- Rational Design of Specific Recognition Molecules for Simultaneously Monitoring of Endogenous Polysulfide and Hydrogen Sulfide in the Mouse Brain
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A biosensor was created for the simultaneous monitoring of endogenous H2Sn and H2S in mouse brains and exploring their roles in activation of the TRPA1 channel under two types of brain disease models: ischemia and Alzheimer's disease (AD). Based on DFT calculations and electrochemical measurements, two probes, 3,4-bis((2-fluoro-5-nitrobenzoyl)oxy)-benzoic acid (MPS-1) and N-(4-(2,5-dinitrophenoxy) phenyl)-5-(1, 2-dithiolan-3-yl)pentanamide (MHS-1), were synthesized for specific recognition of H2Sn and H2S. Through co-assembly of the two probes at the mesoporous gold film with good anti-biofouling ability and electrocatalytic activity, this microsensor showed high selectivity for H2Sn and H2S against potential biological interferences. The biosensor can simultaneously determine the concentration of H2Sn from 0.2 to 50 μm, as well as that of H2S from 0.2 to 40 μm. The expression of TRPA1 protein positively correlated with levels of H2Sn under both ischemia and AD.
- Dong, Hui,Zhou, Qi,Zhang, Limin,Tian, Yang
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Read Online
- A near-infrared fluorescent probe that can image endogenous hydrogen polysulfidesin vivoin tumour-bearing mice
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Hydrogen polysulfides (H2Sn,n> 1), which are important reactive sulfur species, play crucial roles in H2S-related bioactivities, including antioxidation, cytoprotection, activation of ion channels, transcription factor functions and tumour suppression. Monitoring H2Snin vivois of significant interest for exploring the physiological roles of H2Snand the exact mechanisms of H2Sn-related diseases. Herein, we conceive a novel near-infrared fluorescent probe, NIR-CPS, that is used to detect H2Snin living cells andin vivo. With the advantages of high sensitivity, good selectivity and a remarkably large Stokes shift (100 nm), NIR-CPS was successfully applied in visualizing H2Snin living cells and mice. More importantly, NIR-CPS monitored H2Snstimulated by lipopolysaccharide in tumour-bearing mice. These results demonstrate that the NIR-CPS probe is a potentially powerful tool for the detection of H2Snin vivo, thus providing a valuable approach in H2Sn-related medical research.
- Zhang, Ling,Liu, Huizhen,Wu, Chunli,Zheng, Youguang,Kai, Xiaoning,Xue, Yunsheng
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Read Online
- A single fluorescent probe for one- and two-photon imaging hydrogen sulfide and hydrogen polysulfides with different fluorescence signals
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Reactive sulfur species (RSS), primarily containing glutathione (GSH), cysteine (Cys), hydrogen sulfide (H2S) and hydrogen polysulfides (H2Sn, n > 1), were crucial endogenous biological signal molecules. Among them, H
- Zhao, Xinxin,He, Fangru,Dai, Yanpeng,Ma, Fulong,Qi, Zhengjian
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Read Online
- Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases
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Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of t
- Nagle, Advait,Biggart, Agnes,Be, Celine,Srinivas, Honnappa,Hein, Andreas,Caridha, Diana,Sciotti, Richard J.,Pybus, Brandon,Kreishman-Deitrick, Mara,Bursulaya, Badry,Lai, Yin H.,Gao, Mu-Yun,Liang, Fang,Mathison, Casey J.N.,Liu, Xiaodong,Yeh, Vince,Smith, Jeffrey,Lerario, Isabelle,Xie, Yongping,Chianelli, Donatella,Gibney, Michael,Berman, Ashley,Chen, Yen-Liang,Jiricek, Jan,Davis, Lauren C.,Liu, Xianzhong,Ballard, Jaime,Khare, Shilpi,Eggimann, Fabian Kurt,Luneau, Alexandre,Groessl, Todd,Shapiro, Michael,Richmond, Wendy,Johnson, Kevin,Rudewicz, Patrick J.,Rao, Srinivasa P.S.,Thompson, Christopher,Tuntland, Tove,Spraggon, Glen,Glynne, Richard J.,Supek, Frantisek,Wiesmann, Christian,Molteni, Valentina
