- Modification of the estrogenic properties of diphenols by the incorporation of ferrocene. Generation of antiproliferative effects in vitro
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We report here the synthesis and the strong and unexpected antiproliferative effect of the organometallic diphenolic compound 1,1-bis(4′-hydroxyphenyl)-2-ferrocenyl-but-1-ene (4) on both hormone-dependent (MCF7) and -independent (MDA-MB231) breast cancer cells (IC50 = 0.7 and 0.6 μM). Surprisingly, 6 [1,2-bis(4′- hydroxyphenyl)-2-ferrocenyl-but-1-ene], the regioisomer of 4, shows only a modest effect on these cell lines. This pertinent organometallic modification seems to trigger an intracellular oxidation of the structurally favorable compound 4, leading to the generation of a potent cytotoxic compound.
- Vessières, Anne,Top, Siden,Pigeon, Pascal,Hillard, Elizabeth,Boubeker, Leila,Spera, Daniela,Jaouen, Gérard
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Read Online
- Light activated recombination
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Many genes elicit their actions through their expression in precise spatial patterns in tissues. Photoregulated expression systems offer a means to remotely pattern gene expression in tissues. Using currently available photopatterning methods, gene expres
- Link, Kristian H.,Shi, Youheng,Koh, John T.
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Read Online
- Synthesis of Tamoxifen-Artemisinin and Estrogen-Artemisinin Hybrids Highly Potent Against Breast and Prostate Cancer
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In the search for new and effective treatments of breast and prostate cancer, a series of hybrid compounds based on tamoxifen, estrogens, and artemisinin were successfully synthesized and analyzed for their in vitro activities against human prostate (PC-3) and breast cancer (MCF-7) cell lines. Most of the hybrid compounds exhibit a strong anticancer activity against both cancer cell lines – for example, EC50 (PC-3) down to 1.07 μM, and EC50 (MCF-7) down to 2.08 μM – thus showing higher activities than their parent compounds 4-hydroxytamoxifen (afimoxifene, 7; EC50=75.1 (PC-3) and 19.3 μM (MCF-7)), dihydroartemisinin (2; EC50=263.6 (PC-3) and 49.3 μM (MCF-7)), and artesunic acid (3; EC50=195.1 (PC-3) and 32.0 μM (MCF-7)). The most potent compounds were the estrogen-artemisinin hybrids 27 and 28 (EC50=1.18 and 1.07 μM, respectively) against prostate cancer, and hybrid 23 (EC50=2.08 μM) against breast cancer. These findings demonstrate the high potential of hybridization of artemisinin and estrogens to further improve their anticancer activities and to produce synergistic effects between linked pharmacophores.
- Fr?hlich, Tony,Mai, Christina,Bogautdinov, Roman P.,Morozkina, Svetlana N.,Shavva, Alexander G.,Friedrich, Oliver,Gilbert, Daniel F.,Tsogoeva, Svetlana B.
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p. 1473 - 1479
(2020/07/06)
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- Developing tamoxifen-based chemical probes for use with a dual-modality fluorescence and optical coherence tomography imaging needle
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Fluorescent small molecules based on the chemotherapeutic tamoxifen have been synthesised for use with an imaging needle capable of acquiring simultaneous fluorescence and optical coherence tomography (OCT) images. The chemical probes are based on the active metabolite of the drug, 4-hydroxytamoxifen that is coupled with a diamine linker to commercially available Alexa Fluor or 4, 4-difluoro-4-bora-3a, 4a-diaza-s-indacene (BODIPY) dyes. The tamoxifen derivatives were then added to cultures of live oestrogen receptor positive MCF-7 human breast cancer cells and imaged using the miniaturised fibre-optic device enclosed within a 23-gauge needle (outer diameter 640 μm). The OCT images showed the micro-architecture of the cell culture, while the fluorescence identified oestrogen receptor positive cells. Both dyes were found to have suitable excitation and emission properties and are good candidates to further develop as probes for fluorescence-guided surgery.
- Ho, Louisa A.,Scolaro, Loretta,Thomas, Elizabeth,Quirk, Bryden C.,Kirk, Rodney W.,McLaughlin, Robert A.,Fuller, Rebecca O.
