- Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRγ
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The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor γ and the classical estrogen receptor α demonstrate that analogs bearing hydroxyalkyl g
- Chao, Esther Y.H.,Collins, Jon L.,Gaillard, Stephanie,Miller, Aaron B.,Wang, Liping,Orband-Miller, Lisa A.,Nolte, Robert T.,McDonnell, Donald P.,Willson, Timothy M.,Zuercher, William J.
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Read Online
- A multi-gram-scale stereoselective synthesis of Z-endoxifen
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Z-Endoxifen is widely regarded as the most active metabolite of tamoxifen, and has recently demonstrated a 26.3% clinical benefit in a phase I clinical trial to treat metastatic breast cancer after the failure of standard endocrine therapy. Future pharmac
- Milroy, Lech-Gustav,Koning, Bartjan,Scheppingen, Daphne S.V.,Jager, Nynke G.L.,Beijnen, Jos H.,Koek, Jan,Brunsveld, Luc
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Read Online
- Rational design of ERα targeting hypoxia turn-on fluorescent probes with antiproliferative activity for breast cancer
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The overexpression of estrogen receptor (ER) α is not only closely related to the development of ER+ breast cancer, but is also an important biomarker for clinical diagnosis and treatment. Herein, we report several ERα targeting hypoxia turn-on fluorescent probes with antitumor activity for breast cancer cells. Among them, probes 3 and 5 displayed good ERα targeting ability and favorable hypoxia turn-on response in MCF-7 cells. Moreover, the probes 3 and 5 exhibited good antiproliferative activity towards MCF-7 cells (IC50 = 8.5 μM, 10.3 μM) and a much lower cytotoxicity to normal cells compared with the positive control. It is expected that these novel fluorescent probes may provide useful tools for the theranostics of ER+ breast cancer.
- Dong, Chune,Hu, Zhiye,Ma, Xiaoyu,Meng, Qiuyu,Xie, Baohua,Zhou, Fuling,Zhou, Hai-Bing
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supporting information
p. 10493 - 10496
(2020/10/02)
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- NOVEL COMPOUNDS HAVING ESTROGEN RECEPTOR ALPHA DEGRADATION ACTIVITY AND USES THEREOF
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The present disclosure relates to novel compounds having estrogen receptor alpha degradation activity, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of cancer and related diseases and conditions.
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Paragraph 0564-0565
(2020/06/08)
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- NOVEL ARYL ETHANE DERIVATIVE AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT
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The present invention relates to an aryl ethene derivative, for inhibiting an estrogen-related receptor gamma (ERRγ) activity, a prodrug of same, a solvate of same, a stereoisomer of same or pharmaceutically acceptable salts of same, and a pharmaceutical
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- ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS
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The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.
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Page/Page column 215
(2019/12/04)
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- NOVEL ARYL ETHENE DERIVATIVES AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME AS AN ACTIVE INGREDIENT
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The present invention relates to an aryl ethene derivative represented by chemical formula 1 which suppresses the activity of estrogen-related receptor gamma (ERRandgamma;), a prodrug thereof, a solvate thereof, a stereomer thereof, or a pharmaceutically acceptable salt thereof, and to a pharmaceutical composition comprising the same as an effective component. In the chemical formula 1, R^1, R^2, L and Ar are the same as defined in the detailed description of the invention.COPYRIGHT KIPO 2018
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- Utilization of the inherent nucleophile for regioselective O-acylation of polyphenols via an intermolecular cooperative transesterification
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A green and efficient method for regioselective O-acylation of polyphenols has been developed. The acylation can be carried out in potassium carbonate/dimethyl sulphoxide system by utilizing the ‘inherent nucleophile’ via an intermolecular cooperative transesterification under mild condition. This method shows particular advantage in regioselective acylation of polyphenols bearing 2′,4′-dihydroxyacetophenone moiety and can be extended to the synthesis of mono or multiple acetates of polyphenols without this moiety in good yields. Compared with other reported approaches, this method is endowed with atom economy and is more environment-friendly for avoiding the use of any metal-based catalysts.
- Liu, Jingchao,Fu, Junjie,Li, Wenlong,Zou, Yu,Huang, Zhangjian,Xu, Jinyi,Peng, Sixun,Zhang, Yihua
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p. 4103 - 4110
(2016/07/06)
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- Synthesis and biological evaluation of novel 4-hydroxytamoxifen analogs as estrogen-related receptor gamma inverse agonists
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Estrogen-related receptor gamma (ERRγ) has recently been recognized as an attractive target for treating inflammation, cancer, and metabolic disorders. Herein, we discovered and demonstrated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that could act as highly selective inverse agonists for ERRγ. The results were comparable to those for GSK5182 (4), a leading ERRγ inverse agonist ligand. Briefly, the half-maximal inhibitory concentration (IC50) range of the synthesized compounds for ERRγ was 0.1-10 μM. Impressively, compound 24e exhibited potency comparable to 4 but was more selective for ERRγ over three other subtypes: ERRα, ERRβ, and estrogen receptor α. Furthermore, compound 24e exhibited a superior in vitro ADMET profile compared to the other compounds. Thus, the newly synthesized class of ERRγ inverse agonists could be lead candidates for developing clinical therapies for ERRγ-related disorders.
