Untitled

Yang, David J.; Wallace, Sidney; Tansey, Wayne; Wright, Kenneth C.; Kuang, Li-Ren; Tilbury, R.S.; Diego, Isabel; Lim, Jean-Luc; Emran, Ali M.; Kim, E. Edmund

doi:10.1023/a:1015879717742

Cited by 14 publications

(3 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Binding assays were carried out for selected compounds, representing highly potent members of their corresponding series. A novel radiolabeled estradiol displacement protocol was developed from existing studies. , ERα-rich cytosol isolated from rat uteri was used in the procedure. Binding affinity as determined by the K i value was measured for compounds 2a , 3a , 4d , and 5e and is illustrated (with reference to TAM) in Table .…”

Section: Biochemistrymentioning

confidence: 99%

“…It has been suggested that building flexibility into the rigid backbone of antiestrogens could enhance their activity and binding affinity for the estrogen receptor ,− The chemotherapeutic and antiestrogenic potential of the compounds prepared is determined through appropriate biochemical assays. − The availability of highly resolved crystal structure studies of the estrogen receptor α (ERα) allows the investigation of both actual and theoretical interactions of both estrogenic and antiestrogenic materials in the LBD. − A thorough computational investigation of the predicted orientation and interaction of representative compounds within the LBD of the human ERα is undertaken, with a view to rationalizing antiestrogenic activity observed through analyzing ligand−receptor interactions, to provide an insight into the basis for biological activity of the compounds prepared . Such work further illustrates the eclectic liganding behavior of ERα and its tolerance for flexible antiestrogen systems.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Flexible Estrogen Receptor Modulators: Design, Synthesis, and Antagonistic Effects in Human MCF-7 Breast Cancer Cells

et al. 2001

View full text Add to dashboard Cite

Although many series of estrogen receptor antagonists continue to be produced, the majority are direct structural analogues of existing modulators. To examine the tolerance of the estrogen receptor toward flexible ligands, a series of novel flexible estrogen receptor antagonists were prepared and their antiproliferative effects on human MCF-7 breast tumor cells investigated. Each of these compounds deviated from the traditional triphenylethylene backbone associated with common tamoxifen analogues through the introduction of a flexible methylene (benzylic) spacing group between one of the aryl rings and the ethylene group and through variations in the basic side chain moiety. The compounds prepared, when assayed in conjunction with a tamoxifen standard, demonstrated high potency in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity and high binding affinity. A computational study was undertaken to investigate the compounds' potential interactions with specific residues within the human estrogen receptor alpha ligand-binding domain (ER-LBD), predicting these compounds bind in an antiestrogenic fashion within the ER-LBD and interact with those important residues previously identified in the structures of ER-LBD agonist/antagonist cocrystals. These compounds further illustrate the eclectic nature of the estrogen receptor in terms of ligand flexibility tolerance.

show abstract

Section: Biochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Flexible Estrogen Receptor Modulators: Design, Synthesis, and Antagonistic Effects in Human MCF-7 Breast Cancer Cells

et al. 2001

View full text Add to dashboard Cite

show abstract

“…To confirm our hypothesis that these compounds were acting through the estrogen receptor, an initial binding investigation ,, was carried out using compounds 7 and 15 as representative candidates. The study indicates the compounds are competitive antagonists with moderate binding affinity for the ER (binding K i 3.2 ± 2.1 μM ( 7 ) and 828 ± 106 nM ( 15 )), marginally weaker than that measured for tamoxifen ( 1 ) and the structurally related benzocycloheptenes .…”

mentioning

confidence: 99%

Benzoxepin-Derived Estrogen Receptor Modulators: A Novel Molecular Scaffold for the Estrogen Receptor

et al. 2004

View full text Add to dashboard Cite

We present and examine the efficacy of a novel benzoxepin-based scaffold for modulation of the human estrogen receptor. Receptor tolerance of this new molecular scaffold is examined through presentation of experimentally determined antiproliferative effects on human MCF-7 breast tumor cells and measured binding affinities. The effect of functional group substitution on the benzoxepin scaffold is explored through a brief computational structure-activity relationship investigation with molecular simulation.

show abstract