Identification and Structure–Activity Relationships of a Novel Series of Estrogen Receptor Ligands Based on 7-Thiabicyclo[2.2.1]hept-2-ene-7-oxide

Wang, Pengcheng; Min, Jian; Nwachukwu, Jerome C.; Cavett, V.; Carlson, Kathryn E.; Guo, Pengju; Zhu, Manghong; Zheng, Yangfan; Dong, Chune; Katzenellenbogen, John A.; Nettles, K.W.; Zhou, Hai-Bing

doi:10.1021/jm201556r

Cited by 37 publications

(45 citation statements)

References 66 publications

(147 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…11, 22 In agonist mode assays, cells were treated with increasing concentrations of estradiol or ligands, from which we were able to obtain measures of potency (as EC 50 values) as well as efficacy values relative to estradiol (Eff; % of E2). The antagonist mode assays, cells were treated with an increasing concentration of ligands in the presence of 10 nM estradiol, and we obtained IC 50 values and final efficacy values at the highest concentrations, again as Eff, % of E2; low numbers indicate more complete antagonism.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Exploring the Structural Compliancy versus Specificity of the Estrogen Receptor Using Isomeric Three-Dimensional Ligands

et al. 2016

Self Cite

View full text Add to dashboard Cite

The estrogen receptors (ER) bind with high affinity to many structurally diverse ligands by significantly distorting the contours of their ligand-binding pockets. This raises a question: To what degree is ER able to distinguish between structurally related regioisomers and enantiomers? We have explored the structural compliance and specificity of ERα with a set of ligands having a 7-oxa-bicyclo[2.2.1]hept-5-ene sulfonate core and basic side chains typical of selective ER modulators (SERMs). These ligands have two regioisomers, each of which is a racemate of enantiomers. Using orthogonal protecting groups and chiral HPLC, we isolated all 4 isomers and assigned their absolute stereochemistry by X-ray analysis. The 1S,2R,4S isomer has a 80–170-fold higher affinity for ERα than the others, and it profiles as a partial agonist/antagonist in cellular reporter gene assays and in suppressing proliferation of MCF-7 breast cancer cells with subnanomolar potency, far exceeding that of the other isomers. It is the only isomer found bound to ERα by X-ray analysis after crystallization with 4-isomer mixtures of closely related analogs. Thus, despite the general compliance of this receptor for binding a large variety of ligand structures, ER demonstrates marked structural- and stereo-specificity by selecting a single component from a mixture of structurally related isomers to drive ER-regulated cellular activity. Our findings lay the necessary groundwork for seeking unique ER-mediated pharmacological profiles by rational structural perturbations of two different types of side chains in this unprecedented class of ER ligands, which may prove useful in developing more effective endocrine therapies for breast cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

“…11 A third series with a sulfonamide linker (OBHS-N) enabled attachment of two pendent groups, some of which reached a full antagonist profile comparable to fulvestrant on the wild type receptor. 11, 14 …”

Section: Introductionmentioning

confidence: 99%

Exploring the Structural Compliancy versus Specificity of the Estrogen Receptor Using Isomeric Three-Dimensional Ligands

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Pharmacoinformatics models were derived from a congeneric dataset of 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide derivatives (Wang et al 2012) (Table 1) to explore QSAR and pharmacophore modeling studies to determine pharmacophoric features of the small molecule required for binding affinity of ER subtypes.…”

Section: Methodsmentioning

confidence: 99%

“…In the present study, a series of 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide derivatives (Wang et al 2012), reported as promising SERMs (Wang et al 2012) for estrogen therapy were evaluated with their relative binding affinity for pharmacoinformatics studies to explore the physicochemical properties and 3D structural conformation of chemical moieties for selective estrogenic actions, through both 2D QSAR and pharmacophore studies. The QSAR modelling was carried out to obtained statistical validated models useful in exploring structure activity relationship (SAR) of the compounds, while pharmacophore concept was based on the type of interactions observed in the molecular recognition and alternatively can be used as a query in a 3D database search to identify new structural classes of potential lead compounds and also can serve as a template for generating alignment for 3D QSAR analysis.…”

