- Rational Development of Novel Activity Probes for the Analysis of Human Cytochromes P450
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The identification and quantification of functional cytochromes P450 (CYPs) in biological samples is proving important for robust analyses of drug efficacy and metabolic disposition. In this study, a novel CYP activity-based probe was rationally designed and synthesised, demonstrating selective binding of CYP isoforms. The dependence of probe binding upon the presence of NADPH permits the selective detection of functionally active CYP. This allows the detection and analysis of these enzymes using biochemical and proteomic methodologies and approaches.
- Sellars, Jonathan D.,Skipsey, Mark,Sadr-ul-Shaheed,Gravell, Sebastian,Abumansour, Hamza,Kashtl, Ghasaq,Irfan, Jawaria,Khot, Mohamed,Pors, Klaus,Patterson, Laurence H.,Sutton, Chris W.
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- Synthesis and Configurations of (-)-Furospongin-1 and (+)-Dihydrofurospongin-2
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The long-known furanoterpenes furospongin-1 and dihydrofurospongin-2 were synthesized for the first time using a chiral-pool-based route in an effort to secure the previous configurational assignments. The key C-11 stereogenic centre was taken from D-mannose, and the C-13 alkyl centre was installed exploiting the chirality of mannose. Due to deprotonation and/or enolization of the building blocks used, introduction of the furan moieties was problematic, and so some reactions had to be avoided. The trisubstituted alkene was most satisfactorily constructed using a Julia-Kocienski olefination in 1,2-dimethoxyethane, with the best (E)/(Z) ratio achieved using a secondary sulfone. The synthetic samples not only provided the first unequivocal piece of evidence for the C-13 configuration of both natural products, but also confirmed the absolute configuration at C-11 of furospongin-1.
- Tan, Dong-Xing,Xu, Ze-Jun,Chen, Hui-Jun,Wu, Yikang,You, Jun
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- A new two-dimensional donor/acceptor copolymer based on 4,8-bis(2′-ethylhexylthiophene)thieno[2,3-f]benzofuran for high-performance polymer solar cells
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A new alkylthienyl substituted thieno[2,3-f]benzofuran (TBF)-based polymer (PTBFTDTBT) was synthesized and characterized. PTBFTDTBT had a high molecular weight, good solubility in common organic solvents, broad visible absorption from 300 to 750 nm, and a relatively deep highest occupied molecular orbital level (-5.2 eV). PTBFTDTBT also showed a field hole mobility up to the order of 10-2 using an organic field effect transistor (OFET) method and an order of 10-2 using a space-charge-limited current (SCLC) method. With the structure of indium tin oxide (ITO)/poly(3,4-ethylenedioxythiophene): polystyrene sulfonate/PTBFTDTBT:PC71BM (1:2, w/w)/Ca/Al, a power conversion efficiency of 6.42% was obtained with a high short circuit current (Jsc) of 13.51 mA cm-2 and fill factor (FF) of 61%, under the illumination of AM1.5G, at 100 mW cm-2, without any post-treatment. The study demonstrates that TBF is a promising building block for organic electronics. This journal is the Partner Organisations 2014.
- Fan, Ling,Cui, Ruili,Guo, Xiuping,Qian, Dong,Qiu, Beibei,Yuan, Jun,Li, Yongfang,Huang, Wenlong,Yang, Junliang,Liu, Weifang,Xu, Xinjun,Li, Lidong,Zou, Yingping
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- Directed metalation cascade to access highly functionalized thieno[2,3-f ]benzofuran and exploration as building blocks for organic electronics
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A tandem directed metalation has been successfully applied to the preparation of thieno[2,3-f]benzofuran-4,8-dione, providing an efficient and facile approach to symmetrically and unsymmetrically functionalize the thieno[2,3-f]benzofuran core at the 2,6 positions as well as to introduce the electron-withdrawing or -donating groups (EWG or EDG) at its 4,8 positions. The presence of various functional groups makes late-stage derivatization attainable.
- Aeschi, Yves,Li, Hui,Cao, Zhencai,Chen, Songjie,Amacher, Anneliese,Bieri, Nathalie,Oezen, Bilal,Hauser, Juerg,Decurtins, Silvio,Tan, Songting,Liu, Shi-Xia
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- Synthesis of a 4,8-dialkoxy-benzo[1,2-b:4,5-b′]difuran unit and its application in photovoltaic polymer
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A new building block of benzo[1,2-b:4,5-b′]difuran (BDF) was firstly designed and synthesized. The newly designed unit was applied for constructing a new photovoltaic low band gap polymer, PBDFDTBT, which exhibited promising power conversion efficiency of 5.0%. The Royal Society of Chemistry 2012.
- Huo, Lijun,Huang, Ye,Fan, Benhu,Guo, Xia,Jing, Yan,Zhang, Maojie,Li, Yongfang,Hou, Jianhui
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- A new benzo[1,2-b:4,5-b′]difuran-based copolymer for efficient polymer solar cells
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A new donor-acceptor type copolymer, namely poly{4,8-bis(2-ethylhexyloxy) benzo[1,2-b:3,4-b′]difuran-alt-6-octylnaphtho[2,3-c]thiophene-4,9-dione} (PBDFNTDO) was synthesized by a Stille coupling reaction and characterized by 1H NMR, GPC, TGA, UV-Vis absorption spectroscopy and cyclic voltammetry. PBDFNTDO is readily soluble in common organic solvents with a number-average molecular weight (Mn) of 10.7 kDa mol-1 and a polydispersity index of 1.71. TGA analysis shows the copolymer exhibits good thermal stability with 5% weight loss at a temperature of 341 °C. PBDFNTDO possesses a broad absorption band at 300-750 nm with an optical bandgap of 1.65 eV. Cyclic voltammetry gives HOMO and LUMO energy levels of -5.33 eV and -3.40 eV, respectively. The hole mobility of PBDFNTDO:PC71BM (1:1.5, w/w) reaches up to 5.0 × 10-3 cm2 V-1 s -1 by the space-charge-limited current (SCLC) method. A polymer solar cell with the configuration of ITO/PEDOT:PSS/PBDFNTDO:PC71BM (1:1.5, w/w)/Ca/Al demonstrates a promising power conversion efficiency of 4.71% under the illumination of AM 1.5 G, 100 mW cm-2.
