- Stereoselective formation of eight-membered rings by radical cyclization of silylenedioxy-tethered bis-methacrylate derivatives
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Radical-initiated addition of CCl4, Cl3CBr, PhSH, and (TMS)3SiH to (bisisopropyl)silylenedioxy-tethered bis-methacrylate derivatives gives the corresponding eight-membered ring cyclic adducts stereoselectively. Hydrolysis
- Meng, Fan-Yi,Huang, Shou-Ling,Liu, Yi-Hung,Hu, Ziqiang,Lai, Guoqiao,Luh, Tien-Yau
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Read Online
- Asymmetric Total Synthesis of (-)-Spirochensilide A
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An asymmetric total synthesis of (-)-spirochensilide A has been achieved for the first time. The synthesis features a semipinacol rearrangement reaction to stereoselectively construct the two-vicinal quaternary chiral centers at C8 and C10, a tungsten-med
- Liang, Xin-Ting,Chen, Jia-Hua,Yang, Zhen
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Read Online
- Macrocycle embrace: Encapsulation of fluoroarenes by m-phenylene ethynylene host
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We report structural characterization of a new member of m-phenylene ethynylene ring family. This shape-persistent macrocycle also co-crystallizes with hexafluoro-, 1,2,4,5-tetrafluoro-, 1,3,5-trifluoro, and 1,4-difluorobenzene. The four complexes are alm
- Popov, Ilya,Chen, Teng-Hao,Belyakov, Sergey,Daugulis, Olafs,Wheeler, Steven E.,Miljani, Ognjen .
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Read Online
- Staphylococcus aureus rnpa inhibitors: Computational-guided design, synthesis and initial biological evaluation
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Antibiotic resistance is spreading worldwide and it has become one of the most important issues in modern medicine. In this context, the bacterial RNA degradation and processing machinery are essential processes for bacterial viability that may be exploited for antimicrobial therapy. In Staphylococcus aureus, RnpA has been hypothesized to be one of the main players in these mech-anisms. S. aureus RnpA is able to modulate mRNA degradation and complex with a ribozyme (rnpB), facilitating ptRNA maturation. Corresponding small molecule screening campaigns have recently identified a few classes of RnpA inhibitors, and their structure activity relationship (SAR) has only been partially explored. Accordingly, in the present work, using computational modeling of S. aureus RnpA we identified putative crucial interactions of known RnpA inhibitors, and we used this information to design, synthesize, and biologically assess new potential RnpA inhibitors. The present results may be beneficial for the overall knowledge about RnpA inhibitors belonging to both RNPA2000-like thiosemicarbazides and JC-like piperidine carboxamides molecular classes. We evaluated the importance of the different key moieties, such as the dichlorophenyl and the piperidine of JC2, and the semithiocarbazide, the furan, and the i-propylphenyl ring of RNPA2000. Our efforts could provide a foundation for further computational-guided investigations.
- Suigo, Lorenzo,Chojnacki, Michaelle,Zanotto, Carlo,Sebastián-Pérez, Victor,Morghen, Carlo De Giuli,Casiraghi, Andrea,Dunman, Paul M.,Valoti, Ermanno,Straniero, Valentina
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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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- Organocatalytic Nitroaldol Reaction Associated with Deuterium-Labeling
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A deuterium-labeling reaction of nitroalkanes in deuterium oxide and the subsequent nitroaldol reaction have been accomplished under basic and organocatalytic conditions to provide the deuterium-labeled β-nitroalcohols in high yields and high deuterium contents. β-Deuterated β-nitroalcohols could be smoothly obtained from the reaction of nitroalkanes and various electrophiles using the easily-removal basic resin WA30. Furthermore, the asymmetric nitroaldol reaction using nitromethane and α-keto esters as electrophiles in the presence of a quinine-derived organocatalyst in deuterium oxide could provide the desired β-deuterated nitroalcohol derivatives with high enantioselectivities. (Figure presented.).
- Yamada, Tsuyoshi,Kuwata, Marina,Takakura, Ryoya,Monguchi, Yasunari,Sajiki, Hironao,Sawama, Yoshinari
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supporting information
p. 637 - 641
(2017/12/13)
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- Hydroxybiphenylamide GroEL/ES Inhibitors Are Potent Antibacterials against Planktonic and Biofilm Forms of Staphylococcus aureus
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We recently reported the identification of a GroEL/ES inhibitor (1, N-(4-(benzo[d]thiazol-2-ylthio)-3-chlorophenyl)-3,5-dibromo-2-hydroxybenzamide) that exhibited in vitro antibacterial effects against Staphylococcus aureus comparable to vancomycin, an antibiotic of last resort. To follow up, we have synthesized 43 compound 1 analogs to determine the most effective functional groups of the scaffold for inhibiting GroEL/ES and killing bacteria. Our results identified that the benzothiazole and hydroxyl groups are important for inhibiting GroEL/ES-mediated folding functions, with the hydroxyl essential for antibacterial effects. Several analogs exhibited >50-fold selectivity indices between antibacterial efficacy and cytotoxicity to human liver and kidney cells in cell culture. We found that MRSA was not able to easily generate acute resistance to lead inhibitors in a gain-of-resistance assay and that lead inhibitors were able to permeate through established S. aureus biofilms and maintain their bactericidal effects.