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Read Online
- Oxidative induction of β-turn conformations in cyclic peptidomimetics: Conformational analyses as indicators of configuration
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Solid-phase syntheses of the cyclic peptidomimetics 1-4 were performed. Sulfide 1 and sulfoxide 3 did not tend to exist in β-turn conformations in solution, but the sulfone 2 and the epimeric sulfoxide 4 did. The assignment of configuration of the sulfoxi
- Jiang, Luyong,Burgess, Kevin
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- A NIR fluorescent chemodosimeter for imaging endogenous hydrogen polysulfides via the CSE enzymatic pathway
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Sodium polysulfides (Na2Sn, n > 1) as important raw materials in the chemical industry can afford hydrogen polysulfides (H2Sn, n > 1) under physiological conditions. Hydrogen polysulfides are important reactive sulfide species that play crucial roles in biological systems. The simple detection of H2Sn in solution and biosystems becomes very important as a consequence of the foregoing applications. Herein, we report a NIR fluorescent chemodosimeter, Cy-Sn, displaying turn-on fluorescence after reaction with H2Sn, which exhibits good selectivity and sensitivity in solution and biosystems. Moreover, it was applied successfully to monitor endogenous hydrogen polysulfides via the cystathionine γ-lyase (CSE) enzymatic pathway during inflammation and anti-inflammation in living RAW 264.7 cells. Mouse experiments indicated that this chemodosimeter has good potential to be employed in the imaging of living biosystems.
- Ma, Jianhua,Fan, Jiangli,Li, Haidong,Yao, Qichao,Xu, Feng,Wang, Jingyun,Peng, Xiaojun
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Read Online
- A highly selective fluorescent probe for hydrogen polysulfides in living cells based on a naphthalene derivative
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Hydrogen polysulfides (H2Sn, n > 1) are members of reactive sulfur species (RSS) and signaling molecules derived from hydrogen sulfide (H2S). Recently, the functions of H2Sn in physiological and patho
- Wang, Chunyan,Xu, Junhong,Ma, Qiujuan,Bai, Yu,Tian, Meiju,Sun, Jingguo,Zhang, Zhijuan
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Read Online
- Polyhydrogen sulfide fluorescent probe as well as preparation method and application thereof
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The invention relates to a polyhydrogen sulfide fluorescent probe as well as a preparation method and application thereof. The fluorescent probe AIE-PS2 has the advantages of relatively large Stokes shift (254nm), good selectivity, high sensitivity, low d
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Paragraph 0081; 0086; 0087
(2021/08/11)
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- A Dinuclear Persulfide-Bridged Ruthenium Compound is a Hypoxia-Selective Hydrogen Sulfide (H2S) Donor
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Hydrogen sulfide (H2S) is a gaseous molecule that has received attention for its role in biological processes and therapeutic potential in diseases, such as ischemic reperfusion injury. Despite its clinical relevance, delivery of H2S to biological systems is hampered by its toxicity at high concentrations. Herein, we report the first metal-based H2S donor that delivers this gas selectively to hypoxic cells. We further show that H2S release from this compound protects H9c2 rat cardiomyoblasts from an in vitro model of ischemic reperfusion injury. These results validate the utility of redox-activated metal complexes as hypoxia-selective H2S-releasing agents for use as tools to study the role of this gaseous molecule in complex biological systems.
- Woods, Joshua J.,Wilson, Justin J.
