- Concise syntheses of the 1,7-dihydropyrano[2,3-g]indole ring system of the stephacidins, aspergamides and norgeamides
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Three approaches towards the synthesis of the 1,7-dihydropyrano[2,3-g] indole ring system of the stephacidins, paraherquamides and norgeamides have been investigated. The first involves a tandem nitrene insertion/aromatic Claisen rearrangement. The second
- Grubbs, Alan W.,Artman III, Gerald D.,Williams, Robert M.
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- Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species
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An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.
- Stachel, Shawn J.,Egbertson, Melissa S.,Wai, Jenny,Machacek, Michelle,Toolan, Dawn M.,Swestock, John,Eddins, Donnie M.,Puri, Vanita,McGaughey, Georgia,Su, Hua-Poo,Perlow, Debbie,Wang, Deping,Ma, Lei,Parthasarathy, Gopal,Reid, John C.,Abeywickrema, Pravien D.,Smith, Sean M.,Uslaner, Jason M.
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- FRET events in fluorescent pentapeptides containing aliphatic triazolo amino acid scaffolds: Role of spacer lengths
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The FRET efficiencies in donor/acceptor pairs in the two termini of designed fluorescent pentapeptides depend on the flexibility of two arms of triazolyl amino acid scaffolds positioned in the center of the backbones inducing predominant β-sheet conformations. Flexible N-Terminus of the scaffold in a pentapeptide has led to higher FRET efficiency and makes it different from other peptide with flexible C-terminus.
- Bag, Subhendu Sekhar,Yashmeen, Afsana
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- Facile preparation of mono-, Di- and mixed-carboxylato platinum(IV) complexes for versatile anticancer prodrug design
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Facile strategies were developed for the versatile functionalization of platinum(IV) axial sites, allowing for easy accessibility to unsymmetric mono- and mixed-carboxylato, as well as symmetric di-substituted platinum(IV) complexes. The first method involves the direct oxidation and carboxylation of the platinum(II) center using an appropriate peroxide and the carboxylate of choice to firstly yield a monocarboxylato monohydroxido platinum(IV) complex. This platinum(IV) intermediate can undergo further carboxylation to give rise to a mixed-carboxylato platinum(IV) complex. The second method involves the activation of the carboxylate of choice by a common carbodiimide coupling reagent, and its reaction with a dihydroxido platinum(IV) precursor to give the monocarboxylato platinum(IV) complex. Uronium salts can be employed to promote efficient dicarboxylation of the dihydroxido platinum(IV) precursor. Lastly, an axial azide pendant group was demonstrated to be suitable for orthogonal "click" conjugation reactions. Copyright
- Zhang, Jenny Z.,Bonnitcha, Paul,Wexselblatt, Ezequiel,Klein, Alice V.,Najajreh, Yousef,Gibson, Dan,Hambley, Trevor W.
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- A telescoped protocol for the synthesis of new pyrrolo [3,4-d]pyridazinones by cascade reactions
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A new one-pot method, for the synthesis of polysubstituted pyrrolo[3,4-d]pyridazinones, is presented. The protocol consists in cascade reactions performed in the same media: (i) the thermal in situ pyrrole formation by the reaction of vinyl azides with 1,
- Bonacorso, Helio G.,Libero, Francieli M.,Dal Forno, Gean M.,Pittaluga, Everton P.,Porte, Liliane M.F.,Martins, Marcos A.P.,Zanatta, Nilo
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- New regioselective synthesis of polyfunctionalized 3-ferrocenyl-1H-pyrroles under microwave irradiation
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A facile and regioselective synthesis of a series of new methyl 3-ferrocenyl-1H-pyrrole-2-carboxylates obtained from methyl ferrocenyl azido acrylate and symmetrical or non-symmetrical 1,3-dicarbonyl compounds under microwave-assisted conditions is report
- Bonacorso, Helio G.,Libero, Francieli M.,Dal Forno, Gean M.,Pittaluga, Everton P.,Back, Davi F.,H?rner, Manfredo,Martins, Marcos A.P.,Zanatta, Nilo
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- Coumarin-based tripodal chemosensor for selective detection of Cu(II) ion and resultant complex as anion probe through a Cu(II) displacement approach
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In this paper, a novel tripodal fluorescent receptor based on naturally occurring coumarin was synthesized and its ionic recognition properties were fully investigated by spectroscopic techniques. As revealed by the results, tripodal 1 exhibits excellent selectivity toward copper(II) by forming a 1:1 complex with triazole N as the main binding sites. And the resulted 1·Cu2+ complex shows recognition ability toward H2PO4? by metal displacement approach. The recognition mechanism was further investigated by computer calculation.