- Chen, Xuewen,Liu, Bo,Zou, Yingping,Xiao, Lu,Guo, Xiuping,He, Yuehui,Li, Yongfang
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Read Online
- Benzamide compound and application thereof as herbicide
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The invention discloses a benzamide compound and an application thereof as a herbicide. The compound is shown in a general formula (I) as shown in the specification, and each substituent group in the general formula I is defined in the specification. The
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Paragraph 0059; 0063-0065
(2021/06/12)
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- Synthesis of N-trifluoromethyl amides from carboxylic acids
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Found in biomolecules, pharmaceuticals, and agrochemicals, amide-containing molecules are ubiquitous in nature, and their derivatization represents a significant methodological goal in fluorine chemistry. Trifluoromethyl amides have emerged as important functional groups frequently found in pharmaceutical compounds. To date, there is no strategy for synthesizing N-trifluoromethyl amides from abundant organic carboxylic acid derivatives, which are ideal starting materials in amide synthesis. Here, we report the synthesis of N-trifluoromethyl amides from carboxylic acid halides and esters under mild conditions via isothiocyanates in the presence of silver fluoride at room temperature. Through this strategy, isothiocyanates are desulfurized with AgF, and then the formed derivative is acylated to afford N-trifluoromethyl amides, including previously inaccessible structures. This method shows broad scope, provides a platform for rapidly generating N-trifluoromethyl amides by virtue of the diversity and availability of both reaction partners, and should find application in the modification of advanced intermediates.
- Flavell, Robert R.,Liu, Jianbo,Parker, Matthew F. L.,Toste, F. Dean,Wang, Sinan,Wilson, David M.
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supporting information
p. 2245 - 2255
(2021/08/12)
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- Design and synthesis of heteroaromatic-based benzenesulfonamide derivatives as potent inhibitors of H5N1 influenza A virus
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Influenza A virus is an enveloped negative single-stranded RNA virus that causes febrile respiratory infection and represents a clinically challenging threat to human health and even lives worldwide. Even more alarming is the emergence of highly pathogenic avian influenza (HPAI) strains such as H5N1, which possess much higher mortality rate (60%) than seasonal influenza strains in human infection. In this study, a novel series of heteroaromatic-based benzenesulfonamide derivatives were identified as M2 proton channel inhibitors. A systematic investigation of the structure-activity relationships and a molecular docking study demonstrated that the sulfonamide moiety and 2,5-dimethyl-substituted thiophene as the core structure played significant roles in the anti-influenza activity. Among the derivatives, compound 11k exhibited excellent antiviral activity against H5N1 virus with an EC50 value of 0.47 μM and selectivity index of 119.9, which are comparable to those of the reference drug amantadine.
- Yu, Yongshi,Tazeem,Xu, Zhichao,Du, Liaoqi,Jin, Mengyu,Dong, Chune,Zhou, Hai-Bing,Wu, Shuwen
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- Noncanonical cation-π cyclizations of alkylidene β-ketoesters: Synthesis of spiro-fused and bridged bicyclic ring systems
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Three cation-π cyclization cascades initiated at alkylidene β-ketoesters bearing pendent alkenes are described. Depending upon the alkene substitution pattern and the reaction conditions employed, it is possible to achieve selective synthesis of the three different types of products, including 1-halo-3-carbomethoxycyclohexanes, spiro-fused tricyclic systems, and [4.3.1] bridged bicyclic ring systems. All three reactions begin with 6-endo addition of an olefin to the alkylidene β-ketoester electrophile, followed by one of three different cation capture events.
- Parsons, Dylan E.,Frontier, Alison J.
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supporting information
p. 2008 - 2012
(2019/03/26)
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- Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents
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Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2′-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC50 value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC50 value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.
- Sijm, Maarten,Siciliano de Araújo, Julianna,Ramos Llorca, Alba,Orrling, Kristina,Stiny, Lydia,Matheeussen, An,Maes, Louis,de Esch, Iwan J. P.,de Nazaré Correia Soeiro, Maria,Sterk, Geert Jan,Leurs, Rob
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supporting information
p. 1662 - 1668
(2019/08/30)
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- Structure-Activity Relationships for CYP4B1 Bioactivation of 4-Ipomeanol Congeners: Direct Correlation between Cytotoxicity and Trapped Reactive Intermediates
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Cytochrome P450 4B1 (CYP4B1) has been explored as a candidate enzyme in suicide gene systems for its ability to bioactivate the natural product 4-ipomeanol (IPO) to a reactive species that causes cytotoxicity. However, metabolic limitations of IPO necessitate discovery of new "pro-toxicant" substrates for CYP4B1. In the present study, we examined a series of synthetically facile N-alkyl-3-furancarboxamides for cytotoxicity in HepG2 cells expressing CYP4B1. This compound series maintains the furan warhead of IPO while replacing its alcohol group with alkyl chains of varying length (C1-C8). Compounds with C3-C6 carbon chain lengths showed similar potency to IPO (LD50 ≈ 5 μM). Short chain analogs (6 carbons) exhibited reduced toxicity, resulting in a parabolic relationship between alkyl chain length and cytotoxicity. A similar parabolic relationship was observed between alkyl chain length and reactive intermediate formation upon trapping of the putative enedial as a stable pyrrole adduct in incubations with purified recombinant rabbit CYP4B1 and common physiological nucleophiles. These parabolic relationships reflect the lower affinity of shorter chain compounds for CYP4B1 and increased ω-hydroxylation of the longer chain compounds by the enzyme. Furthermore, modest time-dependent inhibition of CYP4B1 by N-pentyl-3-furancarboxamide was completely abolished when trapping agents were added, demonstrating escape of reactive intermediates from the enzyme after bioactivation. An insulated CYP4B1 active site may explain the rarely observed direct correlation between adduct formation and cell toxicity reported here.