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supporting information
p. 1588 - 1592
(2020/11/30)
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- New cysteine protease inhibitors: Electrophilic (Het)arenes and unexpected prodrug identification for the trypanosoma protease rhodesain
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Electrophilic (het)arenes can undergo reactions with nucleophiles yielding π- or Meisenheimer (σ-) complexes or the products of the SNAr addition/elimination reactions. Such building blocks have only rarely been employed for the design of enzyme inhibitors. Herein, we demonstrate the combination of a peptidic recognition sequence with such electrophilic (het)arenes to generate highly active inhibitors of disease-relevant proteases. We further elucidate an unexpected mode of action for the trypanosomal protease rhodesain using NMR spectroscopy and mass spectrometry, enzyme kinetics and various types of simulations. After hydrolysis of an ester function in the recognition sequence of a weakly active prodrug inhibitor, the liberated carboxylic acid represents a highly potent inhibitor of rhodesain (Ki = 4.0 nM). The simulations indicate that, after the cleavage of the ester, the carboxylic acid leaves the active site and re-binds to the enzyme in an orientation that allows the formation of a very stable π-complex between the catalytic dyad (Cys-25/His-162) of rhodesain and the electrophilic aromatic moiety. The reversible inhibition mode results because the SNAr reaction, which is found in an alkaline solvent containing a low molecular weight thiol, is hindered within the enzyme due to the presence of the positively charged imidazolium ring of His-162. Comparisons between measured and calculated NMR shifts support this interpretation.
- Barthels, Fabian,Distler, Ute,Engels, Bernd,Hellmich, Ute A.,Johe, Patrick,Jung, Sascha,Kühlborn, Jonas,Klein, Philipp,Opatz, Till,Schirmeister, Tanja,Tenzer, Stefan,Wagner, Annika,Waigel, Waldemar
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supporting information
(2020/03/27)
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- POLYCYCLIC COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES
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The present disclosure relates to bifunctional compounds, ULM— L—PTM, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A- RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 1573; 1574
(2020/03/29)
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- Synthesis, docking, 3-D-qsar, and biological assays of novel indole derivatives targeting serotonin transporter, dopamine D2 receptor, and mao-a enzyme: In the pursuit for potential multitarget directed ligands
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A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a-o) and (2-{4-[3-(1H-3-indolyl) -propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a-l) were synthesized and evaluated as novel multitarget ligands towards dopamine D2 receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying Ki values from 5 to 10 nM. Compounds 7k, Ki = 5.63 ± 0.82 nM, and 13c, Ki = 6.85 ± 0.19 nM, showed the highest potencies. The affinities for D2 ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D2 receptor in the nanomolar range (7n: Ki = 307 ± 6 nM and 7m: Ki = 593 ± 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D2 receptor (D2/SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure-activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q2 = 0.625, 0.523 for CoMFA and CoMSIA and r2ncv = 0.967, 0.959 for CoMFA and CoMSIA, respectively).
- Alarcón-Espósito, Jazmín,Araya-Maturana, Ramiro,Cabezas, David,Cerda-Cavieres, Christopher,Chung, Hery,Iturriaga-Vásquez, Patricio,Mella-Raipán, Jaime,Ojeda-Gómez, Claudia,Pessoa-Mahana, Carlos D.,Pessoa-Mahana, Hernán,Quiroz, Gabriel,Reyes-Parada, Miguel,Rodríguez-Lavado, Julio,Saitz, Claudio
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- Near-infrared fluorescent probe for hydrogen polysulfides, and preparation method and application of near-infrared fluorescent probe
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The invention relates to a near-infrared fluorescent probe for hydrogen polysulfides, and a preparation method and application of the near-infrared fluorescent probe, and belongs to the field of chemistry and analysis detection. The near-infrared fluoresc
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Paragraph 0018; 0110-0111
(2019/10/17)
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- APOPTOSIS SIGNAL-REGULATING KINASE 1 (ASK 1) INHIBITOR COMPOUNDS
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Described herein are ASK1 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with ASK1
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Paragraph 00271
(2019/06/09)
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- Novel quinazoline derivatives bearing various 6-benzamide moieties as highly selective and potent EGFR inhibitors
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A series of novel quinazoline derivatives bearing various C-6 benzamide substituents were synthesized and evaluated as EGFR inhibitors, and most showed significant inhibitory potency against EGFR kinase. In particular, compound 6g possessed potent inhibitory activity against EGFR wild-type (IC50 = 5 nM), and strong antiproliferative activity against HCC827 and Ba/F3 (L858R) cell lines. Kinase profiling against a panel of 365 kinases showed that 6g was highly selective for EGFR. Furthermore, 6g showed desirable properties in assays of liver microsome metabolic stability and cytochromes P450 inhibition and preliminary pharmacokinetic study. The overall attractive profile of 6g made it an interesting compound for further development.
