- Identification and optimization of biphenyl derivatives as novel tubulin inhibitors targeting colchicine-binding site overcoming multidrug resistance
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Microtubule targeting agents (MTAs) are among the most successful chemotherapeutic drugs, but their efficacy is often limited by the development of multidrug resistance (MDR). Therefore, the development of novel MTAs with the ability to overcome MDR is urgently needed. In this contribution, through modification of the unsymmetric biaryl compounds, we discovered a novel compound dxy-1-175 with potent anti-proliferative activity against cancer cells. Mechanistic study revealed that dxy-1-175 inhibited tubulin polymerization by interacting with the colchicine-binding site of tubulin, which caused cell cycle arrest at G2/M phase. Based on the predicted binding model of dxy-1-175 with tubulin, a series of new 4-benzoylbiphenyl analogues were designed and synthesized. Among them, the hydrochloride compound 12e with improved solubility and good stability in human liver microsome, exhibited the most potent anti-proliferative activity with IC50 value in the low nanomolar range, and markedly inhibited the growth of breast cancer 4T1 xenograft in vivo. Notably, 12e effectively overcame P-gp-mediated MDR and our preliminary data suggested that 12e may not be a substrate of P-glycoprotein (P-gp). Taken together, our study reveals a novel MTA 12e targeting the colchicine-binding site with potent anticancer activity and the ability to circumvent MDR.
- Cheng, Bao,Zhu, Guirong,Meng, Linghua,Wu, Guolin,Chen, Qin,Ma, Shengming
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supporting information
(2021/11/22)
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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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Paragraph 0122; 0124
(2019/04/16)
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- Visible Light-Mediated [2 + 2] Cycloaddition Reactions of 1,4-Quinones and Terminal Alkynes
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A single-step synthesis of 4-hydroxy-functionalized bi-aryl and aryl/alkyl ketones via oxidative coupling of terminal alkynes with benzoquinones is reported. Furthermore, with naphthoquinones, owing to the cross-resonance of carbonyl with the aromatic ring, alkene-alkyne cycloaddition is more favored to give four-membered carbocyclic adducts, thereby precluding the requirement of preactivated alkynes.
- Sultan, Shaista,Bhat, Muneer-Ul-Shafi,Rizvi, Masood Ahmad,Shah, Bhahwal Ali
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p. 8948 - 8958
(2019/08/12)
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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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Paragraph 0248; 0251; 0252
(2018/05/03)
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- Strategies to Enhance the Photosensitization: Polymerization and the Donor–Acceptor Even–Odd Effect
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A particular challenge in the design of organic photosensitizers (PSs) with donor–acceptor (D-A) structures is that it is based on trial and error rather than specific rules. Now these challenges are addressed by proposing two efficient strategies to enhance the photosensitization efficiency: polymerization-facilitated photosensitization and the D-A even–odd effect. Conjugated polymers have been found to exhibit a higher 1O2 generation efficiency than their small molecular counterparts. Furthermore, PSs with A-D-A structures show enhanced photosensitization efficiency over those with D-A-D structures. Theoretical calculations suggest an enhanced intersystem crossing (ISC) efficiency by these strategies. Both in vitro and in vivo experiments demonstrate that the resulting materials can be used as photosensitizers in image-guided photodynamic anticancer therapy. These guidelines are applicable to other polymers and small molecules to lead to the development of new PSs.
- Liu, Shunjie,Zhang, Haoke,Li, Yuanyuan,Liu, Junkai,Du, Lili,Chen, Ming,Kwok, Ryan T. K.,Lam, Jacky W. Y.,Phillips, David Lee,Tang, Ben Zhong
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supporting information
p. 15189 - 15193
(2018/10/26)
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- Organic Nanocrystals with Bright Red Persistent Room-Temperature Phosphorescence for Biological Applications
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Persistent room-temperature phosphorescence (RTP) in pure organic materials has attracted great attention because of their unique optical properties. The design of organic materials with bright red persistent RTP remains challenging. Herein, we report a n
- Fateminia, S. M. Ali,Mao, Zhu,Xu, Shidang,Yang, Zhiyong,Chi, Zhenguo,Liu, Bin
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supporting information
p. 12160 - 12164
(2017/09/06)
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- Visible Light Copper Photoredox-Catalyzed Aerobic Oxidative Coupling of Phenols and Terminal Alkynes: Regioselective Synthesis of Functionalized Ketones via C C Triple Bond Cleavage
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Direct oxidative coupling of phenols and terminal alkynes was achieved at room temperature by a visible-light-mediated copper-catalyzed photoredox process. This method allows regioselective synthesis of hydroxyl-functionalized aryl and alkyl ketones from simple phenols and phenylacetylene via C C triple bond cleavage. 47 examples were presented. From a synthetic perspective, this protocol offers an efficient synthetic route for the preparation of pharmaceutical drugs, such as pitofenone and fenofibrate.