- Sun, Jinzhi,Xu, Xiang,Yu, Guanghui,Li, Weina,Shi, Jinsheng
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- Development of a Safe Continuous Manufacturing Route to 2-(4-Isopropyl-1H-1,2,3-triazol-1-yl)acetic Acid
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Starting from sodium azide, methyl-bromoacetate, and 3-methylbut-1-yne, a safe and efficient three-step continuous process was developed to obtain 2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid. Isolation of hazardous intermediates was avoided, and by u
- Karlsson, Staffan,Cook, Calum,Emten?s, Hans,Fan, Kenny,Gillespie, Paul,Mohamed, Mubina
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- Synthesis of Novel Pyrrolo[3,2- c ]carbazole and Dipyrrolo[3,2- c:2′,3′- g ]carbazole Derivatives
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Pyrrolocarbazole and dipyrrolocarbazoles have been synthesized via the Hemetsberger indole synthesis, starting from 9-ethyl carbazole-3-carbaldehyde and 9-ethylcarbazole-3,6-dicarbaldeyde, respectively. The pyrrolocarbazole structures were confirmed through 1H NMR, 13C NMR, IR, mass spectrometry and single crystal X-ray diffraction techniques. The targeted compounds showed potent in vitro cytotoxicity against human colon cancer HT29 cells.
- Sengul, Ibrahim Fazil,Astarci, Erhan,Kandemir, Hakan
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- Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry
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An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chemistry to generate linker-connected molecules was applied. Inhibitor 17 exhibited Ki values of 41.3 nM, 27.3 nM, or 19.2 nM, depending on the substrate and pH of the assay. Kinetic data were discussed with respect to the conformational selection and induced fit models.
- Schmitz, Janina,Li, Tianwei,Bartz, Ulrike,Gütschow, Michael
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- Bacterial versus human sphingosine-1-phosphate lyase (S1PL) in the design of potential S1PL inhibitors
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A series of potential active-site sphingosine-1-phosphate lyase (S1PL) inhibitors have been designed from scaffolds 1 and 2, arising from virtual screening using the X-ray structures of the bacterial (StS1PL) and the human (hS1PL) enzymes. Both enzymes ar
- Sanllehí, Pol,Abad, José-Luis,Casas, Josefina,Bujons, Jordi,Delgado, Antonio
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- Synthesis of MUC1 Peptide and Glycopeptide Dendrimers
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Several dendrimers possessing multiple copies of peptides and glycopeptides belonging to the MUC1 eicosapeptide tandem repeat sequence have been prepared. Fmoc-strategy solid-phase peptide synthesis was used to construct the peptides and glycopeptides, which were conjugated to suitably functionalized dendrimer cores using the copper-catalyzed azide-alkyne cycloaddition reaction to produce multivalent peptide and glycopeptide dendrimers.
- Chun, Candy K. Y.,Payne, Richard J.
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- Design and synthesis of new 5-aryl-4-arylethynyl-1H-1,2,3-triazoles with valuable photophysical and biological properties
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Cu-catalyzed 1,3-dipolar cycloaddition of methyl 2-azidoacetate to iodobuta-1,3-diynes and subsequent Suzuki-Miyaura cross-coupling were used to synthesize new triazoles derivatives: 5aryl-4-arylethynyl-1H-1,2,3-triazoles. Investigation of their optical p
- Efremova, Mariia M.,Govdi, Anastasia I.,Frolova, Valeria V.,Rumyantsev, Andrey M.,Balova, Irina A.
