- Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction
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Disruption of EZH2-embryonic ectoderm development (EED) protein-protein interaction (PPI) is a new promising cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2-EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 ?. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2-EED interaction inhibitor, DC-PRC2in-01, with an affinityKdof 4.56 μM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.
- Du, Daohai,Xu, Dandan,Zhu, Licheng,Stazi, Giulia,Zwergel, Clemens,Liu, Yanli,Luo, Zhongyuan,Li, Yuanqing,Zhang, Yuanyuan,Zhu, Kongkai,Ding, Yiluan,Liu, Jingqiu,Fan, Shijie,Zhao, Kaiyan,Zhang, Naixia,Kong, Xiangqian,Jiang, Hualiang,Chen, Kaixian,Zhao, Kehao,Valente, Sergio,Min, Jinrong,Duan, Wenhu,Luo, Cheng
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p. 8194 - 8207
(2021/06/28)
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- Structure-Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum in Vitro
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In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds 21, 30, and 33 displayed high activities against asexual blood stage parasites (PfNF54 IC50 = 0.025-0.043 μM), whereas amide compound 46 additionally showed activity against late-stage gametocytes (stage IV/V; PfLG IC50 = 0.6 ± 0.1 μM) and 860-fold higher selectivity over hERG (46, SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 μM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.
- Birkholtz, Lyn-Marie,Chibale, Kelly,Coertzen, Dina,Ferger, Richard,Kumar, Malkeet,Mambwe, Dickson,Njoroge, Mathew,Reader, Janette,Taylor, Dale,Van Der Watt, Mari?tte
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supporting information
p. 1333 - 1341
(2021/08/24)
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- Multistage Antiplasmodium Activity of Astemizole Analogues and Inhibition of Hemozoin Formation as a Contributor to Their Mode of Action
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A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against the Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liver, and sexual gametocytic stages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated. Ten of the 17 derivatives showed half-maximal inhibitory concentrations (IC50s) of 50 100). Screening of AST and its analogues against gametocytes revealed their moderate activity (IC50: 1-5 μM) against late stage P. falciparum gametocytes, while the evaluation of activity against P. berghei liver stages identified one compound (3) with 3-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-hematin formation by the AST derivatives and their antiplasmodium IC50s. Analyses of intracellular inhibition of hemozoin formation within the parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery.
- Kumar, Malkeet,Okombo, John,Mambwe, Dickson,Taylor, Dale,Lawrence, Nina,Reader, Janette,Van Der Watt, Mari?tte,Fontinha, Diana,Sanches-Vaz, Margarida,Bezuidenhout, Belinda C.,Lauterbach, Sonja B.,Liebenberg, Dale,Birkholtz, Lyn-Marie,Coetzer, Theresa L.,Prudêncio, Miguel,Egan, Timothy J.,Wittlin, Sergio,Chibale, Kelly
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p. 303 - 315
(2019/01/15)
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- Astemizole-based turn-on fluorescent probes for imaging hERG potassium channel
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Based on the scaffold of astemizole, three novel turn-on fluorescent probes (N1-N3) for human ether-a-go-go-related gene (hERG) potassium channel were developed herein. These probes have reasonable fluorescence properties, acceptable cell toxicity, and potent inhibitory activity, all of which contribute to cell imaging at the nanomolar level. Overall, these probes have the potential for setting up a screening system for hERG channels.
- Zhang, Xiaomeng,Liu, Tingting,Wang, Beilei,Gao, Yuqi,Liu, Pan,Li, Minyong,Du, Lupei
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p. 513 - 516
(2019/04/30)
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- A benzimidazole hERG potassium ion channel of small molecule fluorescent probe and its preparation method and application
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The invention relates to a benzimidazole hERG potassium ion channel small-molecular fluorescent probe and a preparation method and applications thereof; the fluorescent probe has the structural general formula represented by the formula (I), wherein in the formula, R1 is hydroxyl, halogen, alkyl or alkoxy monosubstituent or polysubstituent, R2 is fluorophore, n is 1-6, particularly, R1 is p-halogen, and R2 is coumarin, naphthalene diimide, NBD, Cy5 or fluorescein isothiocyanate fluorophore. The invention discloses the applications of the probe in marking of hERG potassium ion channels and high-expression tumor cells or tissues, high-throughput screening of hERG potassium ion channel inhibitors, evaluation of new drug cardiotoxicity, use as a probe for identification of the hERG potassium ion channels and studies on hERG potassium ion channel physiological, pathological and related diseases.