- Girhard, Marco,Guttman, Miklos,Hanenberg, Helmut,Kowalski, John P.,Mcdonald, Matthew G.,Rettie, Allan E.,Scian, Michele,Whittington, Dale,Wiek, Constanze
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p. 2488 - 2498
(2019/12/24)
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- Design and Synthesis of Natural Product Inspired Libraries Based on the Three-Dimensional (3D) Cedrane Scaffold: Toward the Exploration of 3D Biological Space
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A chemoinformatic method was developed to extract nonflat scaffolds embedded in natural products within the Dictionary of Natural Products (DNP). The cedrane scaffold was then chosen as an example of a nonflat scaffold that directs substituents in three-dimensional (3D) space. A cedrane scaffold that has three orthogonal handles to allow generation of 1D, 2D, and 3D libraries was synthesized on a large scale. These libraries would cover more than 50% of the natural diversity of natural products with an embedded cedrane scaffold. Synthesis of three focused natural product-like libraries based on the 3D cedrane scaffold was achieved. A phenotypic assay was used to test the biological profile of synthesized compounds against normal and Parkinson's patient-derived cells. The cytological profiles of the synthesized analogues based on the cedrane scaffold revealed that this 3D scaffold, prevalidated by nature, can interact with biological systems as it displayed various effects against normal and Parkinson's patient-derived cell lines.
- Tajabadi, Fatemeh Mazraati,Pouwer, Rebecca H.,Liu, Miaomiao,Dashti, Yousef,Campitelli, Marc R.,Murtaza, Mariyam,Mellick, George D.,Wood, Stephen A.,Jenkins, Ian D.,Quinn, Ronald J.
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p. 6609 - 6628
(2018/07/25)
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- Merging gold catalysis, organocatalytic oxidation, and Lewis acid catalysis for chemodivergent synthesis of functionalized oxazoles from: N -propargylamides
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Novel catalytic systems consisting of cationic gold complexes, N-hydroxyphthalimide (NHPI), and transition-metal-based Lewis acids have been developed for the one-pot synthesis of functionalized oxazoles from N-propargylamides with excellent functional group tolerance. These transformations demonstrated the excellent compatibility of homogeneous gold catalysis with organocatalytic oxidative carbon-nitrogen bond formations using tert-butyl nitrite as the terminal oxidant. Moreover, oxazolecarbonitriles or carboxamides can be easily synthesized in a one-pot protocol according to the different synthetic requirements.
- Mai, Shaoyu,Rao, Changqing,Chen, Ming,Su, Jihu,Du, Jiangfeng,Song, Qiuling
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supporting information
p. 10366 - 10369
(2017/09/25)
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- Design, synthesis and activity evaluation study of novel substituted N-sulfonyl homoserine lactone derivatives as bacterial quorum sensing inhibitors
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A novel series of N-sulfonyl homoserine lactone derivatives 7a–7m has been designed, synthesized, and evaluated for quorum sensing inhibitory activities through the violacein inhibition in Chromobacterium violaceum CV026. Compound 7e displayed the high level of inhibitory activity among all the compounds synthesized. Studies of structure-activity relationship indicated that compounds with thiophene group in side chain showed better activity than those substituted by furan, pyrrole, pyridyl, and phenethyl group. Thiophene substituted compounds which connected electron withdrawing group exhibited better inhibitory activity relate to those connected electron donating group. Further analysis indicated that compound bearing an electron withdrawing substituent at the position 2 of their thiophene ring exhibited superior activity against violacein production to those bearing the substituent at the position 3 and 4. Compound 7e in particular, with IC50 value of 6.19 μM, were identified as promising lead compounds for further development.
- Sun, Qi,Zhao, Mingming,Liang, Jingwei,Xiao, Junhai,Meng, Fanhao
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p. 3345 - 3353
(2017/11/16)
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- Rh(III)-Catalyzed Redox-Neutral Annulation of Primary Benzamides with Diazo Compounds: Approach to Isoquinolinones
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Reported herein is a Rh-catalyzed redox-neutral annulation of primary benzamides with diazo compounds, representing an efficient and economic protocol to isoquinolinones. The procedure exhibited good functional group tolerability, scalability, and regioselectivity, obviating the need for oxidants, and only environmentally benign N2 and H2O were released. Further utilization of the method provided an alternative route to functionalized isoquinolines.
- Wu, Youzhi,Sun, Peng,Zhang, Kaifan,Yang, Tie,Yao, Hequan,Lin, Aijun
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p. 2166 - 2173
(2016/03/15)
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- Nickel(II)-Mediated Regioselective C H Monoiodination of Arenes and Heteroarenes by using Molecular Iodine
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The 8-aminoquinoline-directed, nickel(II)-mediated ortho-iodination of benzamides using molecular iodine has been developed. The process is highly regioselective and furnishes only monoiodinated products. A broad range of arenes and heteroarenes with diverse functional groups provided monoiodinated products in good to excellent yields. (Figure presented.) .
