- tBuOK-Promoted Cyclization of Imines with Aryl Halides
-
A transition-metal-free indole synthesis using radical coupling of 2-halotoluenes and imines via the later-stage C-N bond construction was reported for the first time. It includes an aminyl radical generation by C-H cleaving addition of 2-halotoluenes to imines via the carbanion radical relay and an intramolecular coupling of aryl halides with aminyl radicals. One standard condition can be used for all halides including F, Cl, Br, and I. No extra oxidant or transition metal is required.
- Li, Ya-Wei,Zheng, Hong-Xing,Yang, Bo,Shan, Xiang-Huan,Qu, Jian-Ping,Kang, Yan-Biao
-
p. 4553 - 4556
(2020/06/08)
-
- Cross-coupling strategy for the synthesis of diazocines
-
Ethylene bridged azobenzenes are novel, promising molecular switches that are thermodynamically more stable in the (Z) than in the (E) configuration, contrary to the linear azobenzene. However, their previous synthetic routes were often not general, and yields were poorly reproducible, and sometimes very low. Here we present a new synthetic strategy that is both versatile and reliable. Starting from widely available 2-bromobenzyl bromides, the designated molecules can be obtained in three simple steps.
- Eleya, Nadi,Li, Shuo,Staubitz, Anne
-
supporting information
p. 1624 - 1627
(2020/03/13)
-
- S29434, a quinone reductase 2 inhibitor: Main biochemical and cellular characterization
-
Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH, such as N-methyl- and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here, we present a thorough description of the potent, nanomolar inhibitor [2-(2-methoxy-5H-1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434 or NMDPEF; IC505 5–16 nM) of QR2 at different organizational levels. We provide full detailed syntheses, describe its cocrystallization with and behavior at QR2 on a millisecond timeline, show that it penetrates cell membranes and inhibits QR2-mediated reactive oxygen species (ROS) production within the 100 nM range, and describe its actions in several in vivo models and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathologic conditions, including neurodegenerative diseases.
- Boutin, Jean A.,Bouillaud, Frederic,Janda, Elzbieta,Gacsalyi, István,Guillaumet, Gérald,Hirsch, Etienne C.,Kane, Daniel A.,Nepveu, Fran?oise,Reybier, Karine,Dupuis, Philippe,Bertrand, Marc,Chhour, Monivan,Le Diguarher, Thierry,Antoine, Mathias,Brebner, Karen,Da Costa, Hervé,Ducrot, Pierre,Giganti, Adeline,Goswami, Vishalgiri,Guedouari, Hala,Michel, Patrick P.,Patel, Aakash,Paysant, Jér?me,Stojko, Johann,Viaud-Massuard, Marie-Claude,Ferry, Gilles
-
p. 269 - 285
(2019/05/14)
-
- Preparation of 1,5-Dihydropyrazolo[3′,4′:5,6]pyrano[3,4- b]pyridines via a Microwave-Assisted, Palladium-Catalyzed Regioselective C-H Heteroarylation of Electron-Rich Pyrazoles
-
Here we report the first synthesis of a family of novel heterocyclic compounds based on a 5-dihydropyrazolo[3′,4′:5,6]pyrano[3,4-b]pyridine core. In the course of our drug discovery programs, we had need to access the previously unknown 5-dihydropyrazolo[3′,4′:5,6]pyrano[3,4-b]pyridine core. Initial attempts required long reaction times, which led to degradation and side products. Reaction optimization identified a Pd-catalyzed, microwave-assisted C-H heteroarylation protocol for the rapid, general, and high yielding synthesis of this tricyclic core (as well as related analogs) suitable to drive optimization efforts.
- Garrison, Aaron T.,Childress, Elizabeth S.,Davis, Dexter C.,Lindsley, Craig W.