- Kim, Jina,Chin, Jungwook,Im, Chun Young,Yoo, Eun Kyung,Woo, Seoyeon,Hwang, Hee Jong,Cho, Joong-Heui,Seo, Kyung-Ah,Song, Jaeyoung,Hwang, Hayoung,Kim, Kyung-Hee,Kim, Nam Doo,Yoon, Suk Kyoon,Jeon, Jae-Han,Yoon, Seung-Yun,Jeon, Yong Hyun,Choi, Hueng-Sik,Lee, In-Kyu,Kim, Seong Heon,Cho, Sung Jin
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p. 338 - 352
(2016/07/06)
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- Synthesis of mixed (E, Z)-, (E)-, and (Z)-norendoxifen with dual aromatase inhibitory and estrogen receptor modulatory activities
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The first synthesis of the tamoxifen metabolite norendoxifen is reported. This included syntheses of (E)-norendoxifen, (Z)-norendoxifen, and (E,Z)-norendoxifen isomers. (Z)-Norendoxifen displayed affinity for aromatase (Ki 442 nM), estrogen receptor-α (EC50 17 nM), and estrogen receptor-β (EC50 27.5 nM), while the corresponding values for (E)-norendoxifen were aromatase (Ki 48 nM), estrogen receptor-α (EC50 58.7 nM), and estrogen receptor-β (EC50 78.5 nM). Docking and energy minimization studies were performed with (E)-norendoxifen on aromatase, and the results provide a foundation for structure-based drug design. The oral pharmacokinetic parameters for (E,Z)-norendoxifen were determined in mice, and (Z)-norendoxifen was found to result in significantly higher plasma concentrations and exposures (AUC values) than (E)-norendoxifen. The affinities of both isomers for aromatase and the estrogen receptors, as well as the pharmacokinetic results, support the further development of norendoxifen and its analogues for breast cancer treatment.
- Lv, Wei,Liu, Jinzhong,Lu, Deshun,Flockhart, David A.,Cushman, Mark
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p. 4611 - 4618
(2013/07/19)
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- Organometallic analogues of tamoxifen: Effect of the amino side-chain replacement by a carbonyl ferrocenyl moiety in hydroxytamoxifen
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Since the widely prescribed selective estrogen receptor modulator (SERM) tamoxifen encounters growing cases of resistance in long-term treatments, alternative drugs with different therapeutic scopes have to be developed. Many investigators have modified t
- Nguyen, Anh,Top, Siden,Vessières, Anne,Pigeon, Pascal,Huché, Michel,Hillard, Elizabeth A.,Jaouen, Gérard
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p. 1219 - 1225
(2008/02/04)
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- Optimised synthesis and photochemistry of antenna-sensitised 1-acyl-7-nitroindolines
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Benzophenone antenna-sensitised 1-acyl-7-nitroindolines show a significantly enhanced extent of photochemical cleavage in aqueous solution over their non-sensitised analogues and release the carboxylate derived from their 1-acyl group. The present work in
- Papageorgiou, George,Corrie, John E.T.
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p. 609 - 616
(2007/10/03)
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- Novel estrogen receptor ligand binding domain variants and novel ligands and pharmaceutical compositions
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Mutants of steroid receptor ligand binding domains and synthetic ligands which have specific binding affinities for these receptors are provided. The use of these LBD-ligand combinations for construction of selective “molecular gene switches” is disclosed
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- Identification of new triarylethylene oxyalkanoic acid analogues as bone selective estrogen mimetics
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Previously, the estrogen receptor (ER) ligand 4-[1-(p-hydroxyphenyl)-2-phenylethyl]phenoxyacetic acid (5) was found to have differential bone loss suppressive effects in the ovariectomized (OVX) rat approaching those of selective ER modulators (SERMs) suc
- Rubin, Valeria N,Ruenitz, Peter C,Boudinot,Boyd, Jason L
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p. 1579 - 1587
(2007/10/03)
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- (Acyloxy)benzophenones and (Acyloxy)-4-pyrones. A New Class of Inhibitors of Human Neutrophil Elastase
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A series of 4-(acyloxy)- and 4,4'-bis(acyloxy)benzophenones were synthesized.Some of them, pivalates (trimethylacetates) and isobutyrates in particular, were found to be potent and selective inhibitors of human neutrophil (leukocyte) elastase.A series of 2--5-(acyloxy)-4-pyrones were synthesized regioselectively from kojic acid.The 4-pyrones bearing a long chain acyl group at the 2-position and either pivaloyloxy or isobutyryloxy at the 5-position were potent and selective inhibitors of the human elastase.A number of analogues and derivatives in both series were synthesized in order to study the structure-activity relationship as summarized in Tables I-VI and in Tables IX and X.The inhibition was selective to human neutrophil elastase.No inhibition of porcine pancreatic elastase or bovine pancreatic chymotrypsin (Tables VII and XI) was observed.The most likely mechanism of inhibition is discussed.The implication of these findings for the treatment of rheumatoid arthritis and emphysema is outlined.
- Miyano, Masateru,Deason, James R.,Nakao, Akira,Stealey, Michael A.,Villamil, Clara I.,et al.
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p. 1052 - 1061
(2007/10/02)
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