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p. 903 - 910
(2019/12/24)
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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 0580-0581
(2020/06/08)
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- ESTROGEN RECEPTOR TARGETING ANTAGONISTS
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The present disclosure relates to compounds that act as antagonists via binding to the ER ligand binding domain non-covalently or covalently, or act as both antagonists and ER protein degraders, and the synthesis of the same. Further, the present disclosure teaches the utilization of such compounds in a treatment for proliferative diseases, including cancer, particularly breast cancer, and especially ER+ breast cancer.
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Paragraph 0023; 0087-0088
(2020/05/07)
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- New approach based on immunochemical techniques for monitoring of selective estrogen receptor modulators (SERMs) in human urine
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Antiestrogenic compounds such as tamoxifen, toremifen and chlomifen are used illegally by athletes to minimize physical impacts such as gynecomastia resulting from the secondary effects of anabolic androgenic steroids, used to increase athletic efficiency unlawfully. The use of these compounds is banned by the World Anti-Doping Agency (WADA) and controls are made through analytical methodologies such as HPLC–MS/MS, which do not fulfil the sample throughput requirements. Moreover, compounds such as tamoxifen are also used to treat hormone receptor-positive breast cancer (ER +).Therapeutic drug monitoring (TDM) of tamoxifen may also be clinically useful for guiding treatment decisions. An accurate determination of these drugs requires a solid phase extraction of patient serum followed by HPLC–MS/MS. In the context of an unmet need of high-throughput screening (HTS) and quantitative methods for antiestrogenic substances we have approached the development of antibodies and an immunochemical assay for the determination of these antiestrogenic compounds. The strategy applied has taken into consideration that these drugs are metabolized and excreted in urine as the corresponding 4-hydroxylated compounds. A microplate-based ELISA procedure has been developed for the analysis of these metabolites in urine with a LOD of 0.15, 0.16 and 0.63 μg/L for 4OH-tamoxifen, 4OH-toremifen and 4OH-clomifen, respectively, much lower than the MRPL established by WADA (20 μg/L).
- Salvador, J.-Pablo,Vila-Roca, Ester,Monfort, Núria,Ventura, Rosa,Marco, M.-Pilar
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p. 147 - 152
(2018/05/04)
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- ANTICANCER AGENT DELIVERY MOLECULE
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PROBLEM TO BE SOLVED: To provide a compound which can be used as an anticancer agent targeting a cancer cell that highly expresses Lysine-specific demethylase 1 (LSD1) or salt thereof. SOLUTION: The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, where Ar, R1, R2, L, Z, p, q, *1 and *2 are as defined in the specifications. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0150-0151; 0157
(2017/08/04)
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- A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β
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The design and synthesis of dual aromatase inhibitors/selective estrogen receptor modulators (AI/SERMs) is an attractive strategy for the discovery of new breast cancer therapeutic agents. Previous efforts led to the preparation of norendoxifen (4) deriva
- Zhao, Li-Ming,Jin, Hai-Shan,Liu, Jinzhong,Skaar, Todd C.,Ipe, Joseph,Lv, Wei,Flockhart, David A.,Cushman, Mark
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p. 5400 - 5409
(2016/10/24)
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- Targeting Cancer with PCPA-Drug Conjugates: LSD1 Inhibition-Triggered Release of 4-Hydroxytamoxifen
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Targeting cancer with small molecule prodrugs should help overcome problems associated with conventional cancer-targeting methods. Herein, we focused on lysine-specific demethylase 1 (LSD1) to trigger the controlled release of anticancer drugs in cancer cells, where LSD1 is highly expressed. Conjugates of the LSD1 inhibitor trans-2-phenylcyclopropylamine (PCPA) were used as novel prodrugs to selectively release anticancer drugs by LSD1 inhibition. As PCPA-drug conjugate (PDC) prototypes, we designed PCPA-tamoxifen conjugates 1 a and 1 b, which released 4-hydroxytamoxifen in the presence of LSD1 in vitro. Furthermore, 1 a and 1 b inhibited the growth of breast cancer cells by the simultaneous inhibition of LSD1 and the estrogen receptor without exhibiting cytotoxicity toward normal cells. These results demonstrate that PDCs provide a useful prodrug method that may facilitate the selective release of drugs in cancer cells.
