- An alternative synthesis of Vandetanib (Caprelsa) via a microwave accelerated Dimroth rearrangement
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Vandetanib is an orally available tyrosine kinase inhibitor used in the treatment of cancer. The current synthesis proceeds via an unstable 4-chloroquinazoline, using harsh reagents, in addition to requiring sequential protection and deprotection steps. In the present work, use of the Dimroth rearrangement in the key quinazoline forming step enabled the synthesis of Vandetanib in nine steps (compared to the previously reported 12–14).
- Brocklesby, Kayleigh L.,Waby, Jennifer S.,Cawthorne, Chris,Smith, Graham
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supporting information
p. 1467 - 1469
(2017/03/23)
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- Cellular Compositions Used To Restore Stem Cell or Progenitor Cell Function and Methods Related Thereto
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This disclosure relates to compounds, compositions and methods of epigenetically transforming cells. In certain embodiments, the disclosure relates to methods of generating epigenetically altered cells comprising mixing isolated cells with compositions di
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Paragraph 0137
(2017/07/01)
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- Identification and Structure–Activity Relationship Studies of Small-Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1
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The methyllysine reader protein Spindlin1 has been implicated in the tumorigenesis of several types of cancer and may be an attractive novel therapeutic target. Small-molecule inhibitors of Spindlin1 should be valuable as chemical probes as well as potential new therapeutics. We applied an iterative virtual screening campaign, encompassing structure- and ligand-based approaches, to identify potential Spindlin1 inhibitors from databases of commercially available compounds. Our in silico studies coupled with in vitro testing were successful in identifying novel Spindlin1 inhibitors. Several 4-aminoquinazoline and quinazolinethione derivatives were among the active hit compounds, which indicated that these scaffolds represent promising lead structures for the development of Spindlin1 inhibitors. Subsequent lead optimization studies were hence carried out, and numerous derivatives of both lead scaffolds were synthesized. This resulted in the discovery of novel inhibitors of Spindlin1 and helped explore the structure–activity relationships of these inhibitor series.
- Robaa, Dina,Wagner, Tobias,Luise, Chiara,Carlino, Luca,McMillan, Joel,Flaig, Ralf,Schüle, Roland,Jung, Manfred,Sippl, Wolfgang
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p. 2327 - 2338
(2016/10/24)
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- Compounds and compositions used to epigenetically transform cells and methods related thereto
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This disclosure relates to compounds, compositions and methods of epigenetically transforming cells. In certain embodiments, the disclosure relates to methods of generating epigenetically altered cells comprising mixing isolated cells with compositions di
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Page/Page column 14
(2016/10/24)
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- COMPOUNDS AND COMPOSITIONS USED TO EPIGENETICALLY TRANSFORM CELLS AND METHODS RELATED THERETO
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This disclosure relates to compounds, compositions and methods of epigenetically transforming cells. In certain embodiments, the disclosure relates to methods of generating epigenetically altered cells comprising mixing isolated cells with compositions disclosed herein under conditions such that epigenetically altered cells are formed. In certain embodiments, the disclosure contemplates inducing cells, such as adult somatic cells or cells that are not naturally pluripotent, into cells with chemically induce pluripotency. In certain embodiments, the disclosure contemplates certain compounds disclosed herein, compounds disclosed herein optionally substituted with one or more substituents, derivatives, or salts thereof, for these purposes.
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Page/Page column 18
(2013/05/23)
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- Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy- quinazolines
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Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most potent G9a inhibitor to date, via structure-based design and structure-activity relationship (SAR) exploration of the quinazoline scaffold represented by BIX01294 (1). Despite its very high in vitro potency, compound 3 lacks sufficient cellular potency. The design and synthesis of several generations of new analogues aimed at improving cell membrane permeability while maintaining high in vitro potency resulted in the discovery of a number of novel G9a inhibitors such as UNC0646 (6) and UNC0631 (7) with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity. The design, synthesis, and cellular SAR of these potent G9a inhibitors are described.
