- Live-Cell Localization Microscopy with a Fluorogenic and Self-Blinking Tetrazine Probe
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Recent developments in fluorescence microscopy call for novel small-molecule-based labels with multiple functionalities to satisfy different experimental requirements. A current limitation in the advancement of live-cell single-molecule localization micro
- Werther, Philipp,Yserentant, Klaus,Braun, Felix,Kaltwasser, Nicolai,Popp, Christoph,Baalmann, Mathis,Herten, Dirk-Peter,Wombacher, Richard
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Read Online
- Synthesis of 8-bromo-5,12-tetracenequinone and 2-bromotetracene derivatives
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A series of bromotetracenequinones 1 and bromotetracenes 2 were prepared from 4-bromophthalic anhydride. The parent tetracenequinone 1a and tetracene 2a were sparingly soluble in organic solvents. In contrast, dipropyl-substituted tetracenequinone 1b and
- Kitamura, Chitoshi,Taka, Naohiro,Kawase, Takeshi
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Read Online
- CYCLIC PEPTIDE ANALOGS OF MELANOCORTIN AND AMANITIN AND METHODS OF MAKING SUCH
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The invention described herein is based in part on the discovery of a protein/peptide crosslink, which introduces fluorescent properties, and which has been applied to synthesize analogues of melanocortin and amanitin as choice peptides to be explored in the context of isoindole peptides. Without limitation, it is expected that those trained in the art of peptide synthesis and stapling would appreciate the consequences of this invention such that other peptides of varied length can be similarly constrained by isoindole staples as featured herein.
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Paragraph 0114; 0116-0117; 0123
(2021/01/29)
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- Structure-Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens
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Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure-activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, including polymyxin- and carbapenem-resistant strains.
- Wesseling, Charlotte M. J.,Slingerland, Cornelis J.,Veraar, Shanice,Lok, Samantha,Martin, Nathaniel I.
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p. 3314 - 3335
(2021/11/24)
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- IDO/TDO Inhibitor
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A compound of formula (I) given below or a pharmaceutically acceptable salt of the compound is useful as an IDO/TDO inhibitor. Thus, the compound of formula (I) or the pharmaceutically acceptable salt of the compound can be used as, for example, a therapeutic agent for a disease or a disorder selected from tumor, infectious disease, neurodegenerative disorder, cataract, organ transplant rejection, autoimmune disease, postoperative cognitive impairment, and disease related to women's reproductive health [in the following formula (I), ring A represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from an aromatic ring, an aliphatic ring and a heterocyclic ring; X, R1 and R2 represent a substituent on a ring atom constituting ring A; m represents an integer of 0 to 6; X represents, for example, a halogen atom; and R1 and R2 are the same or different and are selected from, for example, the group consisting of groups of formula (a) or formula (b); and in the following formula (a) and formula (b), Y is selected from the group consisting of O, S, and Se, Z is selected from the group consisting of O, S, and Se, n represents an integer of 1 to 8, r represents an integer of 1 to 8, s represents an integer of 1 to 8, R4 represents, for example, —C(═NH)—HN2, and R6 represents, for example, a substituted or unsubstituted aryl group].
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Paragraph 0334-0336; 0384; 0385
(2020/08/19)
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- Optimization of Orally Bioavailable PI3KδInhibitors and Identification of Vps34 as a Key Selectivity Target
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Optimization of a lead series of PI3Kδinhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδover Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.
- Henley, Zo? A.,Amour, Augustin,Barton, Nick,Bantscheff, Marcus,Bergamini, Giovanna,Bertrand, Sophie M.,Convery, Máire,Down, Kenneth,Dümpelfeld, Birgit,Edwards, Chris D.,Grandi, Paola,Gore, Paul M.,Keeling, Steve,Livia, Stefano,Mallett, David,Maxwell, Aoife,Price, Mark,Rau, Christina,Reinhard, Friedrich B. M.,Rowedder, James,Rowland, Paul,Taylor, Jonathan A.,Thomas, Daniel A.,Hessel, Edith M.,Hamblin, J. Nicole
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p. 638 - 655
(2020/02/04)
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- FlICk (fluorescent isoindole crosslinking) for peptide stapling
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The rigidification of peptide secondary structure via stapling is an important and enduring goal in the development of functional peptides for biochemical and pharmaceutical applications. In addition, the incorporation of fluorophores and chromophores has
- Todorovic, Mihajlo,Perrin, David M.