- Ota, Yosuke,Itoh, Yukihiro,Kaise, Asako,Ohta, Kiminori,Endo, Yasuyuki,Masuda, Mitsuharu,Sowa, Yoshihiro,Sakai, Toshiyuki,Suzuki, Takayoshi
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supporting information
p. 16115 - 16118
(2016/12/26)
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- TETRASUBSTITUTED ALKENE COMPOUNDS AND THEIR USE
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Disclosed herein are compounds, or pharmaceutically acceptable salts thereof, and methods of using the compounds for treating breast cancer by administration to a subject in need thereof a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof. The breast cancer may be an ER-positive breast cancer and/or the subject in need of treatment may express a mutant ER-α protein.
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Page/Page column 53; 54
(2016/12/22)
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- NOVEL ARYLALKENE DERIVATIVES AND USE THEREOF AS SELECTIVE ESTROGEN RECEPTOR MODULATORS
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The invention provides novel ethylene derivatives represented by Formula I, which may be used as selective estrogen receptor modulators (SERMs) and useful in the prophylaxis and/or treatment of estrogen-dependent conditions or conditions.
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Paragraph 0116; 0146
(2013/07/19)
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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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- Design of a platinum-acridine-endoxifen conjugate targeted at hormone-dependent breast cancer
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The synthesis of a novel pharmacophore comprising a DNA-targeted platinum-acridine hybrid agent and estrogen receptor-targeted 4-hydroxy-N-desmethyltamoxifen (endoxifen) using carbamate coupling chemistry and its evaluation in breast cancer cell lines are
- Ding, Song,Qiao, Xin,Kucera, Gregory L.,Bierbach, Ulrich
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supporting information
p. 2415 - 2417
(2013/04/23)
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- Boron-based 4-hydroxytamoxifen bioisosteres for treatment of de novo tamoxifen resistant breast cancer
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Tamoxifen remains the first line therapy for estrogen receptor positive (ER+) breast cancer. However, polymorphisms of the gene encoding P450 2D6 could result in no protein expression or no CYP2D6 enzymatic activity and may significantly reduce the benefit of the hormone therapy. To address this issue, we designed and synthesized three 4-hydroxytamoxifen bioisosteres utilizing a boron-aryl carbon bond that can be oxidized under physiological conditions to yield 4-hydroxytamoxifen. We show that the bioisosteres inhibit the growth of two ER+ breast cancer cell lines, MCF-7 and T47D, with potencies comparable to or greater than that of 4-hydroxytamoxifen. We further demonstrate that after incubation with breast cancer cells, the majority of the bioisosteres has been converted to 4-hydroxytamoxifen. Our study suggests that boron-based 4-hydroxytamoxifen bioisosteres may be an effective therapeutic remedy for intrinsic tamoxifen resistance in breast cancer patients deficient in CYP2D6 metabolism.
- Jiang, Quan,Zhong, Qiu,Zhang, Qiang,Zheng, Shilong,Wang, Guangdi
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supporting information; experimental part
p. 392 - 396
(2012/07/13)
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- Structure-function relationships of estrogenic triphenylethylenes related to endoxifen and 4-hydroxytamoxifen
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Estrogens can potentially be classified into planar (class I) or nonplanar (class II) categories, which might have biological consequences. 1,1,2-Triphenylethylene (TPE) derivatives were synthesized and evaluated against 17β-estradiol (E2) for their estrogenic activity in MCF-7 human breast cancer cells. All TPEs were estrogenic and, unlike 4-hydroxytamoxifen (4OHTAM) and Endoxifen, induced cell growth to a level comparable to that of E2. All the TPEs increased ERE activity in MCF-7:WS8 cells with the order of potency as followed: E2 > 1,1-bis(4,4′-hydroxyphenyl)-2-phenylbut-1-ene (15) > 1,1,2-tris(4-hydroxyphenyl)but-1-ene (3) > Z 4-(1-(4-hydroxyphenyl)-1- phenylbut-1-en-2-yl)phenol (7) > E 4-(1-(4-hydroxyphenyl)-1-phenylbut-1-en-2- yl)phenol (6) > Z(4-(1-(4-ethoxyphenyl)-1-(4-hydroxyphenyl)but-1-en-2-yl) phenol (12) > 4-OHTAM. Transient transfection of the ER-negative breast cancer cell line T47D:C4:2 with wild-type ER or D351G ER mutant revealed that all of the TPEs increased ERE activity in the cells expressing the wild-type ER but not the mutant, thus confirming the importance of Asp351 for ER activation by the TPEs. The findings confirm E2 as a class I estrogen and the TPEs as class II estrogens. Using available conformations of the ER liganded with 4OHTAM or diethylstilbestrol, the TPEs optimally occupy the 4OHTAM ER conformation that expresses Asp351.