- Kunkle, Trent,Abdeen, Sanofar,Salim, Nilshad,Ray, Anne-Marie,Stevens, McKayla,Ambrose, Andrew J.,Victorino, José,Park, Yangshin,Hoang, Quyen Q.,Chapman, Eli,Johnson, Steven M.
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supporting information
p. 10651 - 10664
(2019/01/04)
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- COMPOSITIONS AND METHODS FOR INHIBITION OF CATHEPSINS
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This present disclosure is directed to compound of Formula I and methods of using these compounds in the treatment of conditions in which modulation of a cathepsin, particularly cathepsin L, cathepsin K, and/or cathepsin B, will be therapeutically useful.
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Paragraph 0216; 0217
(2017/03/14)
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- Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L
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The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic ca
- Parker, Erica N.,Odutola, Samuel O.,Wang, Yifan,Strecker, Tracy E.,Mukherjee, Rajeswari,Shi, Zhe,Chaplin, David J.,Trawick, Mary Lynn,Pinney, Kevin G.
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supporting information
p. 1304 - 1310
(2017/06/19)
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- METHYLAMINE DERIVATIVES AS LYSYSL OXIDASE INHIBITORS FOR THE TREATMENT OF CANCER
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Provided are compounds of the Formula (I), or a pharmaceutically acceptable salt thereof, wherein W, X, Y, Z, x, R1, R2, R3, x and n are defined in the specification. The compounds are inhibitors of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) family members (LOXL1, LOXL2, LOXL3, LOXL4) and are useful in therapy, particularly in the treatment of cancer. Also disclosed are LOX inhibitors for use in the treatment of a cancer associated with EGFR and biomarkers that predict responsiveness to a LOX inhibitor.
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Paragraph 00884
(2017/09/08)
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- From propargylic amides to functionalized oxazoles: Domino gold catalysis/oxidation by dioxygen
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A new, highly efficient, and atom-economic access to a series of functionalized 2,5-disubstituted oxazoles from propargylic amides is reported. A series of propargylic amides were transformed to the corresponding alkylideneoxazolines by a gold(I) catalyst. The next step was an autoxidation to hydroperoxides bearing the heteroaromatic oxazoles. Experiments addressing the reaction mechanism reveal a radical pathway for this autoxidation process. The hydroperoxides could conveniently be converted to the corresponding alcohols by reduction with sodium borohydride.
- Hashmi, A. Stephen K.,Blanco Jaimes, Maria Camila,Schuster, Andreas M.,Rominger, Frank
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experimental part
p. 6394 - 6408
(2012/09/22)
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- Potent mGluR5 antagonists: Pyridyl and thiazolyl-ethynyl-3,5-disubstituted- phenyl series
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We report the synthesis of four series of 3,5-disubstituted-phenyl ligands targeting the metabotropic glutamate receptor subtype 5: (2-methylthiazol-4-yl) ethynyl (1a-j,), (6-methylpyridin-2-yl)ethynyl (2a-j), (5-methylpyridin-2-yl) ethynyl (3a-j,), and (pyridin-2-yl)ethynyl (4a-j,). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro assay. All compounds were found to be full antagonists and exhibited low nanomolar to subnanomolar activity.
- Alagille, David,Dacosta, Herve,Chen, Yelin,Hemstapat, Kamondanai,Rodriguez, Alice,Baldwin, Ronald M.,Conn, Jeffrey P.,Tamagnan, Gilles D.
