affinity toward ERa), were evaluated by means of a cell proliferation assay using the human breast cancer cell line MCF-7, which shows ER-dependent growth [27,28,29]. Table 1 summarizes the EC 50 , IC 50 , and E max values estimated from the MCF-7 cell proliferation assays.…”

Section: Resultsmentioning

confidence: 99%

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Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens

et al. 2019

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Based upon hydrophobic feedback approaches, we designed and synthesized novel sulfur-containing ERα modulators (4 and 5) as breast cancer therapeutic drug candidates. The tetrahydrothiepine derivative 5a showed the highest binding affinity toward ERα because of its high hydrophobicity, and it acted as an agonist toward MCF-7 cell proliferation. The corresponding alkylamino derivative 5d maintained high binding affinity to ERα and potently inhibited MCF-7 cell proliferation (IC50: 0.09 μM). Docking simulation studies of compound 5d with the ERα BD revealed that the large hydrophobic moiety of compound 5d fit well into the hydrophobic pocket of the ERα LBD and that the sulfur atom of compound 5d formed a sulfur–π interaction with the amino acid residue His524 of the ERα LBD. These interactions play important roles for the binding affinity of compound 5d to the ERα LBD.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens

et al. 2019

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“…43 By comparing BE120 to ERB-041, this same group more recently reported para-carboranylcyclohexanol derivatives with ERβ selective activity. 44 Herein, we describe a novel series of BE120-based para-carborane derivatives demonstrating highly selective ERβ agonist activity.…”

Section: ■ Introductionmentioning

confidence: 99%

“…From this work, the para -carborane BE120 was shown to be an effective 17β-estradiol mimic with sufficient druglike properties to provide in vivo estrogenic effects following daily parenteral dosing in rats . By comparing BE120 to ERB-041, this same group more recently reported para -carboranylcyclohexanol derivatives with ERβ selective activity . Herein, we describe a novel series of BE120 -based para -carborane derivatives demonstrating highly selective ERβ agonist activity.…”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship of para-Carborane Selective Estrogen Receptor β Agonists

et al. 2021

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Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceeding to various stages of clinical development. Carborane scaffolds offer many unique advantages including the potential for novel ligand/receptor interactions but remain relatively unexplored. We synthesized a series of para-carborane estrogen receptor agonists revealing an ERβ selective structure–activity relationship. We report ERβ agonists with low nanomolar potency, greater than 200-fold selectivity for ERβ over ERα, limited off-target activity against other nuclear receptors, and only sparse CYP450 inhibition at very high micromolar concentrations. The pharmacological properties of our para-carborane ERβ selective agonists measure favorably against clinically developed ERβ agonists and support further evaluation of carborane-based selective estrogen receptor modulators.

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“…Besides, stability, low‐toxicity, strong hydrophobicity, resistance to catabolism, kinetic inertness to reagents, spherical geometry and well‐established chemistry of boron clusters may allow their use as scaffold in pharmacophores. As example, the boron compounds related to closo ‐borates, carboranes were investigated as three‐dimensional hydrophobic core in the design of potent estrogen agonists and retinoid antagonists, protein kinase C modulators, and others For carborane‐containing pharmacophores, the ability to prevent the dissociation of transthyretin and thereby its amyloid aggregation by stabilizing the protein tetramer has been shown …”

Section: Introductionmentioning

confidence: 99%

The Discovery of the Effect of closo‐Borate on Amyloid Fibril Formation

Kuperman

Chernii

Varzatskii³

et al. 2017

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The activity of the boron cluster ‐ closo‐borates in protein amyloid fibrillization was first studied. For this, we explored the effect of dianionic compound [B12H12]2− on aggregation of amyloidogenic protein insulin by the circular dichroism spectroscopy, amyloid‐sensitive fluorescent dye based assay and transmission electron microscopy. It was shown that the presence of closo‐borate during fibrillization reaction speeds up the loss of the protein α‐helical structure. This effect of dianionic compound on protein fibrillization process is concentration‐dependent. Closo‐borate at low concentration (10 mM) enhances the intensity of insulin fibrillization, while at higher concentration (50 mM, 100 mM) fluorescent assay showed the decrease of this intensity. The morphology of fibrils formed in the presence of the boron dianion differs from that of free insulin, namely they are less branched and have the bigger diameter. Besides, closo‐borate‐induced fibrils have strong proneness to stick together forming large aggregated clots.

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Design and synthesis of carborane-containing estrogen receptor-beta (ERβ)-selective ligands

Cited by 19 publications

References 35 publications

Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens

Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens

Structure–Activity Relationship of para-Carborane Selective Estrogen Receptor β Agonists

The Discovery of the Effect of closo‐Borate on Amyloid Fibril Formation

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