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p. 313 - 332
(2020/05/18)
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- Fluorescent Isoindole Crosslink (FlICk) Chemistry: A Rapid, User-friendly Stapling Reaction
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The stabilization of peptide secondary structure via stapling is a ubiquitous goal for creating new probes, imaging agents, and drugs. Inspired by indole-derived crosslinks found in natural peptide toxins, we employed ortho-phthalaldehydes to create isoindole staples, thus transforming inactive linear and monocyclic precursors into bioactive monocyclic and bicyclic products. Mild, metal-free conditions give an array of macrocyclic α-melanocyte-stimulating hormone (α-MSH) derivatives, of which several isoindole-stapled α-MSH analogues (Ki≈1 nm) are found to be as potent as α-MSH. Analogously, late-stage intra-annular isoindole stapling furnished a bicyclic peptide mimic of α-amanitin that is cytotoxic to CHO cells (IC50=70 μm). Given its user-friendliness, we have termed this approach FlICk (fluorescent isoindole crosslink) chemistry.
- Todorovic, Mihajlo,Schwab, Katerina D.,Zeisler, Jutta,Zhang, Chengcheng,Bénard, Francois,Perrin, David M.
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p. 14120 - 14124
(2019/07/31)
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- Platinum-on-Carbon-Catalyzed Aqueous Oxidative Lactonization of Diols by Using Molecular Oxygen
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A lactonization of various diols catalyzed by platinum on carbon (Pt/C) in water under an atmosphere of molecular oxygen was developed. Derivatives of 1,4- 1,5- and 1,6-diols were transformed into the corresponding five-, six-, and seven-membered lactones by the present oxidative lactonization method.
- Ban, Kazuho,Sajiki, Hironao,Sawama, Yoshinari,Takakura, Ryoya
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supporting information
p. 1919 - 1923
(2019/09/30)
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- Site-Selective Functionalization of (sp3)C?H Bonds Catalyzed by Artificial Metalloenzymes Containing an Iridium-Porphyrin Cofactor
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The selective functionalization of one C?H bond over others in nearly identical steric and electronic environments can facilitate the construction of complex molecules. We report site-selective functionalizations of C?H bonds, differentiated solely by rem
- Gu, Yang,Natoli, Sean N.,Liu, Zhennan,Clark, Douglas S.,Hartwig, John F.
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supporting information
p. 13954 - 13960
(2019/08/30)
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- Assessment of the regioselectivity in the condensation reaction of unsymmetrical o-phthaldialdehydes with alanine
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One approach for the synthesis of isoindolinones, a privileged bioactive heterocyclic core structure, involves a condensation reaction of o-phthaldialdehydes with a suitable nitrogen-containing nucleophile. This fascinating reaction is revisited here in the context of the use of o-phthaldialdehydes that contain additional substituents in the aromatic ring leading to a detailed analysis of the regioselectivity of the reaction. Eleven monosubstituted o-phthaldialdehydes were synthesised and reacted with alanine. The regioselectivity observed across the eleven substrates led to the design of a disubstituted substrate that reacted with very high control. A gram-scale reaction followed by esterification gave one major regioisomer in high yield. In addition, the regioselectivity observed on reaction of two novel monodeuterated substrates led to an increased mechanistic understanding.
- D'Hollander, Agathe C.A.,Westwood, Nicholas J.
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supporting information
p. 224 - 239
(2017/12/08)
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- ISOQUINOLINE DERIVATIVES AS PERK INHIBITORS
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The invention is directed to substituted isoquinoline derivatives and uses thereof. Specifically, the invention is directed to compounds according to Formula I and the use of compounds of Formula (I) in treating disease states: (I) wherein R1,
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Page/Page column 84
(2018/02/17)
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- PYRAZOLE COMPOUNDS AND METHODS OF MAKING AND USING SAME
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Provided herein are pyrazole compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of MAGL and/or ABHD6. Furthermore, the subject compounds and compositions are useful for the treatment of, for example, pain.
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Page/Page column 00315
(2017/06/12)
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- SPIROCYCLE COMPOUNDS AND METHODS OF MAKING AND USING SAME
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Provided herein are spirocycle compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of MAGL and/or ABHD6. Furthermore, the subject compounds and compositions are useful for the treatment of pain.
