931-54-4Relevant articles and documents
Design, synthesis and anticancer evaluation of 3-methyl-1H-indazole derivatives as novel selective bromodomain-containing protein 4 inhibitors
Dong, Ru,Zhang, Cheng,Wang, Chao,Zhou, Xin,Li, Wen,Zhang, Jin-Yang,Wang, Min,Xu, Yong,Sun, Li-Ping
, (2022/01/11)
Bromodomain-containing Protein 4 (BRD4), an ‘epigenetic reader’, regulates chromatin structure and gene expression via recognizing and binding acetylated lysine in histones. BRD4 has become a therapeutic target for cancers because it promotes the expression of the tumor genes, such as c-Myc, NF-κB, and Bcl-2. In this study, a new series of 3-methyl-1H-indazole derivatives were designed via virtual screening and structure-based optimization. All compounds were synthesized and evaluated for their inhibitory activities to BRD4-BD1 and their antiproliferative effects in cancer cell lines. Among them, several compounds (such as 9d, 9u and 9w) exhibited strong BRD4-BD1 affinities and inhibition activities, and potently suppressed MV4;11 cancer cell line proliferation. Among them, compound 9d showed excellent selectivity for BRD4 and effectively suppressed c-Myc, the downstream protein of BRD4. This study provided new lead compounds for further biological evaluation on BRD4.
Synthesis and Properties of N,N′-Disubstituted Ureas and Their Isosteric Analogs Containing Polycyclic Fragments: XI. 1-[(Adamantan-1 yl)alkyl]-3-arylselenoureas
Kuznetsov, Ya. P.,Rasskazova,Pitushkin,Eshtukov,Vasipov,Burmistrov,Butov
, p. 1036 - 1046 (2021/09/08)
Abstract: A series of N,N′-disubstituted selenoureas containing an adamantane fragmenthave been synthesized in 23–75% yields. Procedures for the isolation andpurification of aromatic isoselenocyanates have been improved. The chemicalshift of the C=Se carbon nucleus in the 13C NMRspectra of selenoureas has been refined. The synthesized selenoureas have beenfound to be promising as inhibitors of not only epoxide hydrolase (sEH-H) butalso phosphatase domains (sEH-P) of human soluble epoxide hydrolase.
Small molecule microarray identifies inhibitors of tyrosyl-DNA phosphodiesterase 1 that simultaneously access the catalytic pocket and two substrate binding sites
Zhao, Xue Zhi,Kiselev, Evgeny,Lountos, George T.,Wang, Wenjie,Tropea, Joseph E.,Needle, Danielle,Hilimire, Thomas A.,Schneekloth, John S.,Waugh, David S.,Pommier, Yves,Burke, Terrence R.
, p. 3876 - 3884 (2021/04/02)
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a member of the phospholipase D family of enzymes, which catalyzes the removal of both 3′- and 5′-DNA phosphodiester adducts. Importantly, it is capable of reducing the anticancer effects of type I topoisomerase (TOP1) inhibitors by repairing the stalled covalent complexes of TOP1 with DNA. It achieves this by promoting the hydrolysis of the phosphodiester bond between the Y723 residue of human TOP1 and the 3′-phosphate of its DNA substrate. Blocking TDP1 function is an attractive means of enhancing the efficacy of TOP1 inhibitors and overcoming drug resistance. Previously, we reported the use of an X-ray crystallographic screen of more than 600 fragments to identify small molecule variations on phthalic acid and hydroxyquinoline motifs that bind within the TDP1 catalytic pocket. Yet, the majority of these compounds showed limited (millimolar) TDP1 inhibitory potencies. We now report examining a 21?000-member library of drug-like Small Molecules in Microarray (SMM) format for their ability to bind Alexa Fluor 647 (AF647)-labeled TDP1. The screen identified structurally similarN,2-diphenylimidazo[1,2-a]pyrazin-3-amines as TDP1 binders and catalytic inhibitors. We then explored the core heterocycle skeleton using one-pot Groebke-Blackburn-Bienayme multicomponent reactions and arrived at analogs having higher inhibitory potencies. Solving TDP1 co-crystal structures of a subset of compounds showed their binding at the TDP1 catalytic site, while mimicking substrate interactions. Although our original fragment screen differed significantly from the current microarray protocol, both methods identified ligand-protein interactions containing highly similar elements. Importantly inhibitors identified through the SMM approach show competitive inhibition against TDP1 and access the catalytic phosphate-binding pocket, while simultaneously providing extensions into both the substrate DNA and peptide-binding channels. As such, they represent a platform for further elaboration of trivalent ligands, that could serve as a new genre of potent TDP1 inhibitors.
Application of proteasome inhibitor in inhibition of novel coronavirus
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Paragraph 0091; 0110-0112; 0130; 0152-0154, (2021/06/22)
The invention provides application of a proteasome inhibitor in inhibition of a novel coronavirus or preparation of novel coronavirus inhibitors. The proteasome inhibitor has a structure represented by a formula (I) or isomers, pharmaceutically acceptable salts thereof and prodrugs thereof. According to the application, by applying the proteasome inhibitor to inhibition of the novel coronavirus, good inhibiting activity is obtained, and a novel treatment way of think is provided for diseases such as pneumonia caused by the novel coronavirus.