- Hou, Weijie,Ren, Yan,Zhang, Zhenhua,Sun, Huan,Ma, Yongfen,Yan, Bo
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p. 1740 - 1750
(2018/03/12)
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- APOPTOSIS SIGNAL-REGULATING KINASE 1 (ASK 1) INHIBITOR COMPOUNDS
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Described herein are ASK1 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with ASK1 activity.
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Paragraph 00260; 00261
(2018/10/25)
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- Design, Synthesis, and Biological Evaluation of Novel Type I1/2 p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine
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We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase's R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I1/2 binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives.
- Walter, Niklas M.,Wentsch, Heike K.,Bührmann, Mike,Bauer, Silke M.,D?ring, Eva,Mayer-Wrangowski, Svenja,Sievers-Engler, Adrian,Willemsen-Seegers, Nicole,Zaman, Guido,Buijsman, Rogier,L?mmerhofer, Michael,Rauh, Daniel,Laufer, Stefan A.
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supporting information
p. 8027 - 8054
(2017/10/18)
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- 2-Halobenzoyl chlorides in the synthesis of [1,3,4]thiadiazolo[3,2-a]quinazolin-5-one derivatives
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New nitro and sulfonamide derivatives of [1,3,4]thiadiazolo[3,2-a]quinazolin-5-one have been synthesized by cyclocondensation of 1,3,4-thiadiazol-2-amines with 2-halobenzoyl chlorides containing electron-withdrawing substituents in positions 3, 4, and 5. An improved procedure has been proposed for the preparation of intermediate 2-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamides containing a sulfamoyl group in the 5-position via selective acylation of 5-methyl-1,3,4-thiadiazol-2-amine with 5-chlorosulfonyl-2-fluorobenzoyl chloride, followed by sulfonylation of amines.
- Shlenev,Tarasov,Filimonov,Agat’ev,Danilova,Suponitskii, K. Yu.
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p. 1870 - 1877
(2018/02/06)
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- Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5
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MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC50 = 0.3 μM) was defined as a potent small molecule to disturb the interaction of MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to block MLL1-WDR5 PPI. Especially, compound 23 (IC50 = 104 nM) was the most potent small molecular, and about 3-times more potent than WDR5-47. We also discussed the SAR of these series of compounds with docking study, which may stimulate more potent compounds.
- Li, Dong-Dong,Chen, Wei-Lin,Xu, Xiao-Li,Jiang, Fen,Wang, Lei,Xie, Yi-Yue,Zhang, Xiao-Jin,Guo, Xiao-Ke,You, Qi-Dong,Sun, Hao-Peng
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supporting information
p. 1 - 8
(2016/05/10)
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- COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF PARASITIC DISEASES
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The present invention provides compounds of Formula A: or a pharmaceutically acceptable salt, tautomer, or stereoisomer, thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds and methods of using such compounds for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a parasite, such as leishmaniasis, human African trypanosomiasis and Chagas disease.