- Liu, Feng,Barsyte-Lovejoy, Dalia,Allali-Hassani, Abdellah,He, Yunlong,Herold, J. Martin,Chen, Xin,Yates, Christopher M.,Frye, Stephen V.,Brown, Peter J.,Huang, Jing,Vedadi, Masoud,Arrowsmith, Cheryl H.,Jin, Jian
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scheme or table
p. 6139 - 6150
(2011/10/09)
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- Protein lysine methyltransferase g9a inhibitors: Design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines.
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Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a?10 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. On the basis of the structural insights revealed by this cocrystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison Ki = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date.
- Liu, Feng,Chen, Xin,Allali-Hassani, Abdellah,Quinn, Amy M.,Wigle, Tim J.,Wasney, Gregory A.,Dong, Aiping,Senisterra, Guillermo,Chau, Irene,Siarheyeva, Alena,Norris, Jacqueline L.,Kireev, Dmitri B.,Jadhav, Ajit,Herold, J. Martin,Janzen, William P.,Arrowsmith, Cheryl H.,Frye, Stephen V.,Brown, Peter J.,Simeonov, Anton,Vedadi, Masoud,Jin, Jian
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experimental part
p. 5844 - 5857
(2010/10/03)
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- Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a
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SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.
- Liu, Feng,Chen, Xin,Allali-Hassani, Abdellah,Quinn, Amy M.,Wasney, Gregory A.,Dong, Aiping,Barsyte, Dalia,Kozieradzki, Ivona,Senisterra, Guillermo,Chau, Irene,Siarheyeva, Alena,Kireev, Dmitri B.,Jadhav, Ajit,Herold, J. Martin,Frye, Stephen V.,Arrowsmith, Cheryl H.,Brown, Peter J.,Simeonov, Anton,Vedadi, Masoud,Jin, Jian
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supporting information; experimental part
p. 7950 - 7953
(2010/08/13)
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- Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors
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The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate tha
- Jung, Frédéric H.,Pasquet, Georges,Lambert-Van Der Brempt, Christine,Lohmann, Jean-Jacques M.,Warin, Nicolas,Renaud, Fabrice,Germain, Hervé,De Savi, Chris,Roberts, Nicola,Johnson, Trevor,Dousson, Cyril,Hill, George B.,Mortlock, Andrew A.,Heron, Nicola,Wilkinson, Robert W.,Wedge, Stephen R.,Heaton, Simon P.,Odedra, Rajesh,Keen, Nicholas J.,Green, Stephen,Brown, Elaine,Thompson, Katherine,Brightwell, Stephen
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p. 955 - 970
(2007/10/03)
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- PHOSPHONOOXY QUINAZOLINE DERIVATIVES AND THEIR PHARMACEUTICAL USE
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Quinazoline derivatives of formula (I) wherein A is 5-membered heteroaryl containing a nitrogen atom and one or two further nitrogen atoms; compositions containing them, processes for their preparation and their use in therapy.
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- QUINAZOLINE COMPOUNDS
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Quinazoline derivatives of formula (I) wherein A is 5-membered heteroaryl containing a sulphur atom and optionally containing one or more nitrogen atoms; compositions containing them, processes for their preparation and their use in therapy.
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- SUBSTITUTED QUINAZOLINE DERIVATIVES AND THEIR USE AS INHIBITORS
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The use of a compound of formula (I) 1 or a salt, ester or amide thereof; where X is O, or S, S(O) or S(O)2, or NR6 where R6 is hydrogen or C1-6 alkyl,; R5 is an optionally substituted 5-membered heteroaromatic ring, R1, R2 ,R3, R4 are independently selected from various specified moieties, in the preparation of a medicament for use in the inhibition of aurora 2 kinase. Certain compounds are novel and these, together with pharmaceutical compositions containing them are also described and claimed
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