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supporting information; experimental part
p. 3243 - 3247
(2011/07/07)
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- FUSED PYRAZINE DERIVATIVES AS KINASE INHIBITORS
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A series of quinoxaline derivatives, and analogues thereof, which are functionalised further by a substituted phenyl or pyridinyl moiety, being selective inhibitors of PO kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
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Page/Page column 38
(2010/06/11)
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- Toward optimization of the second aryl substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies
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Transthyretin (TTR) amyloidogenesis inhibitors are typically composed of two aromatic rings and a linker. We have previously established optimal structures for one aromatic ring and the linker. Herein, we employ a suboptimal linker and an optimal aryl-X substructure to rank order the desirability of aryl-Z substructures-using a library of 56 N-(3,5-dibromo-4-hydroxyphenyl) benzamides. Coconsideration of amyloid inhibition potency and ex vivo plasma TTR binding selectivity data reveal that 2,6, 2,5, 2, 3,4,5, and 3,5 substituted aryls bearing small substituents generate the most potent and selective inhibitors, in descending order. These benzamides generally lack undesirable thyroid hormone receptor binding and COX-1 inhibition activity. Three high-resolution TTR ? inhibitor crystal structures (1.31-1.35 ?) provide insight into why these inhibitors are potent and selective, enabling future structure-based design of TTR kinetic stabilizers.
- Johnson, Steven M.,Connelly, Stephen,Wilson, Ian A.,Kelly, Jeffery W.
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supporting information; experimental part
p. 1115 - 1125
(2009/12/24)
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- Novel process and intermediates 085
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The present invention relates to a novel process suitable for large-scale production of phenyl propane derivatives as well as to novel intermediates in the process.
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Page/Page column 9
(2010/11/29)
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- Hyperbranched oxadiazole-containing polyfluorenes: Toward stable blue light PLEDs
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The synthesis of hyperbranched oxadiazole-containg polyfluores using 'A2 + A2′ + B3' approach based on Suzuki polycondensation was investigated. The molecular structures of the sample polymer were characterized with high-resolution NMR spectroscopy and elemental analysis. The solubility was found to be poor in organic solvents for hyperbranched polymers with higher contents of 2-(4-bromophenyl)-5-(3,5-dibromophenyl)-1,3,4-oxadiazole monomer. The sample polyfluores showed stable blue light emission even after being annealed in the elevated temperatures in the N2 and air.
- Xin, Yu,Wen, Gui-An,Zeng, Wen-Jing,Zhao, Lei,Zhu, Xing-Rong,Fan, Qu-Li,Feng, Jia-Chun,Wang, Lian-Hui,Wei, Wei,Peng, Bo,Cao, Yong,Huang, Wei
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p. 6755 - 6758
(2007/10/03)
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- Marine Bacteria, I. - Synthesis of Pentabromopseudiline, a Cytotoxic Phenylpyrrole from Alteromonas luteo-violaceus
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A new synthesis of 2,3,4-tribromo-5-(3,5-dibromo-2-hydroxyphenyl)pyrrole (1a, pentabromopseudiline), an antibiotic, enzymeinhibitory and cytotoxic active constituent of the marine bacterium Alteromonas luteo-violaceus, is described.For investigation of structure-activity relationships further 2-phenylpyrroles are investigated.Key step in their synthesis is the Grignard reaction of 2-(1,3-dioxan-2-yl)ethylmagnesium bromide (9d) with benzoyl chlorides yielding γ-phenyl-γ-ketoaldehydes 24, and the Paal-Knorr cyclisation of the latter. - Key Words: Alteromonas luteo-violaceus / Bromopyrrole / Marine bacteria / Pentabromopseudiline
- Laatsch, Hartmut,Pudleiner, Heinz
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p. 863 - 882
(2007/10/02)
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- Substitution Reactions of Phenylated Aza-Heterocycles. Part 2. Bromination of Some 2,5-Diaryl-1,3,4-oxadiazoles
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Electrophilic bromination of the title compounds may be achieved using either bromine in oleum, or bromine and potassium bromate in a sulphuric-acetic acid mixture.Under the milder reaction conditions provided by the latter, 2-(p-nitrophenyl)-5-phenyl-1,3,4-oxadiazole (2), the model compound used in this study, is mono- and di-brominated in the phenyl ring.In the first bromination step, all three monobromo-isomers are produced in appreciable amount.The orientation of the second bromination is controlled entirely by the first bromine and not by the oxadiazole substituent: this is confirmed by a separate study of the bromination of the three monobromo-compounds (3a-3c).
- Blackhall, Alexander,Brydon, Donald L.,Javaid, Khalid,Sagar, Anthony J. G.,Smith, David M.
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p. 3485 - 3497
(2007/10/02)
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- Diester of 3,5,3',5'-tetrabromo-bisphenol A with halogenated aromatic carboxylic acid
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A novel diester compound of the formula (I): STR1 wherein each of R1 and R2 represents a group of the formula (II): STR2 wherein n is an integer of 0 to 4; and m an integer of 1 to 5, is found to be capable of imparting excellent flame-retardancy to various inflammable polymeric materials such as polystyrene, polyester, polyamide, polyphenylene oxide, etc. without deleterious effects on other physical properties of such polymeric materials.
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