- Biomimetic alloxan-catalyzed intramolecular redox reaction with O2: One-pot atom-economic synthesis of sulfinyl-functionalized benzimidazoles
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Given the necessity of sacrificial reductants in various biomimetic aerobic oxygenations, alloxan-catalyzed aerobic redox system for one-pot atom-economic synthesis of sulfinyl-functionalized benzimidazoles was developed by ingeniously binding both the substrate sulfide and sacrificial reductant. This mild and transition-metal-free protocol undergoes two oxidations without additional sacrificial reagents, except for the environmentally benign molecular oxygen.
- Zhang, Shiqi,Yi, Dong,Li, Guangxun,Li, Ling,Zhao, Gang,Tang, Zhuo
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supporting information
(2020/12/25)
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- Design, synthesis and biological evaluation of novel 4-phenoxypyridine based 3-oxo-3,4-dihydroquinoxaline-2-carboxamide derivatives as potential c-Met kinase inhibitors
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Blocking c-Met kinase activity by small-molecule inhibitors has been identified as a promising approach for the treatment of cancers. Herein, we described the design, synthesis, and biological evaluation of a series of 4-phenoxypyridine-based 3-oxo-3,4-dihydroquinoxaline derivatives as c-Met kinase inhibitors. Inhibitory activitives against c-Met kinase evaluation indicated that most of compounds showed excellent c-Met kinase activity in vitro, and IC50 values of ten compounds (23a, 23e, 23f, 23l, 23r, 23s, 23v, 23w, 23x and 23y) were less than 10.00 nM. Notably, three of them (23v, 23w and 23y) showed remarkable potency with IC50 values of 2.31 nM, 1.91 nM and 2.44 nM, respectively, and thus they were more potent than positive control drug foretinib (c-Met, IC50 = 2.53 nM). Cytotoxic evaluation indicated the most promising compound 23w showed remarkable cytotoxicity against A549, H460 and HT-29 cell lines with IC50 values of 1.57 μM, 0.94 μM and 0.65 μM, respectively. Furthermore, the acridine orange/ethidium bromide (AO/EB) staining, cell apoptosis assays by flow cytometry, wound-healing assays and transwell migration assays on HT-29 and/or A549 cells of 23w were performed. Especially compound 23w, which displayed potent antitumor, apoptosis induction and antimetastatic activity, could be used as a promising lead for further development. Meanwhile, their preliminary structure-activity relationships (SARs) were also discussed.
- Wang, Zhen,Shi, Jiantao,Zhu, Xianglong,Zhao, Wenwen,Gong, Yilin,Hao, Xuechen,Hou, Yunlei,Liu, Yajing,Ding, Shi,Liu, Ju,Chen, Ye
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- Design, synthesis, and biological evaluation of 4-phenoxyquinoline derivatives as potent c-Met kinase inhibitor
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A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC50 value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC50 values of 0.39 μM, 0.18 μM, 0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.
- Yang, Yifeng,Li, Yingxiu,Hou, Yunlei,Qin, Mingze,Gong, Ping,Liu, Ju,Zhao, Yanfang
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supporting information
(2019/10/28)
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- CHOLECYSTOKININ 2 RECEPTOR TARGETED NIR IMAGING AND USE THEREOF
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Compounds are described herein where CCK2R targeting ligands are attached to an imaging agent through a linker. The compounds can be used in the detection, diagnosis, imaging and treatment of cancer.
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- Diversity of the quaternary ammonium salt of the imidazole aryl and and its preparation method and application
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The present invention discloses a diverse arylimidazole quaternary ammonium salt, a preparation method and an application thereof. The diverse arylimidazole quaternary ammonium salt is a compound represented by a formula (L-n'). The diverse arylimidazole quaternary ammonium salt has the following beneficial effects that: the diverse arylimidazole quaternary ammonium salt can be prepared through the one-pot method and is not prepared in a glove box, the raw material (aliphatic or aromatic imine) is subjected to the reaction, the yield is 78-94%, and the target product with high optical purity dr of more than 98:2 is obtained. According to the present invention, operations can be simplified, the yield can be increased, importantly an application range of the compound is expanded, and wide versatility is provided.
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Paragraph 0146; 0147; 0148; 0149; 0150
(2016/11/24)
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- Rapid construction of imidazopyridines from ortho-haloaminopyridines
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A practical strategy for the preparation of imidazopyridine derivatives from ortho-haloaminopyridines utilizing a two-step C-N coupling/cyclization reaction sequence has been developed. This procedure provides rapid and efficient access to many medicinally interesting imidazopyridine compounds and related imidazopyrazine/purine heterocycles.