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Paragraph 0427; 0428; 0429
(2015/07/02)
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- Metal-Free Synthesis of Dibenzoxazepinones via a One-Pot SNAr and Smiles Rearrangement Process: Orthogonality with Copper-Catalyzed Cyclizations
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Reported is the transition-metal-free synthesis of substituted dibenzoxazepinones using a convergent domino SNAr-Smiles rearrangement-SNAr process. Substrate-scope investigations demonstrated the critical importance of ring electroni
- Hurst, Timothy E.,Kitching, Matthew O.,Da Frota, Lívia C. R. M.,Guimar?es, Keller G.,Dalziel, Michael E.,Snieckus, Victor
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supporting information
p. 1455 - 1460
(2015/06/30)
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- Isoquinolin-1(2H)-ones and 1,6-naphthyridin-5(6H)-ones by an N-acylation-SNAr sequence
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A new synthesis of 2,3-dialkyl-4-carbomethoxyisoquinolin-1(2H)-ones and 6,7-dialkyl-8-carbomethoxy-1,6-naphthyridin-5(6H)-ones is reported. The process involves treatment of a β-enaminoester with 2-fluoro-5-nitrobenzoyl chloride, 2-fluorobenzoyl chloride or 2-chloronicotinoyl chloride followed by heating in the presence of base. The conversion, which proceeds by an N-acylation-SNAr reaction sequence, affords 50-86% yields when R 1 is n-alkyl but ≤30% yields when R1 is α-branched.
- Bunce, Richard A.,Nammalwar, Baskar,Gnanasekaran, Krishna Kumar,Cain, Nicholas R.
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p. 838 - 844
(2014/01/23)
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- 4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B
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Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC 50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.
- Zhi, Ying,Gao, Li-Xin,Jin, Yi,Tang, Chun-Lan,Li, Jing-Ya,Li, Jia,Long, Ya-Qiu
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p. 3670 - 3683
(2014/07/07)
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- Substituted 4-Oxo-1,2,3,4-tetrahydroquinoline-3-carboxylic esters by a tandem imine addition-SNAr reaction
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A tandem imine addition-SNAr annulation reaction has been developed as a new approach to the synthesis of 4-oxo-1,2,3,4- tetrahydroquinoline-3-carboxylic esters. A series of these structures has been generated by reacting selected imines with tert-butyl 2-fluoro-5- nitrobenzoylacetate. Structural variations in the final products are accomplished by changing the substituents on the imine and the alkyl group of the ester. The title compounds are isolated as their enols in 55-97% yield without the need for added base or catalysts. The synthesis of the starting materials as well as mechanistic studies and further synthetic conversions of the products are presented.
- Bunce, Richard A.,Schammerhorn, James E.,Sigle, Jessica
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p. 373 - 380
(2013/06/04)
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- The development of potential new fluorine-18 labelled radiotracers for imaging the GABAA receptor
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Positron emission tomography (PET) using the tracer [11C] Flumazenil has shown changes in the distribution and expression of the GABA A receptor in a range of neurological conditions and injury states. We aim to develop a fluorine-18 labelled PET agent with comparable properties to [11C]Flumazenil. In this study we make a direct comparison between the currently known fluorine-18 labelled GABAA radiotracers and novel imidazobenzodiazepine ligands. A focussed library of novel compound was designed and synthesised where the fluorine containing moiety and the position of attachment is varied. The in vitro affinity of twenty-two compounds for the GABAA receptor was measured. Compounds containing a fluoroalkyl amide or a longer chain ester group were eliminated due to low potency. The fluorine-18 radiochemistry of one compound from each structural type was assessed to confirm that an automated radiosynthesis in good yield was feasible. Eleven of the novel compounds assessed appeared suitable for in vivo assessment as PET tracers.
- Jackson, Alexander,Guilbert, Benedicte B.,Plant, Stuart D.,Goggi, Julian,Battle, Mark R.,Woodcraft, John L.,Gaeta, Alessandra,Jones, Clare L.,Bouvet, Denis R.,Jones, Paul A.,O'Shea, Dennis M.,Zheng, Penny Hao,Brown, Samantha L.,Ewan, Amanda L.,Trigg, William
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supporting information
p. 821 - 826
(2013/03/13)
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- APOPTOSIS SIGNAL-REGULATING KINASE INHIBITORS
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The present invention relates to compounds of Formula (I): wherein X1, X2, X3, X4, X5, R, R1, R2 are as defined above. The compounds have apoptosis signal-regulating k
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Page/Page column 21-22
(2012/01/14)
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- DIAMINO HETEROCYCLIC CARBOXAMIDE COMPOUND
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Provided is a compound useful as an inhibitor against the kinase activity of EML4-ALK fusion protein. As a result of intensive and extensive studies on compounds having inhibitory activity against the kinase activity of EML4-ALK fusion protein, the present inventors found that the diamino heterocyclic carboxamide compounds of the present invention had inhibitory activity against the kinase activity of EML4-ALK fusion protein. By this finding, the present invention was completed. The compounds of the present invention can be used as a pharmaceutical composition for preventing and/or treating cancer, such as lung cancer, non-small cell lung cancer, and small cell lung cancer.
