- Synthesis and photoreactivity of 4,5-dithienyl[1,3]dithiol-2-ones
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Whereas irradiation of 4,5-dithiophen-2-yl[1,3]-dithiol-2-one leads to the expected 2,3,5,6-tetrathiophen-2-yl-l,4-dithiine product, similar reaction of thiophen-3-yl-substituted [1,3]dithioi-2-ones leads to thieno[3,4-c]dithiines via a unique ring cleavage reaction.
- Roberts-Bleming, Susan J.,Davies, Gemma L.,Kalaji, Maher,Murphy, Patrick J.,Celli, Angela Maria,Donati, Donato,Ponticelli, Fabio
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- Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates
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Molecular probes for selective identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying protein aggregation diseases. Here we report the chemical design of a library of anionic luminescent conjugated oligothiophenes (LCOs), which can be utilized as ligands for detection of protein aggregates. Certain molecular requirements were shown to be necessary for detecting (i) early non-thioflavinophilic protein assemblies of Aβ1-42 and insulin preceding the formation of amyloid fibrils and (ii) for obtaining distinct spectral signatures of the two main pathological hallmarks observed in human Alzheimer's diease brain tissue (Aβ plaques and neurofibrillary tangles). Our findings suggest that a superior anionic LCO-based ligand should have a backbone consisting of five to seven thiophene units and carboxyl groups extending the conjugated thiophene backbone. Such LCOs will be highly useful for studying the underlying molecular events of protein aggregation diseases and could also be utilized for the development of novel diagnostic tools for these diseases. The Royal Society of Chemistry 2011.
- Klingstedt, Therese,Aslund, Andreas,Simon, Rozalyn A.,Johansson, Leif B. G.,Mason, Jeffrey J.,Nystroem, Sofie,Hammarstroem, Per,Nilsson, K. Peter R.
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- CEPHALOSPORIN CIPROFLOXACIN HYBRID COMPOUNDS
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A compound of formula (Ia) and related aspects.
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Page/Page column 35; 39
(2020/06/05)
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- Palladium-Catalyzed Distal C?H Selenylation of 2-Aryl Acetamides with Diselenides and Selenyl Chlorides
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A convenient and effective method of palladium-catalyzed C?H selenylation of the 2-aryl acetamides assisted with removable 8-aminoquinoline with readily available diselenides and selenyl chlorides has been developed. This selenylation reaction is scalable and tolerates a wide range of functional groups, providing a straightforward way of the preparing unsymmetrical diaryl selenides and dibenzoselene-pinone. Preliminary mechanistic studies indicated that a single-electron transfer type mechanism and facile C?H metalation are operative. (Figure presented.).
- Gu, Linghui,He, Meicui,Ma, Wenbo,Tan, Yuqiang,Wang, Yang,Wang, Yuchi,Zhang, Chunran
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supporting information
p. 5708 - 5715
(2020/12/01)
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- Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug
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Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic prodrug that combines ciprofloxacin with a β-lactamase-cleavable motif. The prodrug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our prodrug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.
- Evans, Lindsay E.,Krishna, Aishwarya,Ma, Yajing,Webb, Thomas E.,Marshall, Dominic C.,Tooke, Catherine L.,Spencer, James,Clarke, Thomas B.,Armstrong, Alan,Edwards, Andrew M.
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p. 4411 - 4425
(2019/05/17)
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- Synthesis of Unsymmetrical Diaryl Acetamides, Benzofurans, Benzophenones, and Xanthenes by Transition-Metal-Free Oxidative Cross-Coupling of sp3 and sp2 C-H Bonds
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A chemo- and regioselective intermolecular sp3 C-H and sp2 C-H coupling reaction for C-C bond formation is described to access unsymmetrical diaryl acetamides under TM-free conditions from sec- and tert-arylacetamides and nitroarenes using tert-butoxide base in DMSO at room temperature. The coupling partners with sensitive functionalities such as chloro, bromo, hydroxy, and cyano were also amenable to the developed reaction. Synthesized α-(2/4-nitroaryl) phenylacetamides have been transformed into biologically important benzofurans, xanthenes, diaryl indoles, and unsymmetrical benzophenones by novel routes without applying a transition metal. Overall, an economical, yet efficient, strategy has been devised to access unsymmetrical diarylacetamides with the possibility of their further elaboration into a variety of biologically important heterocycles. Mechanistic understanding suggests that the reaction proceeds by a nucleophilic addition of a phenylacetamide carbanion, which is generated in the presence of tert-butoxide base, to the para or ortho (if para is substituted) position of nitrobenzene. The formed α-(4-nitrocyclohexa-2,4-dien-1-yl) phenylacetamide anion intermediate oxidized by a basic solution of DMSO or atmospheric oxygen led to the desired sp3 C-H and sp2 C-H coupled α-(2/4-nitroaryl) phenylacetamides.
