- The clinically used iron chelator deferasirox is an inhibitor of epigenetic jumonjic domain-containing histone demethylases
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Fe(II)- A nd 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are "epigenetic eraser" enzymes involved in the regulation of gene expression and are emerging drug targets in oncology. We screened a set of clinically used iron chelators and report that they potently inhibit JMJD2A (KDM4A) in vitro. Mode of action investigations revealed that one compound, deferasirox, is a bona fide active site-binding inhibitor as shown by kinetic and spectroscopic studies. Synthesis of derivatives with improved cell permeability resulted in significant upregulation of histone trimethylation and potent cancer cell growth inhibition. Deferasirox was also found to inhibit human 2OG-dependent hypoxia inducible factor prolyl hydroxylase activity. Therapeutic effects of clinically used deferasirox may thus involve transcriptional regulation through 2OG oxygenase inhibition. Deferasirox might provide a useful starting point for the development of novel anticancer drugs targeting 2OG oxygenases and a valuable tool compound for investigations of KDM function.
- Roatsch, Martin,Hoffmann, Inga,Abboud, Martine I.,Hancock, Rebecca L.,Tarhonskaya, Hanna,Hsu, Kuo-Feng,Wilkins, Sarah E.,Yeh, Tzu-Lan,Lippl, Kerstin,Serrer, Kerstin,Moneke, Isabelle,Ahrens, Theresa D.,Robaa, Dina,Wenzler, Sandra,Barthes, Nicolas P. F.,Franz, Henriette,Sippl, Wolfgang,Lassmann, Silke,Diederichs, Sven,Schleicher, Erik,Schofield, Christopher J.,Kawamura, Akane,Schüle, Roland,Jung, Manfred
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p. 1737 - 1750
(2019/08/20)
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- Design, synthesis and biological evaluation of benzohydrazide derivatives containing dihydropyrazoles as potential EGFR kinase inhibitors
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A series of novel benzohydrazide derivatives containing dihydropyrazoles have been synthesized as potential epidermal growth factor receptor (EGFR) kinase inhibitors and their biological activities as potential antiproliferative agents have been evaluated. Among these compounds, compound H20 exhibited the most potent antiproliferative activity against four cancer cell line variants (A549, MCF-7, HeLa, HepG2) with IC50 values of 0.46, 0.29, 0.15 and 0.21 μM respectively, which showed the most potent EGFR inhibition activities (IC50 = 0.08 μM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity and activity relationship (SAR) of these benzohydrazide derivatives. These results suggested that compound H20 may be a promising anticancer agent.
- Wang, Hai-Chao,Yan, Xiao-Qiang,Yan, Tian-Long,Li, Hong-Xia,Wang, Zhong-Chang,Zhu, Hai-Liang
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- The indole skeleton-containing [...] steroidal saponin aglycone derivatives, its preparation method and application
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The invention discloses an indole skeleton-containing dihydropyrazolhydroxamic acid steroid sapogenin derivative, and a preparation method and an application thereof. The structure of the indole skeleton-containing dihydropyrazolhydroxamic acid steroid sapogenin derivative is represented by formula VIII shown in the specification; and in the formula VIII, R1 is selected from H and CH3, R2 is selected from H and CH3, R3 is selected from H and F, and R4 is selected from H and CH3. The derivative has an obvious inhibition effect on human breast cancer cells (MCF-7), cervical carcinoma cells (HeLa), lung cancer cells (A549) and liver cancer cells (HepG2), has same or better cytotoxicity on human renal epithelial cells (293T) than positive control drug Celecoxib, and can be used to prepare antitumor drugs. The derivative has the advantages of good bioactivity, high selectivity, low toxicity and short residual life.
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Paragraph 0043; 0045
(2016/10/27)
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- Benzoyl hydrazine derivative containing dihydro-pyrazole structure and preparation method of benzoyl hydrazine derivative
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The invention discloses a benzoyl hydrazine derivative containing a dihydro-pyrazole structure and a preparation method of the benzoyl hydrazine derivative. The structure of the synthesized benzoyl hydrazine derivative is shown as follows.
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Paragraph 0010; 0011; 0012
(2016/12/22)
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- TRIAZOLONE COMPOUNDS AS mPGES-1 INHIBITORS
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The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.
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- Virtual ligand screening of the p300/CBP histone acetyltransferase: Identification of a selective small molecule inhibitor
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The histone acetyltransferase (HAT) p300/CBP is a transcriptional coactivator implicated in many gene regulatory pathways and protein acetylation events. Although p300 inhibitors have been reported, a potent, selective, and readily available active-sitedirected small molecule inhibitor is not yet known. Here we use a structure-based, in silico screening approach to identify a commercially available pyrazolone- containing small molecule p300 HAT inhibitor, C646. C646 is a competitive p300 inhibitor with a Ki of 400 nM and is selective versus other acetyltransferases. Studies on site-directed p300 HAT mutants and synthetic modifications of C646 confirm the importance of predicted interactions in conferring potency. Inhibition of histone acetylation and cell growth by C646 in cells validate its utility as a pharmacologic probe and suggest that p300/CBP HAT is a worthy anticancer target.
- Bowers, Erin M.,Yan, Gai,Mukherjee, Chandrani,Orry, Andrew,Wang, Ling,Holbert, Marc A.,Crump, Nicholas T.,Hazzalin, Catherine A.,Liszczak, Glen,Yuan, Hua,Larocca, Cecilia,Saldanha, S. Adrian,Abagyan, Ruben,Sun, Yan,Meyers, David J.,Marmorstein, Ronen,Mahadevan, Louis C.,Alani, Rhoda M.,Cole, Philip A.
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scheme or table
p. 471 - 482
(2011/08/06)
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- NEW TETRACYCLIC COMPOUNDS
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This disclosure relates to new tetracyclic compounds that may be used to modulate a histamine receptor in an individual. The compounds in one embodiment are tetracyclic [4,3- b]indoles. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.
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Page/Page column 283, 285
(2009/05/30)
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- CHEMOKINE RECEPTOR MODULATORS
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The invention provides compounds of Formula (I) and pharmaceutical compositions comprising compounds of Formula (I). These compounds are useful treating or preventing HIV infections, and in treating proliferative disorders such as inhibiting the metastasis of various cancers.
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Page/Page column 577
(2008/12/07)
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- Development of the traceless phenylhydrazide linker for solid-phase synthesis
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The hydrazide group is a new oxidatively cleavable traceless linker for solid-phase chemistry. It can be readily introduced by hydrazide formation between a carboxy-functionalized resin and different substituted hydrazines. In order to achieve high yields in this step, new carboxylic acid resins were developed that are not prone to undesired imide formation upon activation of the carboxylic acid. The polymer-bound acyl hydrazides were successfully employed in various transformations, namely Heck, Suzuki, Sonogashira, and Stille couplings, as well as Wittig and Grignard reactions. Traceless release of the coupling products from the solid support is achieved selectively under mild conditions and in high purity by oxidation of the aryl hydrazides to acyl diazenes with CuII salts or N-bromosuccinimide (NBS) and subsequent nucleophilic attack of the acyl diazene intermediates. Traceless cleavage by oxidation with NBS can be carried out as a two-step process in which stable acyl diazenes are first generated by treatment with NBS in the absence of a nucleophile. After removal of the reagents by simple resin washing, the traceless release is effected by the addition of methanol, which leads to products of high purity without any additional separation steps.
- Stieber, Frank,Grether, Uwe,Waldmann, Herbert
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p. 3270 - 3281
(2007/10/03)
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