Estrogen Receptor Ligands. II. Discovery of Benzoxathiins as Potent, Selective Estrogen Receptor α Modulators

Kim, Seongkon; Wu, Jane Y.; Birzin, Elizabeth T.; Frisch, Katalin; Chan, Wanda; Pai, Lee-Yuh; Yang, Yi Tien; Mosley, Ralph T.; Fitzgerald, Paul J.; Sharma, Nandini; Dahllund, Johanna; Thorsell, A.G.; DiNinno, Frank; Rohrer, Susan P.; Schaeffer, James M.; Hammond, Milton L.

doi:10.1021/jm034243o

Cited by 96 publications

(80 citation statements)

References 20 publications

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“…The displacement of fluorescein labeled estradiol (fluoromone) in a competitive binding assay from the human recombinant full length receptor proteins ERa and ERb expressed from baculovirus -infected insect cells by the synthesized ligands was observed as a decrease in polarization values. Compounds 13a-c and 14 containing the benzothiepin-derived molecular scaffolds were effective ERa ligands with IC 50 values in the range 8-10 nM (Table I), indicating that the benzothiepin sulfur is equally as effective as the benzoxepin oxygen in facilitating binding of the ligands to the ERa as also reported for benzoxathiins [17]. The ERa and ERb binding values for compounds 13a,13b and 14 were also confirmed in a competitive radiometric binding assay.…”

Section: Biochemistrysupporting

confidence: 63%

“…centchroman [14], benzopyrans such as EM-652 3 which is the active metabolite of EM-800 [15], benzopyranones, dibenzo[b,d]pyran-6-ones, bisbenzopyrans [16] (e.g. 4), dihydrobenzoxathins [17], (e.g. 5), bicyclo[3.3.1]nonene [18] and oxachrysenol [19] while mono [20] and bis-benzo [b ]oxepines [21] have been designed as agonists of the estrogen receptor.…”

Section: Introductionmentioning

confidence: 99%

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Benzothiepin-derived molecular scaffolds for estrogen receptor modulators: synthesis and antagonistic effects in breast cancer cells

Meegan

Barrett

Zimmermann

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of novel benzothiepin-derived compounds are described as potent selective modulators of the human estrogen receptor (SERMs). The objective of the study is to evaluate the antiproliferative effects of the compounds on human MCF-7 breast tumor cells. These heterocyclic compounds contain the traditional triarylethylene arrangement exemplified by tamoxifen, conformationally restrained through the incorporation of the benzothiepin ring system. The compounds demonstrated potency at nanomolar concentrations in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity. The compounds exhibited low nanomolar binding affinity for the estrogen receptor (ER) with some specificity for ERb, and also demonstrate potent antiestrogenic properties in the human uterine Ishikawa cell line. The effect of a number of functional group substitutions on the ER binding properties of the benzothiepin molecular scaffold is explored through a brief computational structure-activity relationship investigation with molecular simulation.

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Section: Biochemistrysupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Benzothiepin-derived molecular scaffolds for estrogen receptor modulators: synthesis and antagonistic effects in breast cancer cells

Meegan

Barrett

Zimmermann

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Numerous reviews of these two studies have been published Kong, Pike, and Hubbard, 2003;MuellerFahrnow and Egner, 1999; as have many further studies on the X-ray structures of SERMs, full antagonists and full agonists bound to the ERs Dykstra et al, 2007;Heldring et al, 2007;Kim et al, 2004;Renaud et al, 2003;Renaud et al, 2005;Tan et al, 2005;Vajdos et al, 2007). The same helix-12 clash has also been demonstrated for AR (Cantin et al, 2007) and GR (Schoch et al, 2010) in recent X-ray structure determination studies.…”

Section: Additional Examplesmentioning

confidence: 80%

Drug Design Approaches to Manipulate the Agonist-Antagonist Equilibrium in Steroid Receptors