Section: Introductionmentioning

confidence: 99%

Identification of structural requirements of estrogen receptor modulators using pharmacoinformatics techniques for application to estrogen therapy

et al. 2016

View full text Add to dashboard Cite

An attempt was made in the present study to explore the structural requirements of known estrogen receptor (ER) modulators for biological activity using pharmacoinformatics approaches to elucidate critical functionalities for new, potent and less toxic chemical agents for successful application in estrogen therapy. For this purpose a group of non-steroidal ligands, 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide derivatives were collected from the literature to perform quantitative structure-activity relationship (QSAR), pharmacophore and molecular docking studies. The 2D QSAR models (R for α-and β-subtypes respectively. The functionalities developed in the QSAR and pharmacophore studies were substantiated by molecular docking which provided the preferred orientation of ligands for effective interaction at the active site cavity.

show abstract

“…[23][24][25][26] DielsAlder chemistry with sulfonate substituents 23 has been extended to the preparation of a variety of structures 24 and has proved particularly useful in the pursuit of the pamamycin macrodiolides 24,27 and estrogen receptor ligands possessing the oxabicyclo[2.2.1]heptene framework. [28][29][30][31] Diels-Alder reactions with sulfinate ester-bearing dienophiles have also been studied. [32][33][34][35] The sulfinate is particularly appealing for its ability to be readily adapted by reduction, 34,36,37 oxidation, [38][39][40] and transformation to sulfoxide.…”

Section: Introductionmentioning

confidence: 99%

Unexpected reactions of Grignard reagents with selected β-carboalkoxy substituted sulfinate esters

et al. 2015

View full text Add to dashboard Cite

A series of six-membered rings bearing cis oriented vicinal carboxylate and sulfinate esters were treated with Grignard reagents with the intention of transforming them to ␤-carboalkoxy substituted sulfoxides. The expected outcome did not transpire and instead the substrates demonstrated the capacity to accept 3 equiv. of organometallic agent in an uncontrollable manner. As such, the substrates possessing eclipsing carboxylate and sulfinate esters accepted two organic ligands at the carboxylate functionality and one at the sulfinyl group. When isomer mixtures of sterically encumbered sulfinate esters were reacted, a single sulfoxide stereochemistry resulted. A mechanism involving the intermediacy of a sulfurane is proposed to account for the experimental observations. Résumé : Une série de cycles à six membres portant des esters carboxyliques et sulfiniques vicinaux ont été traités avec des réactifs de Grignard dans le but de les transformer en ␤-carboalkoxy sulfoxydes substitués. Le résultat espéré n'a pas été obtenu et, au lieu de cela, les substrats ont montré une capacité à accepter trois équivalents d'agent organométallique de manière incontrôlable. En tant que tels, les substrats portant des esters carboxyliques et sulfiniques en position éclipsante ont accepté deux ligands organiques au niveau de la fonction carboxylate et un au niveau du groupe sulfinyl. La réaction de mélanges isomériques d'esters sulfiniques stériquement encombrés a débouché sur une seule stéréochimie du sulfoxyde. Un mécanisme impliquant l'intermédiaire d'un sulfurane est proposé, qui permet d'expliquer les observations expérimentales. [Traduit par la Rédaction]Mots-clés : réactif de Grignard, ester sulfinique, sulfoxyde, réaction d'addition, sulfurane.

show abstract

Identification and Structure–Activity Relationships of a Novel Series of Estrogen Receptor Ligands Based on 7-Thiabicyclo[2.2.1]hept-2-ene-7-oxide

Cited by 37 publications

References 66 publications

Exploring the Structural Compliancy versus Specificity of the Estrogen Receptor Using Isomeric Three-Dimensional Ligands

Exploring the Structural Compliancy versus Specificity of the Estrogen Receptor Using Isomeric Three-Dimensional Ligands

Identification of structural requirements of estrogen receptor modulators using pharmacoinformatics techniques for application to estrogen therapy

Unexpected reactions of Grignard reagents with selected β-carboalkoxy substituted sulfinate esters

Contact Info

Product

Resources

About