- Li, Chaomin,Chen, Lily,Steinhuebel, Dietrich,Goodman, Andrew
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supporting information
p. 2708 - 2712
(2016/06/09)
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- MODULATING FERROPTOSIS AND TREATING EXCITOTOXIC DISORDERS
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The present invention provides, inter alia, a compound having the structure of Formula (I). Also provided are compositions containing a pharmaceutically acceptable carrier and a compound according to the present invention. Further provided are methods for treating or ameliorating the effects of an excitotoxic disorder in a subject, methods of modulating ferroptosis in a subject, methods of reducing reactive oxygen species (ROS) in a cell, and methods for treating or ameliorating the effects of a neurodegenerative disease.
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Paragraph 0274; 0301
(2015/06/18)
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- Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models
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Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington's disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes.
- Skouta, Rachid,Dixon, Scott J.,Wang, Jianlin,Dunn, Denise E.,Orman, Marina,Shimada, Kenichi,Rosenberg, Paul A.,Lo, Donald C.,Weinberg, Joel M.,Linkermann, Andreas,Stockwell, Brent R.
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supporting information
p. 4551 - 4556
(2014/04/17)
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- Synthetic modification of acyclic bent allenes (carbodicarbenes) and further studies on their structural implications and reactivities
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The paper describes the synthetic development of Bertrand-type acyclic carbodicarbene scaffolds derived from an unsymmetrical bis(benzimidazol-2-yl) methane bearing two sterically demanding pendant arms, isopropyl (6a) or cyclohexyl (6b). X-ray crystallographic analysis shows that the impact of these pendant arms on the overall structural parameters of carbodicarbenes is minimal. The chemical reactivity of the carbodicarbenes was evaluated with iodomethane to afford compound 7, illustrating its nucleophilic properties. Finally, experiments were also undertaken to investigate the coordination ability of carbodicarbene toward the formation of rhodium carbonyl (10) and palladium allyl complexes (11). The crystal structures of the metal complexes have been determined, revealing that their metal-carbene distances are elongated only slightly, this fact was rationalized on the basis of geometrical steric considerations with regard to the ligand.
- Chen, Wen-Ching,Hsu, Yu-Chen,Lee, Ching-Yu,Yap, Glenn P. A.,Ong, Tiow-Gan
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supporting information
p. 2435 - 2442
(2013/06/27)
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- "All-water" one-pot diverse synthesis of 1,2-disubstituted benzimidazoles: Hydrogen bond driven 'synergistic electrophile-nucleophile dual activation' by water
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A new "all-water" tandem arylaminoarylation/arylaminoalkylation- reduction-cyclisation route is reported for one-pot diversity oriented synthesis of regiodefined 1,2-disubstituted benzimidazoles. Water plays a crucial and indispensable role through hydrogen bond driven 'synergistic electrophile-nucleophile dual activation' in the formation of N-mono-aryl/aryl alkyl/alkyl/cycloalkyl o-nitroanilines under metal and base-free conditions to replace the transition metal-based C-N bond formation (aryl amination) chemistry and underlines the origin of regiodefined installation of the diverse selection of aryl, aryl alkyl, and alkyl/cycloalkyl groups as substituents on the benzimidazole scaffold to form the 1,2-disubstituted benzimidazoles. The influence of the hydrogen bond effect of water in promoting the arylaminoarylation reaction under base and metal-free conditions has been realized through observation of inferior yields in D2O compared to that obtained in water during the reaction of o-fluoronitrobenzene with aniline separately performed in water and D2O under similar experimental conditions. Water also provides assistance in promoting the subsequent nitro reduction and in the final cyclocondensation steps. The role of water in promoting the cyclocondensation reaction through hydrogen bonds is realized by the differential product yields during the reaction of mono-N-phenyl-o- phenylenediamine with benzaldehyde performed separately in water and D 2O. The better hydrogen bond donor and hydrogen bond acceptor abilities of water compared to those of the organic solvents are the contributing/deciding factors for making the new water-assisted tandem arylaminoarylation/arylaminoalkylation-reduction-cyclisation strategy for the diversified synthesis of the regiodefined 1,2-disubstituted benzimidazoles effective in an aqueous medium, making it represent a true "all-water chemistry."
- Kommi, Damodara N.,Jadhavar, Pradeep S.,Kumar, Dinesh,Chakraborti, Asit K.
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p. 798 - 810
(2013/04/24)
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- COMPOUNDS, COMPOSITIONS, AND METHODS FOR MODULATING FERROPTOSIS AND TREATING EXCITOTOXIC DISORDERS
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The present invention provides, inter alia, a compound having the structure: (Formula (I). Also provided are compositions containing a pharmaceutically acceptable carrier and a compound according to the present invention. Further provided are methods for treating or ameliorating the effects of an excitotoxic disorder in a subject, methods of modulating ferroptosis in a subject, methods of reducing reactive oxygen species (ROS) in a cell, and methods for treating or ameliorating the effects of a neurodegenerative disease.