Silver-Catalyzed Selective Multicomponent Coupling Reactions of Arynes with Nitriles and Isonitriles
Ghorai, Sourav,Lin, Yongjia,Xia, Yuanzhi,Wink, Donald J.,Lee, Daesung
supporting information, p. 642 - 647 (2020/01/31)
Pathway selective aryne-based novel multicomponent coupling reactions with isonitriles and nitriles are described. Crucial to these reactions is the formation of a silver-aryne complex, which shows differential reactivity toward isonitriles and nitriles to form two different forms of ortho-nitrilium organosilver arene species. Interception of the nitrilium of an aryne-isonitrile adduct with another isonitrile leads to the formation of benzocyclobutene-1,2-diimines, whereas the nitrilium of an aryne-nitrile adduct renders selective formation of 3H-indol-3-imines or 3-iminoindolin-2-ol depending on the structure of the nitrile employed.
Bis-Selenoureas for Anion Binding: A 1H NMR and Theoretical Study
Caltagirone, Claudia,Ciancaleoni, Gianluca,Lippolis, Vito,Mocci, Rita,Picci, Giacomo,Zielińska-B?ajet, Mariola
, p. 1389 - 1395 (2020/08/05)
The anion binding ability of a family of bis-selenoureas L1-L3 obtained by the reaction of 1,3-bis(aminomethyl)-benzene and phenylisoselenocyanate, p-methoxyphenylisoselenocyanate and naphtylisoselenocyanate, for L1, L2, and L3, respectively, has been tested and compared to that of previously described bis-urea analogues. Results suggest that the introduction of selenium leads to an increase in the acidity of the urea NH hydrogen atoms, and therefore to a stronger affinity (more than three-fold higher) towards anion species, in particular dihydrogen phosphate, in DMSO-d6. Theoretical calculations allowed for the optimization of the adducts receptors corroborating the experimental results.
Multicomponent Ugi Reaction of Indole- N-carboxylic Acids: Expeditious Access to Indole Carboxamide Amino Amides
Zeng, Linwei,Sajiki, Hironao,Cui, Sunliang
supporting information, p. 5269 - 5272 (2019/07/03)
A novel multicomponent Ugi-type reaction for the synthesis of indole carboxamide amino amides from aldehydes, amines, isocyanides, and indole-N-carboxylic acids, which were simply prepared from indoles and CO2, is described. This method provides an expeditious and practical access to indole tethered peptide units, along with the achievement of remarkable structural diversity and brevity. Gram-scale reaction was conducted to demonstrate the scalability, and the products could be transformed to new indole derivatives.
Synthesis of Imides, Imidates, Amidines, and Amides by Intercepting the Aryne-Isocyanide Adduct with Weak Nucleophiles
Ghorai, Sourav,Lee, Daesung
supporting information, p. 7390 - 7393 (2019/10/02)
New aryne-based multicomponent coupling reactions for the formation of functionalized aromatic compounds have been developed. Arynes generated from triynes or tetraynes through the hexadehydro Diels-Alder reaction readily react with isocyanide to generate nitrilium intermediate. Intercepting this nitrilium species with various weak nucleophile including carboxylic acids, alcohols, sulfonamides, or water generated the corresponding imides, imidates, amidines, or amides. The high regioselectivity of these transformations was mainly controlled by the substituents of the arynes.
Selective Gold-Catalysed Synthesis of Cyanamides and 1-Substituted 1H-Tetrazol-5-Amines from Isocyanides
?koch, Karel,Císa?ová, Ivana,?těpni?ka, Petr
supporting information, p. 13788 - 13791 (2018/09/14)
The newly discovered gold-catalysed reaction of isocyanides with hydrazoic acid generated in situ from trimethylsilyl azide and methanol (or, alternatively, from NaN3/AcOH) produces either cyanamides or 1-substituted 1H-tetrazol-5-amines, depending on the amount of available HN3. The reaction proceeds selectively and in generally high yields of either product, thus providing a particularly convenient access to a wide range of substituted 1H-tetrazol-5-amines that are rather difficult to access otherwise.
Dramatically Enhanced Solubility of Halide-Containing Organometallic Species in Diiodomethane: The Role of Solvent???Complex Halogen Bonding
Kinzhalov, Mikhail A.,Kashina, Mariya V.,Mikherdov, Alexander S.,Mozheeva, Ekaterina A.,Novikov, Alexander S.,Smirnov, Andrey S.,Ivanov, Daniil M.,Kryukova, Mariya A.,Ivanov, Aleksandr Yu.,Smirnov, Sergej N.,Kukushkin, Vadim Yu.,Luzyanin, Konstantin V.
supporting information, p. 12785 - 12789 (2018/09/11)
In the current study, we evaluated the solubility of a number of organometallic species and showed that it is noticeably improved in diiodomethane when compared to other haloalkane solvents. The better solvation properties of CH2I2 w