- Rathore, Vandana,Sattar, Moh.,Kumar, Raushan,Kumar, Sangit
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p. 9206 - 9218
(2016/10/14)
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- Potentiometric and conductometric study of aqueous solutions of lithium and sodium salts of poly (thiophen-3-y lacetic acid)
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The title polymer, PTAA, practically free of ester groups was obtained by oxidative polymerization of methyl thiophen-3-ylacetate and subsequent basic hydrolysis of primary polymer. Poly(thiophen-3-ylacetic acid) has been thoroughly characterized by NMR, IR, Raman, and UV/Vis spectroscopy. The polyacid behavior during neutralization titrations with lithium and sodium hydroxides, carried out under nitrogen atmosphere, has been studied by conductometry and potentiometry. Henderson-Hasselbach plots of Potentiometrie titration curves show a break point at pH around 6, where the curve slope drops from 1.8 (at lower pH) to a value from 1.05 to 1.3 (at higher pH values). The UV/Vis spectra monitored during back titration show: (i) monotonous decrease of both λ,max and εmax as pH decreases, (ii) the presence of the isosbestic point at 401 nm that can be ascribed to conformational transition of PTAA chains, and (iii) absence of the isosbestic point at 392 nm reported previously by other authors.
- Hostnik, Gregor,Vlachy, Vojko,Cerar, Janez,Bondarev, Dmitrij,Vohlidal, Jiri
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supporting information
p. 582 - 589,8
(2020/08/24)
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- Facile preparation of protected benzylic and heteroarylmethyl amines via room temperature Curtius rearrangement
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A step-wise, room temperature procedure for acyl azide formation and the subsequent Curtius rearrangement of phenyl and heteroaryl acetic acids is described. We have developed a protocol for room temperature Curtius rearrangement in MeOH or CHCl3 that provides an improvement over standard conditions, avoiding the use of additives or heat. This room temperature optimization of the Curtius rearrangement prevents the formation of side products often observed with benzylic acids, allowing access to a variety of benzylic and heteroarylmethyl amines.
- Leathen, Matthew L.,Peterson, Emily A.
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supporting information; experimental part
p. 2888 - 2891
(2010/06/14)
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- INDOLE AMIDE DERIVATIVES AND RELATED COMPOUNDS FOR USE IN THE TREATMENT OF NEURODEGENERATIVE DISEASES
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This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterised by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.
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(2010/12/29)
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- 2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H] quinoline-4-carboxylic acid (PSI-697): Identification of a clinical candidate from the quinoline salicylic acid series of P-selectin antagonists
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P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.
- Kaila, Neelu,Janz, Kristin,Huang, Adrian,Moretto, Alessandro,DeBernardo, Silvano,Bedard, Patricia W.,Tam, Steve,Clerin, Valerie,Keith Jr., James C.,Tsao, Desirée H.H.,Sushkova, Natalia,Shaw, Gray D.,Camphausen, Raymond T.,Schaub, Robert G.,Wang, Qin
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- Synthesis of selective SRPK-1 inhibitors: Novel tricyclic quinoxaline derivatives
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SR protein-specific kinase-1 (SRPK-1) has been identified as a validated target for hepatitis B virus (HBV). A series of novel tricyclic quinoxaline derivatives was designed and synthesised as potential kinase inhibitory antiviral agents and was found to be active and selective for SRPK-1 kinase. Most of these novel compounds have drug-like properties according to experimentally determined Log P and Log S values.
- Szekelyhidi, Zsolt,Pato, Janos,Waczek, Frigyes,Banhegyi, Peter,Hegymegi-Barakonyi, Balint,Eros, Daniel,Meszaros, Gyoergy,Hollosy, Ferenc,Hafenbradl, Doris,Obert, Sabine,Klebl, Bert,Keri, Gyoergy,Orfi, Laszlo
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p. 3241 - 3246
(2007/10/03)
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- Methods and compositions for selectin inhibition
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The present invention relates to the field of anti-inflammatory substances, and more particularly to novel compounds that act as antagonists of the mammalian adhesion proteins known as selectins. In some embodiments, methods for treating selectin mediated disorders are provided which include administration of compound of Formula I: wherein the constituent variables are defined herein.