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- Astemizole analogues with reduced hERG inhibition as potent antimalarial compounds
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Astemizole is a H1-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials.
- Tian, Junjun,Vandermosten, Leen,Peigneur, Steve,Moreels, Lien,Rozenski, Jef,Tytgat, Jan,Herdewijn, Piet,Van den Steen, Philippe E.,De Jonghe, Steven
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p. 6332 - 6344
(2017/10/23)
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- Astemizole Derivatives as Fluorescent Probes for hERG Potassium Channel Imaging
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The detection and imaging of hERG potassium channels in living cells can provide useful information for hERG-correlation studies. Herein, three small-molecule fluorescent probes, based on the potent hERG channel inhibitor astemizole, for the imaging of hERG channels in hERG-transfected HEK293 cells (hERG-HEK293) and human colorectal cancer cells (HT-29), are described. These probes are expected to be applied in the physiological and pathological studies of hERG channels.
- Wang, Beilei,Liu, Zhenzhen,Ma, Zhao,Li, Minyong,Du, Lupei
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p. 245 - 249
(2016/03/25)
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- Synthesis and anti-Plasmodium activity of benzimidazole analogues structurally related to astemizole
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A series of compounds structurally related to astemizole were designed and synthesized with the goal of determining their anti-Plasmodium activity. Several modifications of the astemizole structure, namely the removal of the 4-fluorobenzyl and/ or 4-methoxyphenethyl moieties, substitution of the benzene ring of the benzimidazole scaffold, replacement of the fluorine atom in the 4-fluorobenzyl group, and variation of the 4-aminopiperidine moiety, were explored. In vitro evaluation of the anti-Plasmodium activity of these compounds using the ItG strain showed that astemizole and some of its structurally similar derivatives have IC50 values in the nanomolar range and exhibit toxicity towards the parasite over Chinese ovarian hamster (CHO) cells with a selectivity as high as 200. The presence of a secondary cyclic amine at position 2 and substitution with chlorine at positions 4 and 5 in the benzimidazole moiety are two modifications that resulted in potent and selective antimalarials based on astemizole.
- Roman, Gheorghe,Crandall, Ian E.,Szarek, Walter A.
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p. 1795 - 1804
(2014/01/06)
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- Sustainable synthesis of diverse privileged heterocycles by palladium-catalyzed aerobic oxidative isocyanide insertion
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Heterocycles containing a guanidine moiety are of great importance in medicinal chemistry (Scheme 1).[1] As a result, several methods for the synthesis of these "privileged scaffolds" have been reported.[2, 3] Classical approaches, such as the addition of diamines to isothiocyanates followed by condensation and the coupling of diamines with cyanogen bromide,[2, 4] have some clear limitations, such as the availability and toxicity of reagents. Moreover, these procedures suffer from poor atom and/or step efficiency, thus making them unattractive from a sustainability point of view.
- Vlaar, Tj?stil,Cioc, Razvan C.,Mampuys, Pieter,Maes, Bert U. W.,Orru, Romano V. A.,Ruijter, Eelco
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supporting information
p. 13058 - 13061
(2013/02/26)
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- Mepyramine-JNJ7777120-hybrid compounds show high affinity to hH 1R, but low affinity to hH4R
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In literature, a synergism between histamine H1 and H 4 receptor is discussed. Furthermore, it was shown, that the combined application of mepyramine, a H1 antagonist and JNJ7777120, a H 4 receptor ligand leads to a synergistic effect in the acute murine asthma model. Thus, the aim of this study was to develop new hybrid ligands, containing one H1 and one H4 pharmacophor, connected by an appropriate spacer, in order to address both, H1R and H 4R. Within this study, we synthesized nine hybrid compounds, which were pharmacologically characterized at hH1R and hH4R. The new compounds revealed (high) affinity to hH1R, but showed only low affinity to hH4R. Additionally, we performed molecular dynamic studies for some selected compounds at hH1R, in order to obtain information about the binding mode of these compounds on molecular level.