- Khan, Bhuttu,Kant, Ruchir,Koley, Dipankar
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supporting information
p. 2352 - 2358
(2016/07/28)
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- Two new fluorinated copolymers based on thieno[2,3-: F] benzofuran for efficient polymer solar cells
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Two new copolymers named TBFPF-BT and TBFPF-BO, composed of a fluorine substituted thieno[2,3-f]benzofuran donor unit and benzothiadiazole/benzooxadiazole acceptor unit, have been synthesized as the donor materials for polymer solar cell (PSC) applications. Both polymers presented wide absorptions (300-800 nm) in the UV-Vis region. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels were -5.28/-3.60 eV and -5.38/-3.69 eV for TBFPF-BT and TBFPF-BO, respectively. PSCs with the blends of TBFPF-BT/TBFPF-BO and PC71BM (1:2, w/w) as photoactive layers exhibited relatively low photovoltaic performances. After optimizing with 1% 1,8-diiodooctane (DIO) as additive, dramatic changes in short-circuit current density (Jsc) and fill factor (FF) were seen, with PCE up to 6.80% and 5.98% under AM 1.5, 100 mW cm-2 for TBFPF-BT and TBFPF-BO, respectively. Compared to TBFPF-BO, the higher PCE mainly benefits from the higher hole mobility and better morphology for the TBFPF-BT and PC71BM blend film.
- He, Dingjun,Qiu, Lixia,Zhang, Zhiguo,Li, Yongfang,Pan, Chunyue,Zou, Yingping
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p. 62923 - 62933
(2016/07/13)
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- Thieno [2, 3-f] benzofuran compound and its polymers and polymer application
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The invention discloses a thieno (2, 3-f) benzofuran compound, polymers thereof and an application of the polymers. A series of polymers with thieno (2, 3-f) benzofuran compound unit structures are synthesized from the thieno (2, 3-f) benzofuran compound, benzothiadiazole, benzotriazole, benzoxadiazole and other monomers through a Stille coupling polymerization method. The polymers have good thermal stability and electrochemical performance and can be mixed with commonly used fullerene and organic acceptor substances to prepare polymer solar cells with high photoelectric conversion rate, the photoelectric conversion efficiency of single-layer polymer solar cell devices can be as high as 6.4%, and the polymer materials have huge commercial prospects in application of the solar cells.
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Paragraph 0019; 0050; 0051
(2016/10/08)
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- Palladium-mediated intramolecular biaryl coupling reaction: Convenient preparation of furoquinolinone derivatives
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Furo[2,3-c ] or furo[3,2-c ]quinolinone derivatives were prepared via the intramolecular biaryl coupling reaction of 2-furoylanilides or 3-furoylanilides using a palladium catalyst.
- Abe, Hitoshi,Kamimura, Mayu,Komatsu, Yoshinori,Horino, Yoshikazu
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p. 1332 - 1342
(2015/03/04)
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- Dual role of Rh(III) catalyst enables regioselective halogenation of (electron-rich) heterocycles
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The Rh(III)-catalyzed selective bromination and iodination of electron-rich heterocycles is reported. Kinetic investigations show that Rh plays a dual role in the bromination, catalyzing the directed halogenation and preventing the inherent halogenation of these substrates. As a result, this method gives highly selective access to valuable halogenated heterocycles with regiochemistry complementary to those obtained using uncatalyzed approaches, which rely on the inherent reactivity of these classes of substrates. Furans, thiophenes, benzothiophenes, pyrazoles, quinolones, and chromones can be applied.
- Schr?der, Nils,Lied, Fabian,Glorius, Frank
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supporting information
p. 1448 - 1451
(2015/02/19)
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- Synthesis and photovoltaic properties of two new alkoxylphenyl substituted thieno[2,3-f]benzofuran based polymers
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Two new alkoxylphenyl substituted thieno[2,3-f]benzofuran (TBFP)-based polymers (PTBFP-BT and PTBFP-BO) were designed and synthesized. Their structures were verified by nuclear magnetic resonance (NMR) spectroscopy, the molecular weights were determined b
- Qiu, Beibei,Cui, Ruili,Yuan, Jun,Peng, Hongjian,Zhang, Zhiguo,Li, Yongfang,Zou, Yingping
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p. 17592 - 17600
(2015/07/07)
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- Rhodium-catalyzed C-H alkynylation of arenes at room temperature
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The rhodium(III)-catalyzed ortho C-H alkynylation of non-electronically activated arenes is disclosed. This process features a straightforward and highly effective protocol for the synthesis of functionalized alkynes and represents the first example of merging a hypervalent iodine reagent with rhodium(III) catalysis. Notably, this reaction proceeds at room temperature, tolerates a variety of functional groups, and more importantly, exhibits high selectivity for monoalkynylation. Hot rhod: A rhodium-catalyzed, electronically reversed Sonogashira reaction between unbiased arenes and the hypervalent iodine reagent 1 proceeds through C-H activation. This reaction displays excellent functional-group tolerance and high efficiency, and thus opens a new synthetic pathway to access functionalized alkynes. Cp=C5Me5, DCE=1,2-dichloroethane, Piv=pivaloyl, TIPS=triisopropylsilyl.
