2721-59-7Relevant articles and documents
Efficient visible light mediated synthesis of quinolin-2(1H)-ones from quinolineN-oxides
Bhuyan, Samuzal,Chhetri, Karan,Hossain, Jagir,Jana, Saibal,Mandal, Susanta,Roy, Biswajit Gopal
, p. 5049 - 5055 (2021/07/29)
Quinolin-2(1H)-ones are one of the important classes of compounds due to their prevalence in natural products and in pharmacologically useful compounds. Here we present an unconventional and hitherto unknown photocatalytic approach to their synthesis from easily available quinoline-N-oxides. This reagent free highly atom economical photocatalytic method, with low catalyst loading, high yield and no undesirable by-product, provides an efficient greener alternative to all conventional synthesis reported to date. The robustness of the methodology has been successfully demonstrated with easy scaling up to the gram scale.
Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1
Erdmann, Frank,Günther, Stefan,Ghazy, Ehab,Hügle, Martin,Herp, Daniel,Jung, Manfred,Morales, Elizabeth R.,Robaa, Dina,Romier, Christophe,Schmidt, Matthias,Schmidtkunz, Karin,Sippl, Wolfgang,Zeyen, Patrik
supporting information, (2020/06/03)
Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.
O-GLCNAC TRANSFERASE INHIBITORS AND USES THEREOF
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Paragraph 00305-00307, (2020/03/23)
Provided herein are O-GlcNAc transferase (OGT) inhibitor compounds of Formula (I'), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing diseases (e.g., diabetes and complications thereof, neurodegenerative diseases, proliferative diseases such as cancers, autoimmune diseases, and inflammatory diseases) in a subject. Provided are methods of inhibiting OGT in a subject or biological sample.
Visible-Light-Driven alkyne hydro-/carbocarboxylation using CO2 via iridium/cobalt dual catalysis for divergent heterocycle synthesis
Hou, Jing,Ee, Aloysius,Feng, Wei,Xu, Jin-Hui,Zhao, Yu,Wu, Jie
supporting information, p. 5257 - 5263 (2018/04/24)
We present herein the first visible-light-driven hydrocarboxylation as well as carbocarboxylation of alkynes using CO2 via an iridium/cobalt dual catalysis. Such transformations provide access to various pharmaceutically important heterocycles in a one-pot procedure from readily available alkynes. Coumarins, 2-quinolones, and 2-benzoxepinones were directly accessed through a one-pot alkyne hydrocarboxylation/alkene isomerization/cyclization sequence in which the Ir photocatalyst serves a dual role to promote single-electron transfer in alkyne hydrocarboxylation and energy transfer in the subsequent alkene isomerization. Moreover, an unprecedented cobalt carboxylation/acyl migration cascade enables alkyne difunctionalization to introduce γ-hydroxybutenolides with high efficiency. We expect that this cascade strategy will inspire new perspectives for alkyne and alkene difunctionalization.
2 - (1 H) - quinoline compound of microwave-assisted synthesis method (by machine translation)
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Paragraph 0063; 0064, (2018/09/28)
The invention belongs to the field of organic intermediate synthesis, in particular discloses a 2 - (1 H) - quinoline compound of microwave-assisted synthetic method: quinoline raw material, and water in a reaction promoter and microwave under the assistance of the addition reaction, to obtain the 2 - (1 H) - quinoline compound; the quinoline raw material is quinoline, or on the quinoline ring in addition to the 2 other than the position of the substituent on the quinoline derivatives containing; the reaction accelerator is 2 - chloroethyl ester and/or 2 - [...] ester. The method raw materials are easy, simple reaction conditions, the reaction time is short, green energy-saving, reaction selectivity and high yield, excellent substrate functional group compatibility, and has high application value. (by machine translation)
Selectfluor-mediated regioselective nucleophilic functionalization of N-heterocycles under metal- and base-free conditions
Xie, Long-Yong,Qu, Jie,Peng, Sha,Liu, Kai-Jian,Wang, Zheng,Ding, Man-Hua,Wang, Yi,Cao, Zhong,He, Wei-Min
supporting information, p. 760 - 764 (2018/02/14)
A practical and environmentally attractive methodology for the direct diversification of N-heterocycles at ambient temperature under open-air conditions was developed. The obvious advantage of the process is that no toxic reagent, transition metal, base or other additive is employed, thus greatly reducing costs, facilitating post-reaction neutralization and purification and minimizing the environmental impact.
Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides
Waszkowycz, Bohdan,Smith, Kate M.,McGonagle, Alison E.,Jordan, Allan M.,Acton, Ben,Fairweather, Emma E.,Griffiths, Louise A.,Hamilton, Niall M.,Hamilton, Nicola S.,Hitchin, James R.,Hutton, Colin P.,James, Dominic I.,Jones, Clifford D.,Jones, Stuart,Mould, Daniel P.,Small, Helen F.,Stowell, Alexandra I. J.,Tucker, Julie A.,Waddell, Ian D.,Ogilvie, Donald J.
, p. 10767 - 10792 (2019/01/04)
DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however, the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design. 1-Oxetan-3-ylmethyl derivatives 33d and 35d were selected for preliminary investigations in vivo. X-ray crystal structures help rationalize the observed structure-activity relationships of these novel inhibitors.
A nitrogen oxide C2 - bit hydroxylated method (by machine translation)
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Paragraph 0031; 0032; 0033; 0034; 0035; 0036-0038; 0039-0044, (2017/05/19)
The present invention relates to nitrogen oxide C2 - bit hydroxylated method, in particular under reflux conditions in dichloroethane, three pyrrole alkyl bromide (PyBrop) [...] phosphate, sodium acetate, water and nitrogen oxides produced by the reaction of hydroxyl-substituted product. The process has simple operation, mild condition, high reaction selectivity, substrate wide applicability, high yield and the like. The application for the first time using this method to synthesize a series of 2 - hydroxyquinoline, 2 - hydroxy pyridine and 1 - hydroxy isoquinoline compound, in the establishment of the compounds of the library synthesis application have broad prospects. (by machine translation)
Metal-free radical C-H methylation of pyrimidinones and pyridinones with dicumyl peroxide
Zhang, Pei-Zhi,Li, Jian-An,Zhang, Ling,Shoberu, Adedamola,Zou, Jian-Ping,Zhang, Wei
supporting information, p. 919 - 923 (2017/08/18)
A new method for free radical methylation of pyrimidinones and pyridinones with dicumyl peroxide (DCP) under metal-free conditions is introduced. A 50 g-scale reaction could be performed safely at the desired concentration. The reaction solvent and DCP derivative were readily recovered by distillation. The product was purified by crystallization to minimize the amount of waste.
Design of a biased potent small molecule inhibitor of the bromodomain and PHD finger-containing (brpf) proteins suitable for cellular and in vivo studies
Igoe, Niall,Bayle, Elliott D.,Fedorov, Oleg,Tallant, Cynthia,Savitsky, Pavel,Rogers, Catherine,Owen, Dafydd R.,Deb, Gauri,Somervaille, Tim C. P.,Andrews, David M.,Jones, Neil,Cheasty, Anne,Ryder, Hamish,Brennan, Paul E.,Müller, Susanne,Knapp, Stefan,Fish, Paul V.
, p. 668 - 680 (2017/02/05)
The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (Fpo 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.