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- Synthesis and preliminary anticancer evaluation of new triazole bisphosphonate-based isoprenoid biosynthesis inhibitors
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The synthesis of a new set of triazole bisphosphonates 8a-d and 9a-d presenting an alkyl or phenyl substituent at the C-4 or C-5 position of the triazole ring is described. These compounds have been evaluated for their antiproliferative activity against M
- Legigan, Thibaut,Migianu-Griffoni, Evelyne,Redouane, Mohamed Abdenour,Descamps, Aurélie,Deschamp, Julia,Gager, Olivier,Monteil, Ma?lle,Barbault, Florent,Lecouvey, Marc
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- Discovery of 4H-thieno[3,2-b]pyrrole derivatives as potential anticancer agents
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In this study, we describe the discovery of the 4H-thieno[3,2-b]pyrrole derivatives as an useful scaffold to obtain potent lead compounds for the treatment of colon cancer. We first started with the 4H-thieno[3,2-b]pyrrole derivatives which come from comp
- Fang, Bo,Hu, Chunsheng,Ding, Yong,Qin, Hongxia,Luo, Yafei,Xu, Zhigang,Meng, Jiangping,Chen, Zhongzhu
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p. 1610 - 1627
(2021/06/06)
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- Thienopyrrole derivative as well as preparation method and application thereof
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A thienopyrrole derivative is named as 3-phenyl-N-(3-(trifluoromethyl) phenyl)-4H-thieno[3,2-b]pyrrole-5-formamide, the molecular formula of the thienopyrrole derivative is C20H13F3N2OS, and the molecular weight of the thienopyrrole derivative is 386.4. T
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Paragraph 0047-0050; 0062-0065; 0077-0080
(2020/09/08)
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- A Bu4N[Fe(CO)3(NO)]-Catalyzed Hemetsberger–Knittel Indole Synthesis
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The nucleophilic Fe complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]) catalyzes the direct intramolecular amination of aryl vinyl azides to give the corresponding indole derivatives in good to excellent yields.
- Baykal, Aslihan,Plietker, Bernd
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supporting information
(2020/02/20)
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- Cu-Catalyzed Oxidation of C2 and C3 Alkyl-Substituted Indole via Acyl Nitroso Reagents
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The selective oxidation of C2-alkyl-substituted indoles to 3-oxindole and the selective C-H oxygenation or amination of C2,C3-dialkyl-substituted indoles at C2 are reported under mild conditions. The position of the alkyl substitution on the indole directs the reaction to different pathways under similar conditions.
- Zhang, Jun,Torabi Kohlbouni, Saeedeh,Borhan, Babak
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supporting information
p. 14 - 17
(2019/01/08)
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- HETEROCYCLIC COMPOUNDS AS PAD INHIBITORS
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Heterocyclic compounds of Formula (I), (II), and (III) are described herein along with their polymorphs, stereoisomers, prodrugs, solvates, co-crystals, intermediates, pharmaceutically acceptable salts, and metabolites thereof. The compounds described herein, their polymorphs, stereoisomers, prodrugs, solvates, co-crystals, intermediates, pharmaceutically acceptable salts, and metabolites thereof are PAD4 inhibitors and may be useful in the treatment of various disorders, for example rheumatoid arthritis, vasculitis, systemic lupus erythematosis, cutaneous lupus erythematosis, ulcerative colitis, cancer, cystic fibrosis, asthma, multiple sclerosis and psoriasis.
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Paragraph 000396
(2019/04/16)
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- Total Synthesis of Tambromycin by Combining Chemocatalytic and Biocatalytic C?H Functionalization
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A combination of genomic and metabolomic approaches recently resulted in the identification of a nonribosomal tetrapeptide tambromycin, which possesses promising antiproliferative activity and several unusual structural features, including a densely substituted indole, a methyloxazoline ring, and an unusual pyrrolidine-containing amino acid called tambroline. In this work, we identify a concise synthetic route to access tambromycin, which relies on the strategic use of biocatalytic and chemocatalytic C?H functionalization methods to prepare two key precursors to the natural product in an efficient and scalable manner. The success of our study highlights the benefits of applying the principles of biocatalytic retrosynthesis as well as C?H functionalization logic to the synthesis of complex molecular scaffolds.
- Zhang, Xiao,King-Smith, Emma,Renata, Hans
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supporting information
p. 5037 - 5041
(2018/03/27)
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- Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus
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Inspired by our previous efforts on the modifications of diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a “triazole tail” occupying the entrance channel in the NNRTI binding pocket of the reverse transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds showed excellent to good activity against wild-type HIV-1 strain with EC50 of 0.02–1.77 μM. Evaluations of selected compounds against more drug-resistant strains showed these compounds had advantage of inhibiting E138K mutant virus which is a key drug-resistant mutant to the new generation of NNRTIs. Among this series, propionitrile (3b2, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.015 μM, CC50 = 40.15 μM), pyrrolidin-1-ylmethanone (3b8, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.014 μM, CC50 = 58.09 μM) and morpholinomethanone (3b9, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.027 μM, CC50 = 180.90 μM) derivatives are the three most promising compounds which are equally potent to the marketed drug Etravirine against E138K mutant strain but with much lower cytotoxicity. Furthermore, detailed SAR, inhibitory activity against RT and docking study of the representative compounds are also discussed.