- Feng, Chao,Loh, Teck-Peng
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supporting information
p. 2722 - 2726
(2014/03/21)
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- C-H activation by amide chelation control: Ruthenium-catalyzed direct synthesis of 2-Aryl-3-furanamides
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A new, catalytic methodology for the synthesis of heterobiaryls by the ruthenium-catalyzed C-H activation/cross-coupling of heterocyclic amides with aryl boroneopentylates is surveyed. From this survey, the highly regioselective reaction of furan-3-carboxamide to give 2-aryl-3-furanamides is optimized and generalized in scope with respect to the aryl boroneopentylate coupling partners. Established thereby is a one-step synthetic method which may supercede the broadly applied two-step directed ortho metalation (DoM)-cross coupling reaction involving cryogenic and strong base conditions and which has potential for further ortho and remote metalation chemistry.
- Zhao, Yigang,Snieckus, Victor
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supporting information
p. 1527 - 1532
(2014/06/09)
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- Synthesis of C3-substituted enantiopure 2-(p-tolylsulfinyl)-furans: The sulfoxide group as a chiral inductor for furan dienes as precursors of a wide variety of chiral intermediates
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(-)-(1R,2S,5R)-Menthyl (SS)-p-toluenesulfinate and its enantiomer are a common source for a chiral sulfoxide group in organic synthesis, by means of nucleophilic substitution. The replacement of the menthyloxy group, with complete inversion of configuration at the sulfur center of the chiral sulfoxide, allows the inclusion of this organic function into numerous substrates, with defined stereochemistry and high enantiomeric purity. Nine C3-substituted, enantiomerically pure, 2-sulfinylfurans were prepared by this synthetic methodology with moderate to high yields. These enantiopure C3-substituted 2-sulfinylfurans can be used as chiral dienes for [4+3] cycloaddition reactions and in other chemical transformations, in which π-facial selectivity should be induced in order to obtain enantioselective reactions.
- Montana, Angel M.,Grima, Pedro M.,Batalla, Consuelo,Kociok-Koehn, Gabriele
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p. 677 - 689
(2014/05/20)
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- Copper-mediated ortho-nitration of (hetero)arenecarboxylates
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Various (hetero)arenecarboxylic acids were converted to the corresponding Daugulis amides and nitrated selectively in the ortho-position in the presence of [CuNO3(PPh3)2] and AgNO2 at 50 °C. A microwave-assisted saponification allows regenerating the carboxylate group within minutes, which may then be removed tracelessly by protodecarboxylation, or substituted by aryl- or alkoxy-groups via decarboxylative cross-coupling.
- Katayev, Dmitry,Pfister, Kai F.,Wendling, Timo,Goossen, Lukas J.
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supporting information
p. 9902 - 9905
(2014/08/18)
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- Mild rhodium(III)-catalyzed C-H allylation with 4-vinyl-1,3-dioxolan-2-ones: Direct and stereoselective synthesis of (E)-allylic alcohols
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A rhodium(III)-catalyzed C-H direct allylation reaction with 4-vinyl-1,3-dioxolan-2-ones has been developed. The reaction provides a facile and stereoselective access to substituted-(E)-allylic alcohols under mild and redox-neutral reaction conditions. Olefinic C-H activation is applicable, giving multifunctionalized skipped dienes in good yields. Minimal double-bond migration was observed.
- Zhang, Shang-Shi,Wu, Jia-Qiang,Lao, Ye-Xing,Liu, Xu-Ge,Liu, Yao,Lv, Wen-Xin,Tan, Dong-Hang,Zeng, Yao-Fu,Wang, Honggen
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supporting information
p. 6412 - 6415
(2015/01/09)
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- Dibenzosuberones as p38 mitogen-activated protein kinase inhibitors with low ATP competitiveness and outstanding whole blood activity
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p38α mitogen-activated protein (MAP) kinase is a main target in drug research concerning inflammatory diseases. Nevertheless, no inhibitor of p38α MAP kinase has been introduced to the market. This might be attributed to the fact that there is no inhibitor which combines outstanding activity in biological systems and selectivity. Herein an approach to the development of such inhibitors on the basis of the highly selective molecular probe Skepinone-L is described. Introduction of a "deep pocket" moiety addressing the DFG motif led to an increased activity of the compounds. Hydrophilic moieties, addressing the solvent-exposed area adjacent to hydrophilic region II, conserved a high activity of the compounds in a whole blood assay. Combined with their outstanding selectivity and low ATP competitiveness, these inhibitors are very interesting candidates for use in biological systems and in therapy.
- Fischer, Stefan,Wentsch, Heike K.,Mayer-Wrangowski, Svenja C.,Zimmermann, Markus,Bauer, Silke M.,Storch, Kirsten,Niess, Raimund,Koeberle, Solveigh C.,Grütter, Christian,Boeckler, Frank M.,Rauh, Daniel,Laufer, Stefan A.
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supporting information
p. 241 - 253
(2013/03/13)
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- Rapid entry into heterocycle-fused benzylic azepines and azocines via directed metallation/ring-closing metathesis
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The efficient synthesis of a range of heterocycle-fused benzylic azepine and azocine derivatives is reported, employing a directed metallation/ruthenium- catalysed ring-closing metathesis approach. A base-mediated tautomerisation approach can be used to access both the azepine and azocine derivatives from the same starting material.
- Moss, Thomas A.
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supporting information
p. 4254 - 4258
(2013/07/26)
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- Phenolic esters of O-desmethylvenlafaxine with improved Oral bioavailability and brain uptake
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O-Desmethylvenlafaxine (desvenlafaxine, ODV) is a recently approved antidepressant which in some clinical studies failed to meet a satisfactory end-point. The aim of this study was to prepare a series of phenolic esters of ODV and evaluate their potential as ODV prodrugs with improved brain uptake. Fifteen phenolic esters (compounds 1a-o) were synthesized and their pharmacokinetic profiles evaluated in rat. The four compounds producing the highest relative bioavailability of ODV in rat (compounds 1c, 1e, 1n, 1o) were then studied to evaluate their brain uptake. Of these four compounds, compound 1n (the piperonylic acid ester of ODV) demonstrated the highest Cmax of ODV both in the rat hypothalamus and total brain. Finally the pharmacokinetics of 1n were evaluated in beagle dog where the increase in relative bioavailability of ODV was found to be as great as in rat. This high relative bioavailability of ODV coupled with its good brain penetration make 1n the most promising candidate for development as an ODV prodrug.