- Maximov, Philipp Y.,Myers, Cynthia B.,Curpan, Ramona F.,Lewis-Wambi, Joan S.,Jordan, V. Craig
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experimental part
p. 3273 - 3283
(2010/09/09)
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- Synthesis and structure-activity relationships of ferrocenyl tamoxifen derivatives with modifed side chains
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We report here the synthesis and cell-proliferation properties of derivatives of the breast cancer drug tamoxifen, in which the -O(CH 2)2N-(CH3)2 side chain, responsible for the drug's antiestrogenic properties,
- Nguyen, Anh,Top, Siden,Pigeon, Pascal,Vessieres, Anne,Hillard, Elizabeth A.,Plamont, Marie-Aude,Huche, Michel,Rigamonti, Clara,Jaouen, Gerard
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scheme or table
p. 684 - 696
(2009/07/25)
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- Synthesis of the new pseudo-symmetrical tamoxifen derivatives and their anti-tumor activity
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Three new pseudo-symmetrical tamoxifen derivatives, RID-B (15), C (16), and D (17), were synthesized via the novel three-component coupling reaction, and the structure-activity relationships of the pseudo-symmetrical tamoxifen derivatives were examined. I
- Shiina, Isamu,Sano, Yoshiyuki,Nakata, Kenya,Kikuchi, Takaaki,Sasaki, Akane,Ikekita, Masahiko,Hasome, Yoshimune
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p. 2421 - 2424
(2007/10/03)
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- Tamoxifen stimulates calcium entry into human platelets
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The anti-estrogenic drug tamoxifen, which is used therapeutically for treatment and prevention of breast cancer, can lead to the development of thrombosis. We found that tamoxifen rapidly increased intracellular free calcium [Ca]i in human platelets from
- Dobrydneva, Yuliya,Weatherman, Ross V.,Trebley, Joseph P.,Morrell, Melinda M.,Fitzgerald, Megan C.,Fichandler, Craig E.,Chatterjie, Nithiananda,Blackmore, Peter F.
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p. 380 - 390
(2008/03/12)
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- Compounds and methods for treating breast cancer and other diseases
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Disclosed are novel compositions and novel methods for the creation of both the novel compounds and known compounds. Also disclosed are methods for use of the novel compounds for treating a variety of diseases relating to decreasing or preventing activati
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(2008/06/13)
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- Simple and Efficient Production of (Z)-4-Hydroxytamoxifen, a Potent Estrogen Receptor Modulator
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A McMurry coupling reaction and selective crystallization were used to develop a simple and efficient two-step synthesis of (Z)-4-hydroxytamoxifen (2a). This compound is an active metabolite of tamoxifen, a selective estrogen receptor (ER) modulator widely used to treat breast cancer. The synthesis employed 1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene (1) as a useful building block.
- Yu, Donna D.,Forman, Barry M.