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Paragraph 00377
(2017/12/01)
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- Hydrogenation of Esters to Alcohols Catalyzed by Defined Manganese Pincer Complexes
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The first manganese-catalyzed hydrogenation of esters to alcohols has been developed. The combination of Mn(CO)5Br with [HN(CH2CH2P(Et)2)2] leads to a mixture of cationic and neutral Mn PNP pincer complexes, which enable the reduction of various ester substrates, including aromatic and aliphatic esters as well as diesters and lactones. Notably, related pincer complexes with isopropyl or cyclohexyl substituents showed very low activity.
- Elangovan, Saravanakumar,Garbe, Marcel,Jiao, Haijun,Spannenberg, Anke,Junge, Kathrin,Beller, Matthias
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supporting information
p. 15364 - 15368
(2016/12/03)
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- Enantio- and diastereoselective synthesis of highly substituted benzazepines by a multicomponent strategy coupled with organocatalytic and enzymatic procedures
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Enantiomerically pure 4,5-dihydro-1H-benzo[c]azepines with three contiguous stereogenic centers have been assembled by convergent strategy with a good control of diastereoselectivity. The two steps are as follows: an asymmetric organocatalytic Mannich reaction performed on Boc-imines of o-(azidomethyl) benzaldehydes, followed by a one-pot Staudinger/aza-Wittig/Ugi-Joullie sequence. The latter reaction represents one of the first examples of diastereoselective Ugi three-component reaction on a seven-membered cyclic imine. The o-azidomethylbenzaldehydes have been synthesized employing a simple and efficient chemoenzymatic strategy from commercially available building blocks.
- Moni, Lisa,Banfi, Luca,Basso, Andrea,Galatini, Andrea,Spallarossa, Martina,Riva, Renata
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p. 339 - 351
(2014/01/17)
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- Synthesis and preliminary biological evaluation of new antiproliferative aromatic analogues of 1α,25-dihydroxyvitamin D3
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In an effort to develop novel vitamin D3 analogues, a series of aromatic compounds was synthetized, using efficient Negishi cross coupling between alkenylzinc reagents of the C,D-ring moiety of vitamin D3, and various substituted aromatic halides as A-ring mimics. The study aimed at exploring the influence of the replacement of the original vitamin D3 diene by a styrene unit on the biological activities. Potency in the induction of the differentiation of HL-60 cells for the lead compound 36 was 12 fold less important than calcitriol correlating with a weaker binding affinity for VDR.
- Thomas, Emmanuel,Brion, Jean-Daniel,Peyrat, Jean-Fran?ois
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p. 381 - 393
(2014/11/07)
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- Immobilized 1,2-bis(guanidinoalkyl)benzenes: Potentially useful for the purification of arsenic-polluted water
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Guanidines can act as ligands for various organic and inorganic ions. We have previously synthesized polymer-supported aromatic bisguanidine derivatives and evaluated their potential for removing arsenic from polluted water. In this work, we designed and
- Suzuki, Noriyuki,Kishimoto, Kaito,Yamazaki, Kohei,Kumamoto, Takuya,Ishikawa, Tsutomu,Margeti?, Davor
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supporting information
p. 2510 - 2514
(2013/12/04)
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- Selective lithiation of 4- and 5-halophthalans
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The reaction of 4- and 5-halophthalans 5 with lithium and a catalytic amount of DTBB at -78 °C leads to the formation of the corresponding functionalized organolithium intermediates 6 and 11, which by reaction with carbonyl compounds give, after hydrolysis, the expected substituted phthalans 8 and 13, respectively. When after reaction with the carbonyl compound the system is allowed to react at 0 °C, a second lithiation occur: A reductive opening of the heterocycle takes place with some regioselectivity leading to new organolithium intermediates 9 and 14/15 that by reaction with electrophiles lead, after hydrolysis, to polyfunctionalized molecules 10 and 16/17, respectively.