- Zhang, Yang,Yang, Yan,Zhao, Sen,Yang, Zhichao,Yang, Hong,Fawcett, J. Paul,Li, Youxin,Gu, Jingkai,Sun, Tiemin
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p. 14920 - 14934
(2014/01/17)
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- Mild rhodium(III)-catalyzed C-H activation and intermolecular annulation with allenes
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All(enes) great! A novel RhIII-catalyzed oxidative coupling with allenes under mild conditions provides heterocycles with exocyclic double bonds. This reaction features low catalyst loadings, high regio- and stereoselectivity, and excellent substrate scope. The products were derivatized and preliminary mechanistic studies were conducted. Copyright
- Wang, Honggen,Glorius, Frank
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supporting information; experimental part
p. 7318 - 7322
(2012/09/08)
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- Decarbonylative C-H coupling of azoles and aryl esters: Unprecedented nickel catalysis and application to the synthesis of muscoride A
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A nickel-catalyzed decarbonylative C-H biaryl coupling of azoles and aryl esters is described. The newly developed catalytic system does not require the use of expensive metal catalysts or silver- or copper-based stoichiometric oxidants. We have successfully applied this new C-H arylation reaction to a convergent formal synthesis of muscoride A.
- Amaike, Kazuma,Muto, Kei,Yamaguchi, Junichiro,Itami, Kenichiro
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supporting information; experimental part
p. 13573 - 13576
(2012/10/08)
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- Synthesis and optoelectronic properties of novel benzodifuran semiconducting polymers
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Two new semiconducting polymers poly{4,8-bis(4-decylphenylethynyl)benzo[1, 2-b:4,5-b']difuran} (P1) and poly {4,8-bis(4-decylphenylethynyl)benzo[1,2-b:4,5- b']difuran-alt-4,8-bis(4-decylphenylethynyl)benzo[1,2-b:4,5-b']dithiophene} (P2) have been synthesi
- Sista, Prakash,Huang, Peishen,Gunathilake, Samodha S.,Bhatt, Mahesh P.,Kularatne, Ruvini S.,Stefan, Mihaela C.,Biewer, Michael C.
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p. 4316 - 4324
(2012/11/06)
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- Conjugated and nonconjugated substitution effect on photovoltaic properties of benzodifuran-based photovoltaic polymers
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In order to investigate the influence of two-dimensional (2D) conjugated structure on photovoltaic properties of benzo[1,2-b:4,5-b']difuran (BDF)-based polymers, two low band gap photovoltaic polymers, named PBDFTT-CF-O and PBDFTT-CF-T, were designed and synthesized. These two polymers have the same backbones and different side groups. Although these two polymers show similar optical band gaps (ca. 1.5 eV), the polymer with alkylthienyl side groups, PBDFTT-CF-T, exhibits stronger absorption in long wavelength direction than the polymer with alkoxyl side groups, PBDFTT-CF-O. Meanwhile, PBDFTT-CF-T exhibits a HOMO level of -5.21 eV, which is 0.23 eV lower than that of PBDFTT-CF-O due to weaker electron-donating ability of alkylthienyl side groups than that of aloxyl side groups. The hole mobility of the blend of PBDFTT-CF-T/PC71BM (1:1.5, w/w) is 0.128 cm2 V-1 s-1, which is 1 order of magnitude higher than that of the blend of PBDFTT-CF-O/PC 71BM. Density functional theory (DFT) model shows thiophene pendants on dithienyl-BDF are more coplanar than it on dithienyl-BDT. These results indicate that the 2D-conjugated structure is helpful for molecular structure design of the BDF-based polymers in enhancing the intermolecular π-π stacking and improving charge transport property. Furthermore, the photovoltaic devices based on these two polymers show similar short circuit density and fill factor values, while the open circuit voltage of the PBDFTT-CF-T-based device is 0.78 V, which is 0.15 V higher than that of the PBDFTT-CF-O-based device. Therefore, the efficiencies of the devices based PBDFTT-CF-T/PC71BM and PBDFTT-CF-O/PC71BM are 6.26% and 5.22%, respectively. The results in this work demonstrate that the weak electron-donating ability of alkylthienyl side groups can be seen as an effective strategy to improve photovoltaic properties of the BDF-based polymers and the 2D-conjugated molecular structure is favorable to improve hole mobility.
- Huo, Lijun,Ye, Long,Wu, Yue,Li, Zhaojun,Guo, Xia,Zhang, Maojie,Zhang, Shaoqing,Hou, Jianhui
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p. 6923 - 6929
(2012/11/07)
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- Cycloaddition of C-3 substituted furans. Stereoselectivity induced by coordination effects
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Several C-3 substituted furans with chelating groups have been reacted with 2,3-dibromo-3-pentanone in the presence of a reducing metal, resulting in the formation of [4+3]-cycloadducts with complete cis-trans and endo-exo diastereoselectivity and in excellent yield. A certain variability of the conversion and reaction yield could be observed, when changing the reaction conditions, but in all cases the stereoselectivity was complete, compared to that of C-3 substituted furans with non-chelating groups. Also, a general method of assignment of stereochemistry of cycloadducts has been established by NMR, considering diagnostic patterns of signals with different multiplicity and chemical shifts depending on the stereochemistry of diastereomeric cycloadducts.