-
p. 5855 - 5862
(2019/03/19)
-
- Strategy for Overcoming Full Reversibility of Intermolecular Radical Addition to Aldehydes: Tandem C-H and C-O Bonds Cleaving Cyclization of (Phenoxymethyl)arenes with Carbonyls to Benzofurans
-
An intermolecular addition of carbon radicals enabled by a cascade radical coupling strategy is developed. It includes an intermolecular alkyl radical addition to a carbonyl group followed by an intramolecular alkoxy radical addition to haloarenes and produces substituted benzofurans in high yields. The radical nature of this reaction is explored by radical trapping experiments and EPR analysis. The mechanism is investigated by KIE experiments and control experiments. This method could provide rapid and practical access to the key intermediate of TAM-16, a safe and potent antibacterial agent for treating tuberculosis, and, therefore, is of great importance for organic synthesis and the pharmaceutical industry.
- Zheng, Hong-Xing,Shan, Xiang-Huan,Qu, Jian-Ping,Kang, Yan-Biao
-
p. 3310 - 3313
(2018/06/11)
-
- AZAINDOLINE COMPOUNDS AS GRANZYME B INHIBITORS
-
Azaindoline compounds as granzyme B inhibitors, compositions that include the compounds, and methods for using the compounds. Methods for treating cutaneous scleroderma, epidermolysis bullosa, radiation dermatitis, alopecia areata, and discoid lupus erythematosus are provided.
- -
-
Page/Page column 55
(2016/03/12)
-
- Covalent granzyme B inhibitors
-
Covalent Granzyme B inhibitors, compositions that include the compounds, and methods for using the compounds. A method for treating cutaneous scleroderma, epidermolysis bullosa, radiation dermatitis, alopecia areata, and discoid lupus erythematosus are pr
- -
-
Page/Page column 44
(2016/10/27)
-
- Substituted quinazolinones as kinase inhibitors endowed with anti-fibrotic properties
-
Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.
- Marzaro, Giovanni,Castagliuolo, Ignazio,Schirato, Giulia,Palu', Giorgio,Dalla Via, Martina,Chilin, Adriana,Brun, Paola
-
supporting information
p. 416 - 425
(2016/04/09)
-
- CuI-catalyzed coupling of gem-dibromovinylanilides and sulfonamides: An efficient method for the synthesis of 2-amidoindoles and indolo[1,2-a] quinazolines
-
A Cu(I)-catalyzed, intermolecular protocol for the synthesis of 2-amidoindoles and tetrahydroindolo[1,2-a]quinazolines in shorter time and high yields is reported. The key highlight of this disclosure is the formation of 2-amidoindole and tetrahydroindolo[1,2-a]quinazoline moieties directly from gem-dibromovinylanilides and sulfonamides in a one-pot fashion through the in situ formation of ynamides followed by a base-promoted intramolecular hydroamidation.
- Kiruthika, Selvarangam E.,Perumal, Paramasivan Thirumalai
-
p. 484 - 487
(2014/04/03)
-
- SELECTIVE CYP11B1 INHIBITORS FOR THE TREATMENT OF CORTISOL DEPENDENT DISEASES
-
The present invention relates to compounds which selectively inhibit CYP11B1. Preferably, the compounds of the present invention do not substantially inhibit CYP11B2. Moreover, the compounds of the present invention do not substantially inhibit CYP17 and/or CYP19, either. Amongst other applications of the compounds of the present invention, they can be used for the treatment of Cushing's syndrome or metabolic disease.
- -
-
Page/Page column 50
(2012/05/05)
-
- Diastereo- and enantioselective intramolecular C(sp3)-H arylation for the synthesis of fused cyclopentanes
-
All C-H bonds are not equal: The intramolecular arylation of unactivated C(sp3)-H bonds in the presence of a chiral Pd/binepine catalyst allows the synthesis of fused cyclopentanes efficiently and in an diastereo- and enantioselective manner (see scheme).
- Martin, Nicolas,Pierre, Cathleen,Davi, Micha?l,Jazzar, Rodolphe,Baudoin, Olivier
-
supporting information; experimental part
p. 4480 - 4484
(2012/05/20)
-
- SPIROPIPERIDINE COMPOUNDS AS ORL-1 RECEPTOR ANTAGONISTS
-
An ORL-1 receptor antagonist of the formula: its uses, and methods for its preparation are described.