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Paragraph 0174; 0181; 0218
(2013/10/22)
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- Synthesis of a 1,3,5-benzotriazepine-2,4-dione based library
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A library of benzotriazepines have been synthesised employing microwave-mediated synthesis, supported resins and parallel synthesis methodology.
- Chuckowree, Irina,Ali Syed, Murtaza,Getti, Giulia,Parbhu Patel, Asha,Garner, Hannah,Tizzard, Graham J.,Coles, Simon J.,Spencer, John
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scheme or table
p. 3607 - 3611
(2012/09/11)
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- Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity
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A series of N-hydroxy-3-[3-(1-substituted-1H-benzoimidazol-2-yl)-phenyl]-acrylamides (5a-5ab) and N-hydroxy-3-[3-(1,4,5-trisubstituted-1H-imidazol-2-yl)-phenyl]-acrylamides (12a-s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an N1-piperidine demonstrate EC50s of 20-100 nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21waf. Compound 5x displays efficacy in human tumor xenograft models.
- Bressi, Jerome C.,Jong, Ron de,Wu, Yiqin,Jennings, Andy J.,Brown, Jason W.,O'Connell, Shawn,Tari, Leslie W.,Skene, Robert J.,Vu, Phong,Navre, Marc,Cao, Xiaodong,Gangloff, Anthony R.
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scheme or table
p. 3138 - 3141
(2010/09/03)
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- A thiourea-oxazoline library with axial chirality: Ligand synthesis and studies of the palladium-catalyzed enantioselective bis(methoxycarbonylation) of terminal olefins
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We report herein the synthesis of novel chiral S,N-heterobidentate thiourea-oxazoline ligands and their application to palladium-catalyzed enantioselective bis(methoxycarbonylation)s of terminal olefins under mild conditions. Copper salts were found to play multiple roles in this reaction. Substituted 2- phenylsuccinates were obtained in >90% yield and up to 84% ee under optimized conditions.
- Gao, Ying-Xiang,Chang, Le,Shi, Hang,Liang, Bo,Wongkhan, Kittiya,Chaiyaveij, Duangduan,Batsanov, Andrei S.,Marder, Todd B.,Li, Chuang-Chuang,Yang, Zhen,Huanga, Yong
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supporting information; experimental part
p. 1955 - 1966
(2010/11/03)
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- 4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: Potent and selective p70S6 kinase inhibitors
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We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (Ki 100-fold selectivity against PKA, ROCK and GSK3.
- Bandarage, Upul,Hare, Brian,Parsons, Jonathan,Pham, Ly,Marhefka, Craig,Bemis, Guy,Tang, Qing,Moody, Cameron Stuver,Rodems, Steve,Shah, Sundeep,Adams, Chris,Bravo, Jose,Charonnet, Emmanuelle,Savic, Vladimir,Come, Jon H.,Green, Jeremy
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scheme or table
p. 5191 - 5194
(2010/03/24)
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- VASOPRESSIN V1A ANTAGONISTS
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The present invention concerns compounds inter alia according to general formula 1a. Compounds according to the invention are vasopressin V 1a receptor antagonists. Pharmaceutical compositions of the compounds are useful as treatment of dysmenorrhoea.
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Page/Page column 53-54
(2008/06/13)
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- BICYCLIC IMIDAZOL DERIVATIVES AGAINST FLAVIVIRIDAE
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Disclosed are compounds, compositions and methods for treatingFlaviviridae family virus infections.
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Page/Page column 226
(2008/06/13)
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- Novel 1,5-benzodiazepindione gastrin/CCK(B) antagonists
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The development of a potent, selective and orally bioavailable 1,5-benzodiazepindione gastrin/CCK(B) receptor antagonist (compound 7, GR199114X) is described.
- Bailey,Box,Carr,Cooke,Evans,Finch,Head,Pass,Shah,Wheatcroft
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p. 281 - 286
(2007/10/03)
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- BORANE-TETRAHYDROFURAN AS A USEFUL REAGENT IN THE N-MONOALKYLATION OF AMINES AND AMINOALCOHOLS BY CARBONYL COMPOUNDS.
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A new procedure for the high-yield N-monoalkylation of primary aromatic and aliphatic amines is described.
- Morales, Hilda R.,Perez-Juarez, Martin,Cuellar, Laura,Mendoza, Lourdes,Fernandez, Hector,Contreras, Rosalinda
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p. 1213 - 1220
(2007/10/02)
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