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p. 9489 - 9491
(2007/10/03)
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- Investigations on estrogen receptor binding. The estrogenic, antiestrogenic, and cytotoxic properties of C2-alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2-phenylethenes
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C2-Alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2-phenylethenes were synthesized and assayed for estrogen receptor binding in a competition experiment with radiolabeled estradiol ([3H]-E2) using calf uterine cytosol. The relative binding affinity decreased with the length of the side chain R = H (3a: 35.2%) > Me (3b: 32.1%) 2CF3 (3d: 5.95%) > n-Pr (3e: 2.09%) > Bu (3f: 0.62%). Agonistic and antagonistic effects were evaluated in the luciferase assay with MCF-7-2a cells stably transfected with the plasmid EREwtcluc. All compounds showed high antiestrogenic activity without significant agonistic potency. The comparison of the IC50 values for the inhibition of E2 (1 nM) documented the dependence of the antagonistic effects on the kind of the side chain: 3a (IC50 = 150 nM), 3b (IC50 = 30 nM), and 3f (IC50 = 500 nM) were weak antagonists, while 3c (IC50 = 15 nM), 3d (IC50 = 9 nM), and 3e (IC50 = 50 nM) were full antiestrogens and antagonized the effect of E2 completely. The most active compound 3d possessed the same antagonistic potency as 4-hydroxytamoxifen (40HT: IC50= 7 nM) without bearing a basic side chain. 3d as well as all other 1,1-bis(4-hydroxyphenyl)-2-phenylalkenes were not able to influence the proliferation of hormone dependent MCF-7 cells despite the antagonistic mode of action. In this assay tamoxifen (TAM) and 40HT reduced the cell growth concentration dependent up to T/Ccorr = 15% and 25%, respectively.
- Lubczyk, Veronika,Bachmann, Helmut,Gust, Ronald
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p. 5358 - 5364
(2007/10/03)
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- TRIPHENYLETHYLENE DERIVATIVE AND PHARMACEUTICAL PREPARATION CONTAINING THE SAME
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A triphenylalkene derivative represented by general formula (1), a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical composition thereof having a tumor inhibitory action and an osteoporosis curing activity. In general formula (1) R1 represents a group selected among those represented by formulae (2), (3) and (4); R6 and R7 represent each hydrogen, alkyl or cycloalkyl, or R6 and R7 together form a heterocyclic group with the adjacent nitrogen atom, provided that R6 and R7 should not be hydrogen atoms at the same time; R8 represents hydrogen or alkylcarbonyl; R2 represents alkyl or cycloalkyl; R3 represents phenyl or 3,4-methylenedioxyphenyl, provided that when R3 represents phenyl, the case where R1 represents a group of formula (4) is excluded; R4 represents hydrogen, hydroxyl, R9C(O)O-, R10OCH2O-, -OPO(OH)2 or CH = NOR11; R9 represents alkyl; R10 represents alkyl or alkylcarbonyl; R5 represents hydrogen or CH = NOR11; and R11 represents hydrogen, alkyl or substituted alkyl.
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- 1,1,2-Triphenylbut-1-enes: Relationship between Structure, Estradiol Receptor Affinity, and Mammary Tumor Inhibiting Properties
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1,1,2-Triphenylbut-1-enes, which are substituted with acetoxy groups on one, two, or three aromatic rings in the para and/or meta positions, were synthesized.The identity of the occurring E and Z isomers were established by 1H NMR spectroscopy.A study on structure-activity relationships was carried out with regard to estradiol receptor affinity and to inhibiting effects on the growth of a postmenopausal human mammary carcinoma implanted in nude mice.The para-substituted compounds generally exhibited a higher receptor affinity and a better antitumor activity than the corresponding meta-substituted ones.The E isomers were superior to the respective Z isomers in those two properties.The tumor-inhibiting effect of the mono-and disubstituted compounds was better than that of the trisubstituted ones.Except for the trisubstituted compounds, they all showed a good correlation between estradiol receptor affinity and antitumor activity.One of the compounds was also tested on the 9,10-dimethylbenzanthracene-induced, hormone-dependent mammary carcinoma of the Spraque-Dawley rat, and the results corresponded to those obtained in the xenograft tumor.
- Schneider, Martin R.,Angerer, Erwin von,Schoenenberger, Helmut,Michel, Ralf Th.,Fortmeyer, H. P.
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p. 1070 - 1077
(2007/10/02)
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