- -
-
-
- Optimization of the first selective steroid-11β-hydroxylase (CYP11B1) inhibitors for the treatment of cortisol dependent diseases
-
CYP11B1 is the key enzyme in cortisol biosynthesis, and its inhibition with selective compounds is a promising strategy for the treatment of diseases associated with elevated cortisol levels, such as Cushing's syndrome or metabolic disease. Expanding on a
- Hille, Ulrike E.,Zimmer, Christina,Haupenthal, Joerg,Hartmann, Rolf W.
-
supporting information; experimental part
p. 559 - 564
(2011/10/02)
-
- Discovery of orally active 3-pyridinyl-tropane as a potent nociceptin receptor agonist for the management of cough
-
A series of 3-pyridinyl-tropane analogues based on previously reported compound 1 have been synthesized and shown to bind to the nociceptin receptor with high affinity. From the SAR study and our lead optimization efforts, compound 10 was found to possess
- Yang, Shu-Wei,Ho, Ginny,Tulshian, Deen,Greenlee, William J.,Anthes, John,Fernandez, Xiomara,McLeod, Robbie L.,Hey, John A.,Xu, Xiaoying
-
experimental part
p. 5323 - 5329
(2010/02/28)
-
- 4-Anilino-7-pyridyl-3-quinolinecarbonitriles as Src kinase inhibitors
-
A series of 4-anilino-7-pyridyl-3-quinolinecarbonitriles was prepared as Src kinase inhibitors. A systematic SAR study of substitutions on both the pyridine ring and the 3-quinolinecarbonitrile core established the requirements for optimal activity. The l
- Zhang, Nan,Wu, Biqi,Boschelli, Diane H.,Golas, Jennifer M.,Boschelli, Frank
-
scheme or table
p. 5071 - 5074
(2010/03/24)
-
- ACRYLAMIDE DERIVATIVES AS FAB I INHIBITORS
-
In part, the present invention is directed towards compounds with FAB I inhibiting properties. Such compounds may also inhibit other enzymes, including those similar to FAB I either structurally or functionally, for example FAB K. Said compounds and compo
- -
-
Page/Page column 125
(2008/06/13)
-
- Novel fluorinated derivatives of the broad-spectrum MMP inhibitors N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)- and (3-picolyl)-amino]-3- methyl-butanamide as potential tools for the molecular imaging of activated MMPs with PET
-
An approach to the in vivo imaging of locally upregulated and activated matrix metalloproteinases (MMPs) found in many pathological processes is offered by positron emission tomography (PET). Hence, appropriate PET radioligands for MMP imaging are required. Here, we describe the syntheses of novel fluorinated MMP inhibitors (MMPIs) based on lead structures of the broad-spectrum inhibitors N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)-amino]-3-methyl-butanamide (CGS 25966) and N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](3-picolyl)-amino]-3- methyl-butanamide (CGS 27023A). Additionally, tailor-made precursor compounds for radiolabeling with the positron-emitter 18F were synthesized. All prepared hydroxamate target compounds showed high in vitro MMP inhibition potencies for MMP-2, MMP-8, MMP-9, and MMP-13. As a consequence, the promising fluorinated hydroxamic acid derivative 1f was resynthesized in its 18F-labeled version via two different procedures yielding the potential PET radioligand [18F]If. As expected, the biodistribution behavior of this novel compound and that of the more hydrophilic variant [ 18F]1j, also developed by our group, indicates that there was no tissue specific accumulation in wild-type (WT) mice.
- Wagner, Stefan,Breyholz, Hans-J?rg,Law, Marilyn P.,Faust, Andreas,H?ltke, Carsten,Schr?er, Sandra,Haufe, Günter,Levkau, Bodo,Schober, Otmar,Sch?fers, Michael,Kopka, Klaus
-
p. 5752 - 5764
(2008/03/27)
-
- 3 -MONOSUBSTITUTED TROPANE DERIVATIVES AS NOCICEPTIN RECEPTOR LIGANDS
-
Compounds of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl, all optionally substituted; R
- -
-
Page/Page column 20
(2008/06/13)
-
- Intramolecular cyclisation of functionalised heteroaryllithiums. Synthesis of novel indolizinone-based compounds
-
The intramolecular cyclisation of heteroaryllithiums derived from N-heteroarylmethylpyrrole-2-carboxamides takes place smoothly at low temperature when N-methoxy-N-methyl and morpholine amides are used as internal electrophiles. Halogen-lithium exchange using n-BuLi is the method of choice to achieve metalation on the quinoline and pyridine derivatives, while directed lithiation (LDA) works better for furan. In the case of thiophene both methodologies can be applied. These metalation-cyclisation sequences provide a useful entry to several types of indolizidine based compounds (pyrrolo[1,2-b]acridinones, pyrrolo[1,2-g]quinolones, thieno and furo[3,2-f]indolizinones).
