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Bicyclic core estrogens as full antagonists: synthesis, biological evaluation and structure-activity relationships of estrogen receptor ligands based on bridged oxabicyclic core arylsulfonamides.

ABSTRACT: 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 ER? and ER?. 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 ER? than the selective estrogen receptor modulator (SERM) hydroxytamoxifen or OBHS, and they were inverse agonists on ER?. 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.

SUBMITTER: Zhu M

PROVIDER: S-EPMC3500388 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Bicyclic core estrogens as full antagonists: synthesis, biological evaluation and structure-activity relationships of estrogen receptor ligands based on bridged oxabicyclic core arylsulfonamides.

Zhu Manghong M Zhang Chen C Nwachukwu Jerome C JC Srinivasan Sathish S Cavett Valerie V Zheng Yangfan Y Carlson Kathryn E KE Dong Chune C Katzenellenbogen John A JA Nettles Kendall W KW Zhou Hai-Bing HB

Organic & biomolecular chemistry 20121101 43

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. Altho ...[more]

PMID: 23033157

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Project description:The norbornadiene (NBD) molecule, C7H8, owes its fame to its remarkable photoswitching properties that are promising for molecular solar-thermal energy storage systems. Besides this photochemical interest, NBD is a rather unreactive species within astrophysical conditions and it should exhibit high photostability, properties that might also position this molecule as an important constituent of the interstellar medium (ISM)-especially in environments that are well shielded from short-wavelength radiation, such as dense molecular clouds. It is thus conceivable that, once formed, NBD can survive in dense molecular clouds and act as a carbon sink. Following the recent interstellar detections of large hydrocarbons, including several cyano-containing ones, in the dense molecular cloud TMC-1, it is thus logical to consider searching for NBD-which presents a shallow but non-zero permanent electric dipole moment (0.06 D)-as well as for its mono- and dicyano-substituted compounds, referred to as CN-NBD and DCN-NBD, respectively. The pure rotational spectra of NBD, CN-NBD, and DCN-NBD have been measured at 300 K in the 75-110 GHz range using a chirped-pulse Fourier-transform millimetre-wave spectrometer. Of the three species, only NBD was previously studied at high resolution in the microwave domain. From the present measurements, the derived spectroscopic constants enable prediction of the spectra of all three species at various rotational temperatures (up to 300 K) in the spectral range mapped at high resolution by current radio observatories. Unsuccessful searches for these molecules were conducted toward TMC-1 using the QUIJOTE survey, carried out at the Yebes telescope, allowing derivation of the upper limits to the column densities of 1.6 × 1014 cm-2, 4.9 × 1010 cm-2, and 2.9 × 1010 cm-2 for NBD, CN-NBD, and DCN-NBD, respectively. Using CN-NBD and cyano-indene as proxies for the corresponding bare hydrocarbons, this indicates that-if present in TMC-1-NBD would be at least four times less abundant than indene.

Dataset Information

Bicyclic core estrogens as full antagonists: synthesis, biological evaluation and structure-activity relationships of estrogen receptor ligands based on bridged oxabicyclic core arylsulfonamides.

Publications

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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