- Tian, Ye,Liu, Zhaoqiang,Liu, Jinghan,Huang, Boshi,Kang, Dongwei,Zhang, Heng,De Clercq, Erik,Daelemans, Dirk,Pannecouque, Christophe,Lee, Kuo-Hsiung,Chen, Chin-Ho,Zhan, Peng,Liu, Xinyong
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p. 339 - 350
(2018/04/10)
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- C5-ANILINOQUINAZOLINE COMPOUNDS AND THEIR USE IN TREATING CANCER
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The invention concerns compounds of Formula (I): or pharmaceutically acceptable salts thereof, wherein R1, R2, R3 and R4 have any of the meanings hereinbefore defined in the description; process for their prepar
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Paragraph 0241; 0377
(2018/11/21)
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- Dual roles of substituted thiourea as reductant and ligand in CuAAC reaction
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A highly efficient catalytic system, CuSO4·5H2O/1-(4-methoxyphenyl)-3-phenylthiourea, for the copper(I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC) was discovered. In the above catalytic system, substituted thiourea acts both as a reductant and a ligand. CuSO4·5H2O/1-(4-methoxyphenyl)-3-phenylthiourea is both an economical and efficient catalyst for the CuAAC reaction. In addition, the new catalytic system has advantageous features including mild and green reaction conditions, and broad substrate compatibility. A variety of 1,4-disubstituted 1,2,3-triazoles have been prepared with good to excellent yields with the CuSO4·5H2O/1-(4-methoxyphenyl)-3-phenylthiourea catalytic system in aqueous solution.
- Wang, Siyu,Jia, Kai,Cheng, Jiajia,Chen, Yu,Yuan, Yaofeng
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supporting information
p. 3717 - 3721
(2017/09/01)
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- Introducing the 4-Phenyl-1,2,3-Triazole Moiety as a Versatile Scaffold for the Development of Cytotoxic Ruthenium(II) and Osmium(II) Arene Cyclometalates
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Herein we report the synthesis, anticancer potency in vitro, biomolecule interaction, and preliminary mode of action studies of a series of cyclometalated 1,2,3-triazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) organometallics of the general for
- Riedl, Christoph A.,Flocke, Lea S.,Hejl, Michaela,Roller, Alexander,Klose, Matthias H. M.,Jakupec, Michael A.,Kandioller, Wolfgang,Keppler, Bernhard K.
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supporting information
p. 528 - 541
(2017/01/13)
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- Intermolecular Schmidt reaction of alkyl azides with acyl silanes
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The first intermolecular Schmidt reaction of alkyl azides with acyl silanes has been designed and realized, producing a range of amides with absolute site selectivity in good to excellent yields. The mechanism of the conversion has been proposed, and the reaction exhibits scope of substrates.
- Yu, Chun-Jiao,Li, Rui,Gu, Peiming
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supporting information
p. 3568 - 3570
(2016/07/18)
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- Carboxylate-Assisted Iridium-Catalyzed C-H Amination of Arenes with Biologically Relevant Alkyl Azides
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An iridium-catalyzed C-H amination of arenes with a wide substrate scope is reported. Benzamides with electron-donating and -withdrawing groups and linear, branched, and cyclic alkyl azides are all applicable. Cesium carboxylate is crucial for both reactivity and regioselectivity of the reactions. Many biologically relevant molecules, such as amino acid, peptide, steroid, sugar, and thymidine derivatives can be introduced to arenes with high yields and 100 % chiral retention. Ir responsible! A direct C-H amination between benzamide derivatives and various alkyl azides was achieved using iridium catalysis (see scheme; NTf=trifluoromethanesulfonyl amide). Cesium carboxylate was found to be the promoter and regiocontroller of this reaction. By this method, many biological active molecules can be introduced to benzamide components with high yields and 100 % chiral retention.
- Zhang, Tao,Hu, Xuejiao,Wang, Zhen,Yang, Tiantian,Sun, Hao,Li, Guigen,Lu, Hongjian
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supporting information
p. 2920 - 2924
(2016/03/23)
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- Discovery of Indoline-2-carboxamide Derivatives as a New Class of Brain-Penetrant Inhibitors of Trypanosoma brucei
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There is an urgent need for new, brain penetrant small molecules that target the central nervous system second stage of human African trypanosomiasis (HAT). We report that a series of novel indoline-2-carboxamides have been identified as inhibitors of Trypanosoma brucei from screening of a focused protease library against Trypanosoma brucei brucei in culture. We describe the optimization and characterization of this series. Potent antiproliferative activity was observed. The series demonstrated excellent pharmacokinetic properties, full cures in a stage 1 mouse model of HAT, and a partial cure in a stage 2 mouse model of HAT. Lack of tolerability prevented delivery of a fully curative regimen in the stage 2 mouse model and thus further progress of this series.