- Wagner, Eva,Wittmann, Hans-Joachim,Elz, Sigurd,Strasser, Andrea
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p. 6274 - 6280
(2011/11/29)
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- Discovery of the first nonpeptidic, Small-molecule, highly selective somatostatin receptor subtype 5 antagonists: A chemogenomics approach
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We disclose the first selective, nonpeptidic, small-molecule somatostatin receptor subtype 5 (SST5R) antagonists that were identified by a chemogenomics approach based on the analysis of the homology of amino acids defining the putative consensus drug binding site of SST5R. With this strategy, opioid, histamine, dopamine, and serotonine receptors were identified as the closest neighbors of SST5R. The H1 antagonist astemizole was chosen as a seed structure and subsequently transformed into a SST5 receptor antagonist with nanomolar binding affinity devoid of the original target activity.
- Martin, Rainer E.,Green, Luke G.,Guba, Wolfgang,Kratochwil, Nicole,Christ, Andreas
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p. 6291 - 6294
(2008/03/30)
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- Properly tuned first fluoride-catalyzed TGME-mediated amination process for chloroimidazoles: Inexpensive technology for antihistaminic norastemizole
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Fluoride-catalyzed amination process of chloroimidazole 1 proved to be a practical and inexpensive procedure for the preparation of the antihistaminic, norastemizole.
- Senanayake, Chris H.,Hong, Yaping,Xiang, Tingjian,Scott Wilkinson,Bakale, Roger P.,Jurgens, Alex R.,Pippert, Mark F.,Butler, Hal T.,Wald, Stephen A.
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p. 6875 - 6879
(2007/10/03)
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- The high-pressure S(N)AR reaction of N-p-fluorobenzyl-2- chlorobenzimidazole with amines; an approach to norastemizole and analogues
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N-p-fluorobenzyl-2-chlorobenzimidazole was treated under hyperbaric conditions with a variety of primary and secondary amines. The resulting S(N)Ar reaction proceeded smoothly to produce excellent yields of adducts in most cases. This methodology provides rapid access to astemizole, norastemizole and related analogues.
- Barrett, Ian C.,Kerr, Michael A.
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p. 2439 - 2442
(2007/10/03)
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- Palladium catalyzed amination of 2-chloro-1,3-azole derivatives: Mild entry to potent H1- antihistaminic norastemizole
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Palladium-catalyzed selective amination of 4-fluorobenzyl-2-chlorobenzimidazole with 4-aminopiperidine provided a simple solution for the norastemizole synthesis. Pd-catalyzed amination of other 2-chloro-1,3-Azole derivatives are exploited.
- Hong, Yaping,Tanoury, Gerald J.,Wilkinson, H. Scott,Bakale, Roger P.,Wald, Stephen A.,Senanayake, Chris H.
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p. 5607 - 5610
(2007/10/03)
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- A short synthesis of astemizole
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The synthesis of astemizole 6, a potent H1-antihistaminic agent, was achieved in 20% overall yield. Compound 6 was obtained in high purity and on a multigram scale starting from 2-hydroxybenzimidazole.
- De Parrodi, Cecilia Anaya,Quintero-Cortes, Leticia,Sandoval-Ramirez, Jesus
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p. 3323 - 3329
(2007/10/03)
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- Anti-histaminic compositions containing n-heterocyclyl-4-piperidinamines
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Anti-allergic compositions containing one or more pharmaceutical carriers and as active ingredient at least one compound which is a N-heterocyclyl-4-piperidinamine and methods of treating allergic diseases in warm-blooded animals. Novel N-heterocyclyl-4-piperidinamines.
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- New Antihistaminic N-Heterocyclic 4-Piperidinamines. 2. Synthesis and Antihistaminic Activity of 1--N-(4-piperidinyl)-1H-benzimidazol-2-amines
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The synthesis of a series of 1--N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vivo antihistamine activity are described.The title compounds were obtained starting from either 1, 4, 10, or 55 by different synthetic methods.Substitution on the phenyl nucleus of the benzimidazole ring (84-87) was achieved by two different approaches.The in vivo antihistamine activity was evaluated by the compound 48/80 induced lethality test in rats and the antihistamine-induced lethality test in guinea pigs after oral and/o r subcutaneous administration.The duration of action was studied in the guinea pig for three compounds (4, 51, and 55).Compound 51, "astemizole", was also studied in histamine- and serotonin-induced cutaneous reaction and for mydriatic activity in the rat and tested for peripheral and central effects not related to histamine antagonism in a variety of systems.Astemizole has been selected for clinical investigation.
- Janssens, Frans,Torremans, Joseph,Janssen, Marcel,Stokbroekx, Raymond A.,Luyckx, Marcel,Janssen, Paul A. J.
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p. 1934 - 1943
(2007/10/02)
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