- Ruiz, Javier,Lete, Esther,Sotomayor, Nuria
-
p. 6182 - 6189
(2007/10/03)
-
- Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: Structure-activity relationship studies and identification of a potent and highly selective inhibitor JTK-109
-
Following the discovery of a new series of benzimidazole derivatives bearing a diarylmethyl group as inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase (HCV NS5B RdRp), we extended the structure-activity relationship (SAR) study to analogue
- Hirashima, Shintaro,Suzuki, Takayoshi,Ishida, Tomio,Noji, Satoru,Yata, Shinji,Ando, Izuru,Komatsu, Masakazu,Ikeda, Satoru,Hashimoto, Hiromasa
-
p. 4721 - 4736
(2007/10/03)
-
- Free radical-mediated aryl amination: A practical synthesis of (R)- and (S)-7-azaindoline α-amino acid
-
Two nonnatural proline derivatives, (S)- and (R)-7-azaindoline α-amino acid have been prepared and isolated as their trifluoro-acetate salt on gram scale. The convergent sequence (6 steps from 2-bromopyridine) employs a combination of enantioselective phase transfer catalyzed glycine alkylation and free radical-mediated aryl animation. Implementation of the solid-liquid phase transfer conditions requires manual pulverization of cesium hydroxide, efficient mechanical stirring, and effective low temperature control. This large scale free radical cyclization protocol replaces benzene solvent with toluene without complication, and the crystalline nature of the intermediates and final product enables straightforward purification at each stage, including enantiomeric enrichment (89% to >99% ee for 4b, Scheme 1).
- Srinivasan, Jayasree M.,Burks, Heather E.,Smith, Colin R.,Viswanathan, Rajesh,Johnston, Jeffrey N.
-
p. 330 - 333
(2007/10/03)
-
- Heteroaryl radicals. Part 1. Synthesis of linear pyridine-fused ring systems by endo-selective 2-pyridyl radical cyclizations
-
Bu3SnH-induced 2-pyridyl radicals, derived from the 2-bromopyridinyl-substituted methylenecyclohexane 4 and also the vinyl- and the allyl-cyclohexanols 5 and 6, undergo endo-selective cyclizations to give six-, seven- and eight-membered-ring an
- Maiti, Sarbendu,Achari, Basudeb,Mukhopadhyay, Ranjan,Banerjee, Asish Kr.
-
p. 1769 - 1773
(2007/10/03)
-
- Synthesis of biaryls by intramolecular radical transfer in phosphinates
-
Phosphinates 20a-35a give biaryls 20b-35b on heating with stannanes in the presence of AIBN. The process involves a radical ipso substitution on the migrating aryl ring.
- Clive,Kang
-
p. 6083 - 6091
(2007/10/03)
-
- Binding Forces and Catalysis. The Use of Bipyridyl-Metal Chelation to Enhance Reaction Rates
-
The application of a binding force (the chelation of a metal by a 2,2'-bipyridyl) to enhance reaction rates is examined with three systems.Metals are shown to increase the rate of cyclization of certain 3,3'-disubstituted, 2,2'-bipyridyl derivatives.Simil
- Rebek, Julius Jr.,Costello, Timothy,Wattley, Ruth
-
p. 7487 - 7493
(2007/10/02)
-
- BINDING FORCES AND CATALYSIS: RATE ENHANCEMENTS THROUGH CHELATION AT A REMOTE SITE
-
The rate of an elimination reaction is increased by more than three decades through distortions induced by binding at a remote site.
- Rebek, Julius,Costello, Timothy
-
p. 2191 - 2194
(2007/10/02)
-