- Cleghorn, Laura A. T.,Albrecht, Sébastien,Stojanovski, Laste,Simeons, Frederick R. J.,Norval, Suzanne,Kime, Robert,Collie, Iain T.,De Rycker, Manu,Campbell, Lorna,Hallyburton, Irene,Frearson, Julie A.,Wyatt, Paul G.,Read, Kevin D.,Gilbert, Ian H.
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supporting information
p. 7695 - 7706
(2015/10/20)
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- As a receptor antagonist CRTH2 heterorings compd.
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This application relates to a compound of Formula ! (or a pharmaceutically acceptable salt thereof) as defined herein, pharmaceutical compositions thereof, and its use as an antagonist of receptor CRTH2, as well as a process for its preparation and interm
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Paragraph 0076
(2016/10/10)
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- Optimization of chemical functionalities of indole-2-carboxamides to improve allosteric parameters for the cannabinoid receptor 1 (CB1)
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5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (1; ORG27569) is a prototypical allosteric modulator for the cannabinoid type 1 receptor (CB1). Here, we reveal key structural requirements of indole-2-carboxamides for allosteric modulation of CB1: a critical chain length at the C3-position, an electron withdrawing group at the C5-position, the length of the linker between the amide bond and the phenyl ring B, and the amino substituent on the phenyl ring B these significantly impact the binding affinity (KB) and the binding cooperativity (α). A potent CB1 allosteric modulator 5-chloro-N-(4-(dimethylamino)phenethyl)-3-propyl-1H-indole- 2-carboxamide (12d) was identified. It exhibited a KB of 259.3 nM with a strikingly high binding α of 24.5. We also identified 5-chloro-N-(4-(dimethylamino)phenethyl)-3-hexyl-1H-indole-2-carboxamide (12f) with a KB of 89.1 nM, which is among the lowest KB values obtained for any allosteric modulator of CB1 these positive allosteric modulators of orthosteric agonist binding nonetheless antagonized the agonist-induced G-protein coupling to the CB1 receptor, yet induced β-arrestin mediated ERK1/2 phosphorylation.
- Khurana, Leepakshi,Ali, Hamed I.,Olszewska, Teresa,Ahn, Kwang H.,Damaraju, Aparna,Kendall, Debra A.,Lu, Dai
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p. 3040 - 3052
(2014/05/06)
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- A metal-free three-component reaction for the regioselective synthesis of 1,4,5-trisubstituted 1,2,3-triazoles
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A metal-free three-component reaction to synthesize 1,4,5-trisubstituted 1,2,3-triazoles from readily available building blocks,such as aldehydes,nitroalkanes,and organic azides,is described. The process is enabled by an organocatalyzed Knoevenagel condensation of the formyl group with the nitro compound,which is followed by the 1,3-dipolar cycloaddition of the azide to the activated alkene. The reaction features an excellent substrate scope,and the products are obtained with high yield and regioselectivity. This method can be utilized for the synthesis of fused triazole heterocycles and materials with several triazole moieties.
- Thomas, Joice,John, Jubi,Parekh, Nikita,Dehaen, Wim
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supporting information
p. 10155 - 10159
(2015/03/31)
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- Biological evaluation of new largazole analogues: Alteration of macrocyclic scaffold with click chemistry
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We report the design, synthesis, and biological evaluation of a new series of largazole analogues in which a 4-methylthiazoline moiety was replaced with a triazole and tetrazole ring, respectively. Compound 7 bearing a tetrazole ring was identified to show much better selectivity for HDAC1 over HDAC9 than largazole (10-fold). This work could serve as a foundation for further exploration of selective HDAC inhibitors using a largazole molecular scaffold.
- Li, Xianlin,Tu, Zhenchao,Li, Hua,Liu, Chunping,Li, Zheng,Sun, Qiao,Yao, Yiwu,Liu, Jinsong,Jiang, Sheng
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supporting information
p. 132 - 136
(2013/03/13)
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- The first well-defined silver(I)-complex-catalyzed cycloaddition of azides onto terminal alkynes at room temperature
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Silver(I)-catalyzed click chemistry: Substituted 1,2,3-triazoles are versatile intermediates with an expanding array of applications. The discovery and application of a general AgI-catalyzed azide-alkyne cycloaddition reaction (AAC) leading to
- McNulty, James,Keskar, Kunal,Vemula, Ramesh
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supporting information; experimental part
p. 14727 - 14730
(2012/01/19)
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- Continuous flow thermolysis of azidoacrylates for the synthesis of heterocycles and pharmaceutical intermediates
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An efficient, safe and scalable procedure for the continuous flow thermolysis of azidoacrylates to yield indoles has been developed and was applied to the synthesis of related heterocycles. The scalability of the process was demonstrated in the continuous flow synthesis of a precursor to the DAAO inhibitor 4H-furo[3,2-b]pyrrole-5-carboxylic acid.