- Garcia, Daniel,Foubelo, Francisco,Yus, Miguel
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experimental part
p. 991 - 1005
(2010/10/03)
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- AMINO ACID COMPOUNDS
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[Problem] To provide novel compounds that are S1P1 receptor agonists and exhibit an immunosuppressive activities by inducing lymphocyte sequestration in secondary lymphoid tissues. In addition, to provide a pharmaceutical agent which comprises the compounds as an effective component, in particular to provide a therapeutic and/or prophylactic agent for an autoimmune disease and the like. [Solving Means] Amino acid compounds that are represented by the following Formula (1) are provided
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Page/Page column 49
(2009/12/23)
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- USE OF TRIFLUOROMETHYL SUBSTITUTED BENZAMIDES IN THE TREATMENT OF NEUROLOGICAL DISORDERS
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The invention relates to methods of using the compounds of the invention, including trifluoromethyl substituted benzamide compounds and salts thereof, as well as pharmaceutical compositions comprising the same, in the treatment of Eph receptor-related (e.g., neurological) injuries and disorders. The invention also relates to modulating the activity of an Eph receptor in a cell, stimulating neural regeneration, and reversing neuronal degeneration, by administering a compound of the invention to a cell or subject in an effective amount.
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Page/Page column 41
(2008/06/13)
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- COORDINATION METAL COMPOUND, MATERIAL FOR ORGANIC ELECTROLUMINESCENCE DEVICE, MATERIAL FOR LUMINESCENT COATING FORMATION AND ORGANIC ELECTROLUMINESCENCE DEVICE
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A coordination metal compound comprising cordinating at least one ligand having a spiro bond to at least a metal atom; a material for an organic electroluminescence (EL) device, and an organic EL device comprising at least one organic thin film layer sandwiched between a pair of electrodes consisting of an anode and a cathode, wherein at least one organic thin film layer thereof comprises the coordination metal compound or the material for an organic EL device, and a material for luminescence coating formation comprising an organic solvent solution containing the coordination metal compound or the material for the organic EL device is provided. Further, the organic EL device employing either the material for luminescence coating formation or the material for the organic EL device, which exhibits an enhanced efficiency of light emission and is superior in heat resistance, the coordination metal compound having excellent solubility for an organic solvent which realizes the aforementioned, the material for the organic EL device and the material for luminescence coating formation are provided.
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Page/Page column 100
(2010/11/30)
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- Trifluoromethyl substituted benzamides as kinase inhibitors
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The invention relates to trifluoromethyl substituted benzamide compounds of the formula I, pharmaceuticals comprising these compounds, their use as or for the manufacture of pharmaceuticals, particularly as inhibitors of protein kinases, especially of ephrin receptor kinases, and/or the treatment of a condition, disorder or disease state mediated by a protein kinase activity and/or a proliferative disease, methods of treatment comprising administering the compounds, especially of therapeutic and prophylactic treatment, methods for the manufacture of the compounds and novel intermediates and partial steps for their synthesis.
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Page/Page column 22
(2008/06/13)
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- ARYL AND HETEROARYL COMPOUNDS AND METHODS TO MODULATE COAGULATION
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This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as antagonists, or more preferably, partial antagonist of factor IX and thus, may be used to inhibit the intrinsic pathway of blood coagulation. The compounds are useful in a variety of applications including the management, treatment and/or control of diseases caused in part by the intrinsic clotting pathway utilizing factor IX. Such diseases or disease states include stroke, myocardial infarction, aneurysm surgery, and deep vein thrombosis associated with surgical procedures, long periods of confinement, and acquired or inherited pro-coagulant states.
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Page 185-186
(2010/11/30)
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- Indoles
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A 1,4-substituted cyclic amine derivative represented by the following formula or a pharmacologically acceptable salt thereof: wherein A, B, C, D, T, Y, and Z each represent a methine or a nitrogen linkage; R1, R2, R3, R4, and R5 each represent a substituent; n represents 0 or an integer of 1 to 3; m represents 0 or an integer of 1 to 6; and p represents an integer of 1 to 3. The compounds have serotonin antagonism. They are therefore clinically useful as medicaments, in particular, for treating, ameliorating, and preventing spastic paralysis. They are also useful as central muscle relaxants for ameliorating myotonia.
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- α,25-Dihydroxyvitamin D3 analogs featuring aromatic and heteroaromatic rings: Design, synthesis, and preliminary biological testing
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Aromatic compounds 2a-c, analogs of 1α,25-dihydroxyvitamin (calcitriol, 1), and heteroaromatic compounds 4a-c and 5a-c, analogs of 19-nor-1α,25- dihydroxyvitamin D3 (3), were designed to simulate the topology of their biologically potent parent
- Posner,Li,White,Vinader,Takeuchi,Guggino,Dolan,Kensler
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p. 4529 - 4537
(2007/10/03)
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