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Page/Page column 21-22
(2012/03/08)
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- A highly selective tandem cross-coupling of gem-dihaloolefins for a modular, efficient synthesis of highly functionalized indoles
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(Chemical Equation Presented) A highly efficient method of indole synthesis using gem-dihalovinylaniline substrates and an organoboron reagent was developed via a Pd-catalyzed tandem intramolecular amination and an intermolecular Suzuki coupling. Aryl, alkenyl, and alkyl boron reagents are all successfully employed, making for a versatile modular approach. The reaction tolerates a variety of substitution patterns on the aniline leading to indoles with group at C2-C7. The orthogonal approach of the sequential copper- and palladium-mediated synthesis of 1,2-diarylindoles exploited the wide availability of diverse organoboron reagents.
- Fang, Yuan-Qing,Lautens, Mark
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p. 538 - 549
(2008/09/17)
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- Synthesis and structural characterization of new phosphinooxazoline complexes of iron
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The first phosphinooxazoline chelate complexes of iron were synthesized, and their structural and electronic properties were studied. The known phosphinooxazolines 2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole (7a), 2-(2-(diphenylphosphino)phenyl)-4,
- Sedinkin, Sergey L.,Rath, Nigam P.,Bauer, Eike B.
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p. 3081 - 3091
(2008/12/22)
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- Benzoylurea derivatives as a novel class of antimitotic agents: Synthesis, anticancer activity, and structure-activity relationships
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Forty-six new compounds were synthesized on the basis of our knowledge of the 3-haloacylamino benzoylurea (HBU) series. Structure-activity relationship (SAR) analysis indicates that (i) the configuration of the chiral center in 1 (JIMB01) is not indispensable for the activity, (ii) the phenyl ring is essential, and (iii) a substitution at the 6-position of the phenyl ring with a halogen enhances the activity. Among the analogues, 11e and 14b bearing 6-fluoro substitution showed potent activities against nine human tumor cell lines, including CEM (leukemia), Daudi (lymphoma), MCF-7 (breast cancer), Bel-7402 (hepatoma), DU-145 (prostate cancer), PC-3 (prostate cancer), DND-1A(melanoma), LOVO (colon cancer), and MIA Paca (pancreatic cancer) with IC50 values between 0.01 and 0.30 μM. 14b inhibited human hepatocarcinoma by 86% in volume in nude mice. The mechanism of 14b is to inhibit microtubule assembly, followed by the M-phase arrest, bcl-2 inactivation, and then apoptosis. We consider 14b promising for further anticancer investigation.
- Song, Dan-Qing,Wang, Yan,Wu, Lian-Zong,Yang, Peng,Wang, Yue-Ming,Gao, Li-Mei,Li, Yan,Qu, Jing-Rong,Wang, Yong-Hong,Li, Ying-Hong,Du, Na-Na,Han, Yan-Xing,Zhang, Zhi-Ping,Jiang, Jian-Dong
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experimental part
p. 3094 - 3103
(2009/04/06)
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- INSECTICIDAL COMPOUNDS
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A compound of formula (I), wherein A1, A2, A3, A4, R1 , R2, G1, G2, Q1 and Q2 are as defined in claim 1; or salts or N-oxides thereof. Furthermor
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Page/Page column 44
(2008/06/13)
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- Compounds and methods for development of Ret modulators
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Compounds active on Ret are described, as well as methods of using such compounds. Also described are crystal structures of Ret surrogates that were determined using X-ray crystallography. The use of such Ret surrogate crystals and strucural information can, for example, be used for identifying molecular scaffolds and for developing ligands that bind to and modulate Ret and for identifying improved ligands based on known ligands.
