- Identification of an Orally Bioavailable Chromene-Based Selective Estrogen Receptor Degrader (SERD) That Demonstrates Robust Activity in a Model of Tamoxifen-Resistant Breast Cancer
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About 75% of breast cancers are estrogen receptor alpha (ER-α) positive, and women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, but resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrant must be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacy of a chromene series of ER modulators resulting in highly potent and efficacious SERDs such as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy = 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy = 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacy in the MCF-7 cell line leads to compounds with robust effects in models of tamoxifen-resistant breast cancer derived from an MCF-7 background.
- Nagasawa, Johnny,Govek, Steven,Kahraman, Mehmet,Lai, Andiliy,Bonnefous, Celine,Douglas, Karensa,Sensintaffar, John,Lu, Nhin,Lee, Kyoungjin,Aparicio, Anna,Kaufman, Josh,Qian, Jing,Shao, Gang,Prudente, Rene,Joseph, James D.,Darimont, Beatrice,Brigham, Daniel,Maheu, Kate,Heyman, Richard,Rix, Peter J.,Hager, Jeffrey H.,Smith, Nicholas D.
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supporting information
p. 7917 - 7928
(2018/09/06)
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- Development of 3-alkyl-6-methoxy-7-hydroxy-chromones (AMHCs) from natural isoflavones, a new class of fluorescent scaffolds for biological imaging
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Starting from 7-hydroxyisoflavones, we developed a new class of fluorescent scaffolds, 3-alkyl-6-methoxy-7-hydroxy-chromones (AMHCs, MW ~ 205.19, λab ~ 350 nm, λem ~ 450 nm) via a trial and error process. AMHCs have the advantages of being a small molecular moiety, having strong fluorescence in basic buffers, reasonable solubility and stability, non-toxicity, and are conveniently linked to pharmacophores. AMHCs were successfully used in fluorescence microscopy imaging of cells and tissues. This journal is
- Miao, Jianzhuang,Cui, Huaqing,Jin, Jing,Lai, Fangfang,Wen, Hui,Zhang, Xiang,Ruda, Gian Filippo,Chen, Xiaoguang,Yin, Dali
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supporting information
p. 881 - 884
(2015/02/19)
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- Free-radical-scavenging, antityrosinase, and cellular melanogenesis inhibitory activities of synthetic isoflavones
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In this study, we examined the potential of synthetic isoflavones for application in cosmeceuticals. Twenty-five isoflavones were synthesized and their capacities of free-radical-scavenging and mushroom tyrosinase inhibition, as well as their impact on cell viability of B16F10 murine melanoma cells and HaCaT human keratinocytes were evaluated. Isoflavones that showed significant mushroom tyrosinase inhibitory activities were further studied on reduction of cellular melanin formation and antityrosinase activities in B16F10 melanocytes in vitro. Among the isoflavones tested, 6-hydroxydaidzein (2) was the strongest scavenger of both ABTS.+ and DPPH. radicals with SC50 values of 11.3±0.3 and 9.4±0.1 μM, respectively. Texasin (20) exhibited the most potent inhibition of mushroom tyrosinase (IC50 14.9±4.5 μM), whereas retusin (17) showed the most efficient inhibition both of cellular melanin formation and antityrosinase activity in B16F10 melanocytes, respectively. In summary, both retusin (17) and texasin (20) exhibited potent free-radical-scavenging capacities as well as efficient inhibition of cellular melanogenesis, suggesting that they are valuable hit compounds with potential for advanced cosmeceutical development.
- Lu, Tzy-Ming,Ko, Horng-Huey,Ng, Lean-Teik,Hsieh, Yen-Pin
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p. 963 - 979
(2015/06/25)
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- ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
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Described herein are compounds that are estrogen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.
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Page/Page column 103
(2012/01/05)
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- Expedient Synthesis of Polyhydroxyisoflavones
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A general and direct synthesis of polyhydroxy isoflavones (3-phenyl-4H-1-benzopyran-4-ones) starting from the corresponding unprotected phenols and arylacetic acids is described.The aryl rings may carry additional alkyl, methoxy and/or halogeno groups.Intermediate polyhydroxydeoxybenzoins (1,2-diphenylethanones) can also be isolated in good yields.
- Waehaelae, Kristiina,Hase, Tapio A.
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p. 3005 - 3008
(2007/10/02)
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