- O'Brien, Alexander G.,Levesque, Francois,Seeberger, Peter H.
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supporting information; experimental part
p. 2688 - 2690
(2011/04/25)
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- Efficient synthesis and in vitro antitubercular activity of 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis
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Efficient and rapid synthesis of 1,2,3-triazole derivatives has been achieved via Huisgen's 1,3-dipolar cycloaddition between alkyl/arylazides and diethyl/dimethyl acetylenedicarboxylate in excellent yields under solvent-free conditions. The environmentally friendly solvent-free protocol overcomes the limitations associated with the prevailing time-consuming solution phase protocols and affords the triazoles just in 1-3 min. In vitro antitubercular activity of these triazoles was screened against Mycobacterium tuberculosis H37Rv strain. Four of the compounds showed MIC in the range of 1.56-3.13 μg/mL proving their potential activity.
- Shanmugavelan, Poovan,Nagarajan, Sangaraiah,Sathishkumar, Murugan,Ponnuswamy, Alagusundaram,Yogeeswari, Perumal,Sriram, Dharmarajan
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supporting information; experimental part
p. 7273 - 7276
(2012/02/04)
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- (R)-1-(4-(4-FLUORO-2-METHYL-1H-INDOL-5-YLOXY)-5-METHYLPYRROLO[2,1-f][1,2,4]TRIAZIN-6-YLOXY)PROPAN-2-OL METABOLITES
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The present invention is directed to metabolites of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol, the compound of formula (I), pharmaceutical compositions thereof, and to methods of using the metab
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Page/Page column 12-13
(2011/04/26)
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- Inhibition of lymphoid tyrosine phosphatase by benzofuran salicylic acids
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The lymphoid tyrosine phosphatase (Lyp, PTPN22) is a critical negative regulator of T cell antigen receptor (TCR) signaling. A single-nucleotide polymorphism (SNP) in the ptpn22 gene correlates with the incidence of various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Since the disease-associated allele is a more potent inhibitor of TCR signaling, specific Lyp inhibitors may become valuable in treating autoimmunity. Using a structure-based approach, we synthesized a library of 34 compounds that inhibited Lyp with IC50 values between 0.27 and 6.2 μM. A reporter assay was employed to screen for compounds that enhanced TCR signaling in cells, and several inhibitors displayed a dose-dependent, activating effect. Subsequent probing for Lyps direct physiological targets by immunoblot analysis confirmed the ability of the compounds to inhibit Lyp in T cells. Selectivity profiling against closely related tyrosine phosphatases and in silico docking studies with the crystal structure of Lyp yielded valuable information for the design of Lyp-specific compounds.
- Vang, Torkel,Xie, Yuli,Liu, Wallace H.,Vidovi?, Du?ica,Liu, Yidong,Wu, Shuangding,Smith, Deborah H.,Rinderspacher, Alison,Chung, Caty,Gong, Gangli,Mustelin, Tomas,Landry, Donald W.,Rickert, Robert C.,Schürer, Stephan C.,Deng, Shi-Xian,Tautz, Lutz
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experimental part
p. 562 - 571
(2011/03/20)
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- Sequential one-pot ruthenium-catalyzed azide-alkyne cycloaddition from primary alkyl halides and sodium azide
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An experimentally simple sequential one-pot RuAAC reaction, affording 1,5-disubstituted 1H-1,2,3-triazoles in good to excellent yields starting from an alkyl halide, sodium azide, and an alkyne, is reported. The organic azide is formed in situ by treating the primary alkyl halide with sodium azide in DMA under microwave heating. Subsequent addition of [RuClCp*(PPh 3)2] and the alkyne yielded the desired cycloaddition product after further microwave irradiation.
- Johansson, Johan R.,Lincoln, Per,Norden, Bengt,Kann, Nina
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experimental part
p. 2355 - 2359
(2011/05/13)
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- Polymer-peptide chimeras for the multivalent display of immunogenic peptides
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Chimeras of poly(n-isopropyl acrylamide) and immunogenic peptides from the cancer-associated glycoprotein MUC1 were synthesised using a combination of solid-phase peptide synthesis, RAFT polymerisation and copper-catalysed alkyne-azide cycloaddition reactions.