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Page/Page column 25
(2008/06/13)
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- Quinolones as gonadotropin releasing hormone (GnRH) antagonists: Simultaneous optimization of the C(3)-aryl and C(6)-substituents
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A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. A variety of substitution patterns of the 3-aryl substituent are described. The 3,4,5-trimethylphenyl substituent (23h) was found to be optimal. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Young, Jonathan R.,Huang, Song X.,Chen, Irene,Walsh, Thomas F.,DeVita, Robert J.,Wyvratt Jr., Matthew J.,Goulet, Mark T.,Ren, Ning,Lo, Jane,Yang, Yi Tien,Yudkovitz, Joel B.,Cheng, Kang,Smith, Roy G.
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p. 1723 - 1727
(2007/10/03)
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- studies on anti-helicobacter pylori agents. Part 2: New cephem derivatives
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The synthesis and optimization of the anti-Helicobacter pylori activity of a novel series of cephem derivatives are described. Introduction of thio-heterocyclic groups containing N- and S-atoms to the 3-position and phenyl or thienyl acetamido groups to the 7-position of the cephem nucleus dramatically improved the activity. From this series of derivatives, compound 13i was found to have extremely potent in vitro anti-H. pylori activity, superior therapeutic efficacy compared to AMPC and CAM, no cross-resistance between CAM or MNZ and low potential for causing diarrhea due to instability to β-lactamase. Copyright (C) 2000 Elsevier Science Ltd.
- Yoshida, Yoshiki,Matsuda, Keiji,Sasaki, Hiroshi,Matsumoto, Yoshimi,Matsumoto, Satoru,Tawara, Shuichi,Takasugi, Hisashi
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p. 2317 - 2335
(2007/10/03)
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- Intramolecular Cyclization of Amido Acids into Pyrrolidinothieno(or [1]benzothieno)[3]azepinediones
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The synthesis of pyrrolidino[2,1-b]thieno[3,2(2,3)-f[3]azepinediones 7a,b and pyrrolidino[2,1-b]-[11]benzothieno[3,2(2,3)-f][3]azepinediones 7c,d are described starting from thiophenes or [1]benzothiophenes acetic acids. Their selective reduction using triethylsilane led to the corresponding azepinones 17a-d.
- Othman, Mohamed,Netchitailo, Pierre,Decroix, Bernard
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p. 225 - 231
(2007/10/03)
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- Presynaptic cholinergic modulators as potent cognition enhancers and analgesic drugs. 1. Tropic and 2-phenylpropionic acid esters
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Previous studies have shown that (R)-(+)-hyoscyamine has analgesic activity as a consequence of increased ACh release following antagonism of central muscarinic autoreceptors. Since the enhancement of central cholinergic transmission could be beneficial for cognitive disorders, we manipulated (R)-(+)-hyoscyamine, synthesizing several derivatives of tropic and 2-phenylpropionic acids, with the aim of obtaining drugs which are able to increase ACh release and consequently to show analgesic and nootropic activities. The results showed that several new compounds are indeed potent analgesics (with an analgesic efficacy comparable to that of morphine) and that the most potent one ((±)-19, PG9) also has remarkable cognition- enhancing properties. Our study confirmed that the mechanism of action involves ACh release even if it is still unclear whether only muscarinic autoreceptors or, also, heteroreceptors are involved.
- Gualtieri,Conti,Dei,Giovannoni,Nannucci,Romanelli,Scapecchi,Teodori,Fanfani,Ghelardini,Giotti,Bartolini
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p. 1704 - 1711
(2007/10/02)
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- Acid-catalyzed rearrangement of cyclobutanols. A novel rearrangement
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The acid-catalysed dehydration-rearrangement reaction of α-thienyl cyclobutanols 3 and 4 resulted in the formation of tetrahydronaphthothiophenes 5a and 6a.The rearrangement to the linearly fused PAH system instead of the expected angularly fused system reflects α-scission of the cyclobutyl ring.A mechanism based on deuterium labelling studies is propesed to account for the product formation.
- Lee-Ruff, E.,Ablenas, Fred J.
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p. 1663 - 1667
(2007/10/02)
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