Lusher¹,

Conti²,

Dokter³

et al. 2012

Steroids - Basic Science

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“…Finally, the importance of understanding the unique pharmacology of tamoxifen can be placed in perspective. In retrospect, tamoxifen could, in fact, be viewed as the lead compound that was essential to initiate the synthesis of a broad range of new SERMs for the treatment of diseases as diverse as osteoporosis (86)(87)(88)(89)(90)(91)(92) and rheumatoid arthritis (93,94) and the subsequent extrapolation of the SERM concept to all members of the nuclear receptor superfamily (76). The advances documented with targeting tamoxifen now offer the promise of designing drugs to treat diseases previously thought to be impossible.…”

Section: Resultsmentioning

confidence: 99%

Tamoxifen: Catalyst for the change to targeted therapy

Jordan

2008

European Journal of Cancer

176

131

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In the early 1970's, a failed postcoital contraceptive, ICI 46,474, was reinvented as tamoxifen, the first targeted therapy for breast cancer. A cluster of papers published in the European Journal of Cancer described the idea of targeting tamoxifen to patients with oestrogen receptor positive tumours, and proposed the strategic value of using long-term tamoxifen therapy in an adjuvant setting with a consideration of the antitumour properties of the hydroxylated metabolites of tamoxifen. At the time, these laboratory results were slow to be embraced by the clinical community. Today, it is estimated that hundreds of thousands of breast cancer patients are alive today because of targeted long-term adjuvant tamoxifen therapy. Additionally, the first laboratory studies for the use of tamoxifen as a chemopreventive were published. Eventually, the worth of tamoxifen was tested as a chemopreventive and the drug is now known to have an excellent risk benefit ratio in high risk premenopausal women. Overall, the rigorous investigation of the pharmacology of tamoxifen facilitated tamoxifen's ubiquitous use for the targeted treatment of breast cancer, chemoprevention and pioneered the exploration of selective estrogen receptor modulators (SERMs). This new concept subsequently heralded the development of raloxifene, a failed breast cancer drug, for the prevention of osteoporosis and breast cancer without the troublesome side effect of endometrial cancer noted in postmenopausal women who take tamoxifen. Currently, the pharmaceutical industry is exploiting the SERM concept for all members of the nuclear receptor superfamily so that medicines can now be developed for diseases once thought impossible.A new dynasty gives dominion over the ruling dynasty through perseverance and not by sudden action (Ibn Khaldun 14 th Century Arab Historian) -and so it is with changes in the approach to cancer therapy. This article will focus specifically on a cluster of scientific papers (1-3) published in the European Journal of Cancer that presaged the dramatic changes that have occurred in the past 35 years in our approach to cancer therapy. To set the scene, it is first appropriate to describe the research and treatment philosophy for breast cancer before tamoxifen.In the 1960's, the use of combination cytotoxic chemotherapy for the treatment of breast cancer had moved to center stage in the wake of an abstract presented at the American Association for Cancer Research (4). The cytotoxic "cocktail" presented by Cooper, containing cyclophosphamide, methotrexate, 5 fluorouracil, vincristine and prednisone (CMFVP), produced a dramatic response rate of >80% in patients with advanced breast cancer. In the 1960's, there was every reason to believe that cancer would be curable if 1) the right drug Correspondence: V. Craig Jordan, OBE, PhD, DSc, Vice President and Research Director for Medical Sciences, Alfred G. Knudson Chair of Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, Phone: (215) Fax: (215) ...

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Estrogen Receptor Ligands. II. Discovery of Benzoxathiins as Potent, Selective Estrogen Receptor α Modulators

Cited by 96 publications

References 20 publications

Benzothiepin-derived molecular scaffolds for estrogen receptor modulators: synthesis and antagonistic effects in breast cancer cells

Benzothiepin-derived molecular scaffolds for estrogen receptor modulators: synthesis and antagonistic effects in breast cancer cells

Drug Design Approaches to Manipulate the Agonist-Antagonist Equilibrium in Steroid Receptors

Tamoxifen: Catalyst for the change to targeted therapy

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