- Kakwere, Hamilton,Chun, Candy K.Y.,Jolliffe, Katrina A.,Payne, Richard J.,Perrier, Sebastien
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supporting information; experimental part
p. 2188 - 2190
(2010/07/08)
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- One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from aldehydes and amines
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A one-pot, three-step synthesis of 1,4-disubstituted 1,2,3-triazoles from aldehyde and amine has been developed by in situ transformation of aldehyde into alkyne, followed by diazo-transfer of amine into azide and subsequent cycloaddition. This procedure allowed the synthesis of fluorescent amino acid derivatives as well as glycoconjugate mimetics. Georg Thieme Verlag Stuttgart.
- Maisonneuve, Stephane,Xie, Juan
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experimental part
p. 2977 - 2981
(2010/01/21)
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- 5-Hydroxyindole-2-carboxylic acid amides: Novel histamine-3 receptor inverse agonists for the treatment of obesity
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Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H3R) in the regulation of food intake and body weight and the potential therapeutic effect of H3R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds, the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H3R inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-R-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin- 1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)-1H-indol-2-yl]-methanone 36 are detailed.
- Pierson, Pascale David,Fettes, Alec,Freichel, Christian,Gatti-McArthur, Silvia,Hertel, Cornelia,Huwyler, J?rg,Mohr, Peter,Nakagawa, Toshito,Nettekoven, Matthias,Plancher, Jean-Marc,Raab, Susanne,Richter, Hans,Roche, Olivier,Sarmiento, Rosa María Rodríguez,Schmitt, Monique,Schuler, Franz,Takahashi, Tadakatsu,Taylor, Sven,Ullmer, Christoph,Wiegand, Ruby
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supporting information; experimental part
p. 3855 - 3868
(2010/02/28)
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- Using chemical probes to investigate the sub-inhibitory effects of azithromycin
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The antibacterial drug azithromycin has clinically beneficial effects at sub-inhibitory concentrations for the treatment of conditions characterized by chronic Pseudomonas aeruginosa infection, such as cystic fibrosis. These effects are, in part, the result of inhibition of bacterial biofilm formation. Herein, the efficient synthesis of azithromycin in 4 steps from erythromycin and validation of the drug's ability to inhibit biofilm formation at sub-MIC (minimum inhibitory concentration) values are reported. Furthermore, the synthesis of immobilized and biotin-tagged azithromycin analogues is described. These chemical probes were used in pull-down assays in an effort to identify azithromycin's binding partners in vivo. Results from these assays revealed, as expected, mainly ribosomal-related protein binding partners, suggesting that this is the primary target of the drug. This was further confirmed by studies using a P. aeruginosa strain containing plasmid-encoded ermC, which expresses a protein that modifies 23S rRNA and so blocks macrolide entry to the ribosome. In this strain, no biofilm inhibition was observed. This work supports the hypothesis that the sub-inhibitory effects of azithromycin are mediated through the ribosome. Moreover, the synthesis of these chemical probes, and proof of their utility, is of value in global target identification in P. aeruginosa and other species.
- Glansdorp, Freija G.,Spandl, Richard J.,Swatton, Jane E.,Loiseleur, Olivier,Welch, Martin,Spring, David R.
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supporting information; experimental part
p. 4120 - 4124
(2009/02/07)
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- A novel synthesis of EGFR-tyrosine-kinase inhibitors with 4-(indol-3-yl)quinazoline structure
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(Chemical Equation Presented) The epidermal growth factor (EGF) family of membrane receptors has been identified as a key element in the complex signaling network that is utilized by various classes of cell-surface receptors. A new synthetic pathway of 4-(indol-3-yl)quinazolines 15 and 16 is described using cross coupling reactions with quinazoline- and indole moieties. The synthesized compound 15 is a new dual and high potent EGFR- and HER-2-tyrosine kinase inhibitor with excellent cytotoxic properties at different cell lines. Furthermore this substance class shows remarkably strong fluorescence.
- Lueth, Anja,Loewe, Werner
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p. 703 - 708
(2008/09/21)
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- Syntheses of 4-(indole-3-yl)quinazolines - A new class of epidermal growth factor receptor tyrosine kinase inhibitors
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The epidermal growth factor (EGF) family of membrane receptors has been identified as a key element in the complex signaling network that is utilized by various classes of cell-surface receptors. The synthesis and pharmacological results of 4-(indole-3-yl)quinazolines are described. The synthesized compounds are new high potent EGFR-tyrosine kinase inhibitors with excellent cytotoxic properties at different cell lines. Furthermore the 4-(indole-3-yl)quinazolines show some tendencies to inhibit the HER-2 TK, too. Moreover this substance class has remarkable strong fluorescence properties.
