Document Detail

Bicyclic core estrogens as full antagonists: synthesis, biological evaluation and structure-activity relationships of estrogen receptor ligands based on bridged oxabicyclic core arylsulfonamides.
MedLine Citation:
PMID:  23033157     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Organic & biomolecular chemistry     Volume:  10     ISSN:  1477-0539     ISO Abbreviation:  Org. Biomol. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-17     Completed Date:  2013-04-05     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  101154995     Medline TA:  Org Biomol Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  8692-700     Citation Subset:  IM    
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MeSH Terms
Bicyclo Compounds / chemical synthesis*,  chemistry,  pharmacology*
Estrogens / chemical synthesis,  chemistry,  pharmacology*
Models, Molecular
Molecular Structure
Receptors, Estrogen / antagonists & inhibitors*
Structure-Activity Relationship
Sulfonamides / chemical synthesis,  chemistry*,  pharmacology*
Grant Support
Reg. No./Substance:
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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