| Bicyclic core estrogens as full antagonists: synthesis, biological evaluation and structure-activity relationships of estrogen receptor ligands based on bridged oxabicyclic core arylsulfonamides. | |
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MedLine Citation:
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PMID: 23033157 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Compounds that block estrogen action through the estrogen receptor (ER) or downregulate ER levels are useful for the treatment of breast cancer and endocrine disorders. In our search for structurally novel estrogens having three-dimensional core scaffolds, we found some compounds with a 7-oxabicyclo[2.2.1]heptene core that bound well to the ERs. The best of these compounds, a phenyl sulfonate ester (termed OBHS for oxabicycloheptene sulfonate), was a partial antagonist on both ERα and ERβ. Although OBHS bears no structural resemblance to other estrogen antagonists, it appears to achieve its partial antagonist character by stabilizing a novel conformation of the ER that involves a significant distortion of helix-11. To enhance the antagonist properties of these oxabicyclo[2.2.1]heptane core ligands, we expanded the functional diversity of OBHS by replacing the sulfonate with secondary or tertiary sulfonamides (-SO(2)NR-), isoelectronic and potentially isostructural molecular replacements. An array of 16 OBHS sulfonamide analogues were prepared through a Diels-Alder reaction of a 3,4-diarylfuran using various N-aryl vinyl sulfonamide dienophiles. While the more polar secondary sulphonamides were weak ligands, certain of the tertiary sulfonamides had very good ER binding affinity. In HepG2 cell reporter gene assays, the sulphonamides had moderate potency, but they showed lower intrinsic transcriptional activity on ERα than the selective estrogen receptor modulator (SERM) hydroxytamoxifen or OBHS, and they were inverse agonists on ERβ. Thus, the behaviour of these OBH-sulfonamides more closely mirrors the activity of full antagonists like the drug fulvestrant (ICI 182 780), and their greater antagonist biocharacter appears to arise from an accentuated distortion of helix-11. |
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Authors:
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Manghong Zhu; Chen Zhang; Jerome C Nwachukwu; Sathish Srinivasan; Valerie Cavett; Yangfan Zheng; Kathryn E Carlson; Chune Dong; John A Katzenellenbogen; Kendall W Nettles; Hai-Bing Zhou |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Organic & biomolecular chemistry Volume: 10 ISSN: 1477-0539 ISO Abbreviation: Org. Biomol. Chem. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-10-17 Completed Date: 2013-04-05 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 101154995 Medline TA: Org Biomol Chem Country: England |
Other Details:
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Languages: eng Pagination: 8692-700 Citation Subset: IM |
Affiliation:
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Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430072, China. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Bicyclo Compounds
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chemical synthesis*,
chemistry,
pharmacology* Estrogens / chemical synthesis, chemistry, pharmacology* Humans Ligands Models, Molecular Molecular Structure Receptors, Estrogen / antagonists & inhibitors* Structure-Activity Relationship Sulfonamides / chemical synthesis, chemistry*, pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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5R37 DK015556/DK/NIDDK NIH HHS; R01 DK077085/DK/NIDDK NIH HHS; R01 DK077085/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bicyclo Compounds; 0/Estrogens; 0/Ligands; 0/Receptors, Estrogen; 0/Sulfonamides |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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