- Lueth, Anja,Loewe, Werner
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p. 1478 - 1488
(2008/09/21)
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- Highly specific and broadly potent inhibitors of mammalian secreted phospholipases A2
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We report a series of inhibitors of secreted phospholipases A2 (sPLA2s) based on substituted indoles, 6,7-benzoindoles, and indolizines derived from LY315920, a well-known indole-based sPLA2 inhibitor. Using the human group X sPLA2 crystal structure, we prepared a highly potent and selective indole-based inhibitor of this enzyme. Also, we report human and mouse group IIA and IIE specific inhibitors and a substituted 6,7-benzoindole that inhibits nearly all human and mouse sPLA 2s in the low nanomolar range.
- Oslund, Rob C.,Cermak, Nathan,Gelb, Michael H.
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supporting information; experimental part
p. 4708 - 4714
(2009/06/06)
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- WATER-SOLUBLE CC-1065 ANALOGS AND THEIR CONJUGATES
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This invention relates to novel analogs of the DNA-binding alkylating agent CC-1065 and to their conjugates. Furthermore this invention concerns intermediates for the preparation of said agents and their conjugates. The conjugates are designed to release their (multiple) payload after one or more activation steps and/or at a rate and time span controlled by the conjugate in order to selectively deliver and/or controllably release one or more of said DNA alkylating agents. The agents, conjugates, and intermediates can be used to treat an illness that is characterized by undesired (cell) proliferation. As an example, the agents and the conjugates of this invention may be used to treat a tumor.
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Page/Page column 91
(2010/11/28)
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- The use of aminoglycoside derivatives to study the mechanism of aminoglycoside 6′-N-acetyltransferase and the role of 6′-NH2 in antibacterial activity
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Aminoglycoside antibiotics act by binding to 16S rRNA. Resistance to these antibiotics occurs via drug modifications by enzymes such as aminoglycoside 6′-N-acetyltransferases (AAC(6′)s). We report here the regioselective and efficient synthesis of N-6′-ac
- Yan, Xuxu,Gao, Feng,Yotphan, Sirilata,Bakirtzian, Parseh,Auclair, Karine
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p. 2944 - 2951
(2008/02/01)
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- Synthesis of new water-soluble DNA-binding subunits for analogues of the cytotoxic antibiotic CC-1065 and their prodrugs
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Novel water-soluble indole-2-carboxylic acid derivatives (7, 13, 21 and 25) bearing a substituent with a tertiary amino functionality at C-5 have been prepared. These new DNA-binding subunits can be used for the synthesis of new analogues of the cytotoxic antibiotic CC-1065 and their corresponding prodrugs for antibody-directed enzyme prodrug therapy (ADEPT) within a selective treatment of cancer. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Tietze, Lutz F.,Major, Felix
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p. 2314 - 2321
(2007/10/03)
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- Synthesis and evaluation of coumermycin A1 analogues that inhibit the Hsp90 protein folding machinery
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(Chemical Equation Presented) The coumarin antibiotics are not only potent inhibitors of DNA gyrase but also represent the most effective C-terminal inhibitors of 90 kDa heat shock proteins (Hsp90) reported thus far. In contrast to the N-terminal ATP-binding site, little is known about the Hsp90 C-terminus. In addition, very limited structure-activity relationships exist between this class of natural products and Hsp90. In this letter, the syntheses of dimeric coumarin analogues are presented along with their inhibitory values in breast cancer cell lines.
- Burlison, Joseph A.,Blagg, Brian S. J.
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p. 4855 - 4858
(2007/10/03)
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- Inhibitors of aminoglycoside 6'-N-acetyltransferases, compositions and uses thereof
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The present invention relates to inhibitors of aminoglycoside 6''-N-acetyltransferases of Formula I: R-X-Y-Z Formula I wherein: R is selected from the group consisting of: R1 is selected from the group consisting of OH and R2 is selected from the group consisting of OH and R3 is selected from the group consisting of NH2 and OH; R4 is selected from the group consisting of NH2 and R5 is selected from the group consisting of OMe, OEt OPr, and O-iPr; X is selected from the group consisting of NH and O; Y is selected from the group consisting of: R6 is selected from the group consisting of OH, CH3, and OCH3; n is an integer ranging from 1 to 10; and Z is selected from the group consisting of: and R7 is selected from the group consisting of OH, OMe, OEt OPr, O-iPr, O-tBu and
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Page/Page column 15
(2008/06/13)
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