- Montana, Angel M.,Castellvi, Maria,Batalla, Consuelo,Grima, Pedro M.,Font-Bardia, Merce
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p. 9982 - 9998,17
(2012/12/12)
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- Cycloaddition of C-3 substituted furans. Stereoselectivity induced by coordination effects
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Several C-3 substituted furans with chelating groups have been reacted with 2,3-dibromo-3-pentanone in the presence of a reducing metal, resulting in the formation of [4+3]-cycloadducts with complete cis-trans and endo-exo diastereoselectivity and in excellent yield. A certain variability of the conversion and reaction yield could be observed, when changing the reaction conditions, but in all cases the stereoselectivity was complete, compared to that of C-3 substituted furans with non-chelating groups. Also, a general method of assignment of stereochemistry of cycloadducts has been established by NMR, considering diagnostic patterns of signals with different multiplicity and chemical shifts depending on the stereochemistry of diastereomeric cycloadducts.
- Monta?a, ángel M.,Grima, Pedro M.,Castellví, María,Batalla, Consuelo,Font-Bardia, Mercè
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p. 9982 - 9998
(2013/01/14)
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- STAT3 INHIBITOR CONTAINING QUINOLINECARBOXAMIDE DERIVATIVE AS ACTIVE INGREDIENT
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The present invention provides a STAT3 inhibitor containing as an active ingredient, a quinolinecarboxamide derivative represented by the formula (I) (in the formula, W represents a bond or an alkylene chain; X represents O, S, or NR34; and Rs
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Page/Page column 60
(2011/06/24)
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- Synthesis and in vitro anticancer activity of 6,7-methylenedioxy (or 5-hydroxy-6-methoxy)-2-(substituted selenophenyl)quinolin-4-one analogs
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6,7-Methylenedioxy (or 5-hydroxy-6-methoxy)-2-(substituted selenophenyl)quinolin-4-ones and their isosteric compounds were synthesized and evaluated for anticancer activity. Structure-activity relationships (SAR) of these compounds were established. Among all tested compounds, 6,7-methylenedioxy-2-(5-methylselenophen-2-yl)quinolin-4-one (4d) was found to be the most promising anticancer agent. In screening against NCI's 60 human tumor cell line panel, 4d exhibited highly selective and potent inhibitory activity against MDA-MB-435 melanoma. Furthermore, the results of COMPARE analysis suggested that 4d is an antimitotic agent with a different mechanism of action from the conventional antimitotic agents, such as colchicine, vinca alkaloids and paclitaxel. Therefore, 4d was identified as a new lead compound that merits further optimization.
- Chen, Chien-Ting,Hsu, Mei-Hua,Cheng, Yung-Yi,Liu, Chin-Yu,Chou, Li-Chen,Huang, Li-Jiau,Wu, Tian-Shung,Yang, Xiaoming,Lee, Kuo-Hsiung,Kuo, Sheng-Chu
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experimental part
p. 6046 - 6056
(2012/02/05)
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- MELANOCORTIN RECEPTOR AGONISTS
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The present invention relates to a compound having a good agonistic activity to melanocortin receptor, or pharmaceutically acceptable salt or isomer thereof, and an agonistic composition for melanocortin receptor comprising the same as an active ingredient.
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Page/Page column 11
(2010/06/11)
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- MELANOCORTIN RECEPTOR AGONISTS
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The present invention relates to a compound having a good agonistic activity to melanocortin receptor, or pharmaceutically acceptable salt or isomer thereof, and an agonistic composition for melanocortin receptor comprising the same as an active ingredient.
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Page/Page column 24
(2010/06/15)
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- C-RING MODIFIED TRICYCLIC BENZONAPHTHIRIDINONE PROTEIN KINASE INHIBITORS AND USE THEREOF
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Disclosed are C-ring modified tricyclic benzonaphthiridinone compounds and analogs thereof, pharmaceutical compositions comprising such compounds and processes for preparing the same. The compounds are useful in the treatment of diseases amenable to prote
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Page/Page column 66-67
(2010/08/04)
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- Synthesis of novel furo-, thieno-, and pyrroloazepines
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The synthesis of novel furo-, thieno-, and pyrroloazepine compounds, using the oxidative radical alkylation of three five-membered heterocyclic 3-acetic acid derivatives, is described. The bicyclic systems were obtained, via a small number of steps, directly from commercially available materials. Georg Thieme Verlag Stuttgart New York.
- Villarreal, Carlos,Martinez, Roberto
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experimental part
p. 3346 - 3352
(2010/11/17)
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- Design and synthesis of 2-arylbenzimidazoles and evaluation of their inhibitory effect against Chlamydia pneumoniae
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Chlamydia pneumoniae is an intracellular bacterium that responds poorly to antibiotic treatment. Insufficient antibiotic usage leads to chronic infection, which is linked to disease processes of asthma, atherosclerosis, and Alzheimer's disease. The Chlamydia research lacks genetic tools exploited by other antimicrobial research, and thus other approaches to drug discovery must be applied. A set of 2-arylbenzimidazoles was designed based on our earlier findings, and 33 derivatives were synthesized. Derivatives were assayed against C. pneumoniae strain CWL-029 in an acute infection model using TR-FIA method at a concentration of 10 μM, and the effects of the derivatives on the host cell viability were evaluated at the same concentration. Fourteen compounds showed at least 80% inhibition, with only minor changes in host cell viability. Nine most potential compounds were evaluated using immunofluorescence microscopy on two different strains of C. pneumoniae CWL-029 and CV-6. The N-[3-(1H-benzimidazol-2-yl)phenyl]-3-methylbenzamide (42) had minimal inhibitory concentration (MIC) of 10 μM against CWL-029 and 6.3 μM against the clinical strain CV-6. This study shows the high antichlamydial potential of 2-arylbenzimidazoles, which also seem to have good characteristics for lead compounds.