- Sagadevan, Arunachalam,Charpe, Vaibhav Pramod,Ragupathi, Ayyakkannu,Hwang, Kuo Chu
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supporting information
p. 2896 - 2899
(2017/03/11)
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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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- Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities
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Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of br
- Lv, Wei,Liu, Jinzhong,Skaar, Todd C.,Flockhart, David A.,Cushman, Mark
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p. 2623 - 2648
(2015/04/14)
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- Synthesis and biological evaluation of N-cyclopropylbenzamide-benzophenone hybrids as novel and selective p38 mitogen activated protein kinase (MAPK) inhibitors
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A series of hybrid molecules consisting of benzophenones and N-cyclopropyl-3-methylbenzamides were synthesized and biologically evaluated as novel p38 mitogen activated protein kinase (MAPK) inhibitors. In particular, we found that compound 10g displayed
- Heo, Jinyuk,Shin, Hanbo,Lee, Jun,Kim, Taelim,Inn, Kyung-Soo,Kim, Nam-Jung
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p. 3694 - 3698
(2015/08/11)
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- Discovery of 1,4-didydroxy-2-naphthoate prenyltransferase inhibitors: New drug leads for multidrug-resistant gram-positive pathogens
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Since utilization of menaquinone in the electron transport system is a characteristic of Gram-positive organisms, the 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) inhibitors 1a and 2a act as selective antibacterial agents against organisms such as methicillin-resistant Stapylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE), and Mycobacterium spp. Growth of drug-resistant Gram-positive organisms was sensitive to the MenA inhibitors, indicating that menaquinone synthesis is a valid new drug target in Gram-positive organisms.
- Kurosu, Michio,Narayanasamy, Prabagaran,Biswas, Kallolmay,Dhiman, Rakesh,Crick, Dean C.
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p. 3973 - 3975
(2008/02/11)
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- CHEMICAL COMPOUNDS
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The present invention relates to novel compounds with a variety of therapeutic uses, more particularly novel substituted cyclic alkylidene compounds that are particularly useful for selective estrogen receptor modulation.
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Page/Page column 39
(2008/06/13)
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- Synthesis and structure-activity studies of novel orally active non-terpenoic 2,3-oxidosqualene cyclase inhibitors
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New orally active non-terpenoic inhibitors of human 2,3-oxidosqualene cyclase (hOSC) are reported. The starting point for the optimization process was a set of compounds derived from a fungicide project, which in addition to showing high affinity for OSC from Candida albicans showed also high affinity for human OSC. Common structural elements of these inhibitors are an amine residue and an electrophilic carbonyl C atom embedded in a benzophenone system, which are at a distance of about 10.7 ?. Considering that the keto moiety is in a potentially labile position, modifications of the substitution pattern at the benzophenone as well as annelated heteroaryl systems were explored. Our approach combined testing of the compounds first for increased binding affinity and for increased stability in vitro. Most promising compounds were then evaluated for their efficacy in lowering plasma total cholesterol (TC) and plasma low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic hamsters. In this respect, the most promising compounds are the benzophenone derivative 1·fumarate and the benzo[d]-isothiazol 24·fumarate, which lowered TC by 40% and 33%, respectively.
- Dehmlow, Henrietta,Aebi, Johannes D.,Jolidon, Synèse,Ji, Yu-Hua,Von der Mark, Elisabeth M.,Himber, Jacques,Morand, Olivier H.