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Page/Page column 70
(2008/06/13)
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- Potent and orally bioavailable non-peptide antagonists at the human bradykinin B1 receptor based on a 2-alkylamino-5-sulfamoylbenzamide core
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The bradykinin B1 receptor is rapidly induced after inflammation or tissue trauma and appears to play an important role in the maintenance of hyperalgesia in inflammatory conditions. Here, we describe the optimization process to identify novel,
- Ritchie, Timothy J.,Dziadulewicz, Edward K.,Culshaw, Andrew J.,Müller, Werner,Burgess, Gillian M.,Bloomfield, Graham C.,Drake, Gillian S.,Dunstan, Andrew R.,Beattie, David,Hughes, Glyn A.,Ganju, Pam,McIntyre, Peter,Bevan, Stuart J.,Davis, Clare,Yaqoob, Mohammed
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p. 4642 - 4644
(2007/10/03)
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- 2,3-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid derivatives: A novel class of small molecule heparanase inhibitors
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A novel class of 2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acids are described as inhibitors of the endo-β-glucuronidase heparanase. Several of the compounds, for example, 2-[4-propylamino-5-[5-(4-chloro)phenyl-benzoxazol-2- yl]phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid (9c), display potent heparanase inhibitory activity (IC50 200-500nM) and have high selectivity (>100-fold) over human β-glucuronidase. They also show anti-angiogenic effects. Such compounds should serve as useful biological tools and may provide a basis for the design of novel therapeutic agents.
- Courtney, Stephen M.,Hay, Philip A.,Buck, Richard T.,Colville, Claire S.,Porter, David W.,Scopes, David I. C.,Pollard, Faye C.,Page, Martin J.,Bennett, James M.,Hircock, Margaret L.,McKenzie, Edward A.,Stubberfield, Colin R.,Turner, Paul R.
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p. 3269 - 3273
(2007/10/03)
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- PHTHALIMIDE CARBOXYLIC ACID DERIVATIVES
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The present invention relates to phthalimide carboxylic acid derivatives of formula (I), methods for their preparation, pharmaceutical compositions containing them and their use in medicine, specifically in the treatment of cancer. (I), wherein X is O or S; R1 is a phthalimide carboxylic acid group of formula (II). R is hydrogen, C1-C6 alkyl, aryl or C1-C3 alkylaryl and R2, R3 and R4 represent various substituents.
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Page/Page column 40; 52
(2008/06/13)
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- A novel antibacterial 8-chloroquinolone with a distorted orientation of the N1-(5-amino-2,4-difluorophenyl) group
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Fluoroquinolones represent a major class of antibacterial agents with great therapeutic potential. In this study, we designed m-aminophenyl groups as novel N-1 substituents of naphthyridones and quinolones. Among newly synthesized compounds, 7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6- fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4) has extremely potent antibacterial activities against Gram (+) as well as Gram (-) bacteria. This compound is significantly more potent than trovafloxacin against clinical isolates: 30 times against Streptococcus pneumoniae and 128 times against methicillin resistant Staphylococcus aureus. The structure-activity relationship (SAR) study revealed that a limited combination of 1-(5-amino-2,4-difluorophenyl) group, 7-(azetidin-1-yl) group, and 8-Cl atom (or Br atom or Me group) gave potent antibacterial activity. An X-ray crystallographic study of a 7-(3-ethylaminoazetidin-1-yl)-8-chloro derivative demonstrated that the N-1 aromatic group was remarkably distorted out of the core quinolone plane by steric repulsion between the C-8 Cl atom and the N-1 substituent. Furthermore, a molecular modeling study of 4 and its analogues demonstrated that a highly distorted orientation was induced by a steric hindrance of the C-8 substituent, such as Cl, Br, or a methyl group. Thus, their highly strained conformation should be a key factor for the potent antibacterial activity.