- Keurulainen, Leena,Salin, Olli,Siiskonen, Antti,Kern, Jan Marco,Alvesalo, Joni,Kiuru, Paula,Maass, Matthias,Yli-Kauhaluoma, Jari,Vuorela, Pia
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supporting information; experimental part
p. 7664 - 7674
(2011/03/17)
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- Aroylguanidine-based factor Xa inhibitors: The discovery of BMS-344577
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We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC50 = 4 nM, EC2×PT = 7 μM). However, the potent CYP3A4 inhibition activity (IC50 = 0.3 μM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC50 = 9 nM, EC2×PT = 2.5 μM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
- Shi, Yan,Li, Chi,O'Connor, Stephen P.,Zhang, Jing,Shi, Mengxiao,Bisaha, Sharon N.,Wang, Ying,Sitkoff, Doree,Pudzianowski, Andrew T.,Huang, Christine,Klei, Herbert E.,Kish, Kevin,Yanchunas Jr., Joseph,Liu, Eddie C.-K.,Hartl, Karen S.,Seiler, Steve M.,Steinbacher, Thomas E.,Schumacher, William A.,Atwal, Karnail S.,Stein, Philip D.
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scheme or table
p. 6882 - 6889
(2010/07/03)
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- MELANOCORTIN RECEPTOR AGONISTS
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The present invention relates to a compound of the following formula 1, pharmaceutically acceptable salt and isomer thereof effective as agonist of melanocortin receptor, and an agonistic composition of melanocortin receptor comprising the same as active ingredient.
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Page/Page column 31
(2008/06/13)
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- Electron-rich heteroaroylphosphonates and their reaction with trimethyl phosphite
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Dialkyl heteroaroylphosphonates based on thiophene, pyrrole or furan have been prepared and their reactions with trimethyl phosphite investigated. Deoxygenation of the carbonyl groups in these heteroaroylphosphonates occurs to give carbene intermediates, which then undergo further reaction. In the case of the furan-3-oylphosphonates and those systems containing a thiophene or pyrrole ring, the major reaction pathway involves intermolecular trapping of the carbene intermediates by the trimethyl phosphite, leading to the formation of ylidic phosphonates that can be readily converted into the corresponding 1,1-bisphosphonates. However, in some furan-2-oylphosphonates the carbenes generated undergo ring-opening to initially give acyclic alkynylphosphonates which may react further to give other novel phosphorus compounds. The effects of substituents on the extent to which intermolecular trapping of the initially formed carbene competes with intramolecular rearrangement has been investigated. The latter process appears to be suppressed by a substituent at the 5-position of the furan ring, the resulting ylidic phosphonates being a rare example of an efficient intermolecular trapping of a furan-2-yl carbene. The Royal Society of Chemistry 2008.
- Griffiths, D. Vaughan,Al-Jeboori, Mohamad J.,Cheong, Yuen-Ki,Duncanson, Philip,Harris, Jayne E.,Salt, Michael C.,Taylor, Helen V.
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supporting information; experimental part
p. 577 - 585
(2008/10/09)
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- QUINOLONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS
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The present invention relates to novel quinolones of Formula I that inhibit inducible NOS synthase together with methods of synthesizing and using the compounds including methods for inhibiting or modulating nitric oxide synthesis and/or lowering nitric oxide levels in a patient by administering the compounds for the treatment of disease.
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Page/Page column 29
(2008/12/06)
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- Design, synthesis, and evaluation of inhibitors for severe acute respiratory syndrome 3C-like protease based on phthalhydrazide ketones or heteroaromatic esters
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The 3C-like protease (3CLpro), which controls the severe acute respiratory syndrome (SARS) coronavirus replication, has been identified as a potential target for drug design in the treatment of SARS. A series of tetrapeptide phthalhydrazide ketones, pyridinyl esters, and their analogs have been designed, synthesized, and evaluated as potential SARS 3CLpro inhibitors. Some pyridinyl esters are identified as very potent inhibitors, with IC50 values in the nanomolar range (50-65 nM). Electrospray mass spectrometry indicates a mechanism involving acylation of the active site cysteine thiol for this class of inhibitors.
- Zhang, Jianmin,Pettersson, Hanna I.,Huitema, Carly,Niu, Chunying,Yin, Jiang,James, Michael N. G.,Eltis, Lindsay D.,Vederas, John C.
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p. 1850 - 1864
(2008/02/02)
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- Copper-catalysed intramolecular O-arylation of aryl chlorides and bromides: a straightforward approach to benzo[d]oxazoles in water
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A general, efficient and more sustainable protocol for the copper-catalysed intramolecular O-arylation of o′-haloanilides leading to the benzo[d]oxazole core is reported. Remarkably, the optimised conditions allowed for the use of inexpensive and easily available aryl chlorides as arylating agents. Moreover, all reactions were carried out employing exclusively water as the solvent, rendering the methodology presented herein highly valuable from both environmental and economic points of view.
- Barbero, Nekane,Carril, Mónica,SanMartin, Raul,Domínguez, Esther
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p. 10425 - 10432
(2008/02/12)
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- THIAZOLIDINONES, OXAZOLIDINONES, AND PYRROLIDINONES FOR HBV
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The present invention relates to certain single-enantiomer pyrrazol-4-yl derivatives of thiazolidinones, oxazolidinones, and pyrrolidinones which are useful in the treatment of Hepatitis B virus.
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Page/Page column 24
(2010/11/25)
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