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p. 3354 - 3370
(2007/10/03)
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- Synthesis and structure-activity relationship for new series of 4-phenoxyquinoline derivatives as specific inhibitors of platelet-derived growth factor receptor tyrosine kinase
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We discovered a new series of 4-phenoxyquinoline derivatives as potent and selective inhibitors of the platelet-derived growth factor receptor (PDGFr) tyrosine kinase. We researched the highly potent and selective inhibitors on the basis of both PDGFr and epidermal growth factor receptor (EGFr) inhibitory activity. First, we found a compound, Ki6783 (1), which inhibited PDGFr autophosphorylation at 0.13 μM, but it did not inhibit EGFr autophosphorylation at 100 μM. After extensive explorations, we found the two desired compounds, Ki6896 (2) and Ki6945 (3), which are substituted by benzoyl and benzamide at the 4-position of the phenoxy group on 4-phenoxyquinoline, respectively. These inhibitory activities were 0.31 and 0.050 μM, respectively, but neither of them inhibited EGFr autophosphorylation at 100 μM. We further investigated the profile of both compounds toward various tyrosine and serine/threonine kinases. The three compounds specifically inhibited PDGFr rather than the other kinases.
- Kubo, Kazuo,Ohyama, Shin-Ichi,Shimizu, Toshiyuki,Takami, Atsuya,Murooka, Hideko,Nishitoba, Tsuyoshi,Kato, Shinichiro,Yagi, Mikio,Kobayashi, Yoshiko,Iinuma, Noriko,Isoe, Toshiyuki,Nakamura, Kazuhide,Iijima, Hiroshi,Osawa, Tatsushi,Izawa, Toshio
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p. 5117 - 5133
(2007/10/03)
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- Synthesis and structure-activity relationships of benzophenone hydrazone derivatives with insecticidal activity
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A broad range of benzophenone hydrazone derivatives was prepared and tested against selected chewing insect pests, allowing the analysis of structure-activity relationships. Good activity was found only when the aromatic rings were substituted at the 4-positions with an halogen atom and a triflate or perhaloalkoxy group. In contrast, a number of substituents on the hydrazone part led to active compounds, the best results being achieved with acyl-type substituents. The excellent laboratory and greenhouse activity of the best representatives was confirmed in semi-field trials against Spodoptera littoralis. ° 2001 Society of Chemical Industry.
- Boeger, Manfred,Duerr, Dieter,Gsell, Laurenz,Hall, Roger G.,Karrer, Friedrich,Kristiansen, Odd,Maienfisch, Peter,Pascual, Alfons,Rindlisbacher, Alfred
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p. 191 - 202
(2007/10/03)
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- Estrogenic triarylethylene acetic acids: Effect of structural variation on estrogen receptor affinity and estrogenic potency and efficacy in MCF-7 cells
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Triarylethylenecarboxylic acids exemplified by (E,Z)-2-{4-[1-(p- hydroxyphenyl)-2-phenyl]-1-butenyl}phenoxyacetic acid (8) are a new class of estrogen receptor (ER) ligands capable of tissue selective estrogen agonist and antagonist effects. We report the syntheses of 8 and of analogues incorporating structural features known or anticipated to facilitate ER affinity in triarylethylenes. These studies revealed that the p- hydroxyphenyl moiety, ethylenic bond, and ether oxygen of 8 were all critical for high ER affinity. Although a 1,1-bisphenolic analogue bearing the p- (oxyacetic acid) moiety on its 2-phenyl ring, 12, had low ER affinity, it exhibited estrogenic potency approaching that of 8 in MCF-7 cells. Unlike 8 which was a partial agonist with weak antagonist potency, 12 was a full agonist. A similar profile of potency/efficacy in MCF-7 cells was seen in 9, an ethylenic bond saturated analogue of 8. Growth-promoting effects of 8, 9, and 12 were fully antagonized by the antiestrogen tamoxifen, suggesting that such effects were mediated solely via ER. Thus, our studies in MCF-7 cells have confirmed the estrogenicity of 8 and have enabled identification of two analogues with favorable estrogenic potency and full estrogen efficacy. On this basis, these three (triarylethylene)acetic acids have been selected for more intensive animal studies of their extrareproductive tract estrogenic effects.
- Ruenitz, Peter C.,Bourne, Caryl S.,Sullivan, Kelly J.,Moore, Susan A.
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p. 4853 - 4859
(2007/10/03)
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