- Kuramoto, Yasuhiro,Ohshita, Yoshihiro,Yoshida, Jiro,Yazaki, Akira,Shiro, Motoo,Koike, Tohru
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p. 1905 - 1917
(2007/10/03)
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- Synthesis and antimicrobial activities of some new benzimidazole derivatives
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Some benzimidazolylbenzamides were synthesized and their antimicrobial activities against Staphylococcus aureus, Streptococcus faecalis, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Candida albicans evaluated. It was shown that the compound 14 exhibited the best activity against B. subtilis, P. aeruginosa and C. albicans.
- Ayhan-Kilcigil, Guelguen,Altanlar, Nurten
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p. 1345 - 1350
(2007/10/03)
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- Indazole compounds, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation
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Indazole compounds that modulate and/or inhibit cell proliferation, such as the activity of protein kinases are described. These compounds and pharmaceutical compositions containing them are capable of mediating, e.g., kinases-dependent diseases to modulate and/or inhibit unwanted cell proliferation. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds, and to methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis, by administering effective amounts of such compounds.
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- Benzoxazole LPAAT-B inhibitors and uses thereof
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The invention relates to benzoxazoles and the use thereof to inhibit lysophosphatidic acid acyltransferase β (LPAAT-β) activity. The invention further relates to methods of treating cancer using said benzoxazoles. The invention also relates to methods for screening for LPAAT-β activity.
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- Solid-phase S(n)Ar macrocyclizations to give turn-extended-turn peptidomimetics
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Solid-phase supported S(N)Ar macrocyclization reactions were investigated to test the viability of preparing libraries of β-turn mimics. An optimized set of conditions for this type of transformation was developed for various amino acid derived nucleophil
- Feng, Yangbo,Burgess, Kevin
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p. 3261 - 3272
(2007/10/03)
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- Hydroxylamine derivative of 5-nitro-8-hydroxy quinoline
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Novel hydroxylamino derivatives of the formula wherein Ar is selected from the group consisting of mono- and polycyclic aromatics and hetero-aromatics, both optionally substituted with at least one member of the group consisting of --OH, halogen, --NO2, --CN, STR1 --R7, --OR8, STR2 --SO2 R12, --SO3 R13, --COOR14, aryl of 6 to 14 carbon atoms, --OR16, --CH2 --CN and --CH2 SO2 --R15, R1, R2, R3, R4, R5 and R6 are individually selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms, R7 and R8 are optionally unsaturated alkyl of 1 to 8 carbon atoms optionally substituted with at least one member of the group consisting of halogen and cyano, R9, R10, R11, R12 and R13 are alkyl of 1 to 8 carbon atoms, Z is selected from the group consisting of hydrogen, optionally unsaturated alkyl of 1 to 8 carbon atoms and acyl of an organic carboxylic acid of 2 to 18 carbon atoms, R14 is selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms, R15 is selected from the group consisting of alkyl of 1 to 8 carbon atoms and aryl of 6 to 14 carbon atoms optionally substituted with an alkyl of 1 to 8 carbon atoms, R16 is aryl of 6 to 14 carbon atoms optionally substituted with a member of the group consisting of alkyl of 1 to 8 carbon atoms, halogen and --NO2, the substituents of Ar being able to form rings containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur and their non-toxic agriculturally acceptable acid addition salts with the proviso Ar is not phenyl nor phenyl with one methyl in the 2,3 or 4 position, a nitro in the 2- or 4-position, a chlorine in the 3- or 4-position, a bromine in the 4-position or a --CF3 in the 4-position nor 2,4-dinitrophenyl nor 2-nitro-4-trifluoromethylphenyl nor 2,6-dinitrophenyl nor 2,4,6-trinitrophenyl nor 2,4-dinitro-6-trifluoromethylphenyl useful for increasing vegetation growth and increasing crop yields and their preparation.
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