- INHIBITORS OF ADENYLATE-FORMING ENZYME MENE
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Provided herein are compounds of Formula (I) and pharmaceutically acceptable salts or tautomers thereof which may inhibit adenylate-forming enzymes. Also provided are pharmaceutical compositions, kits, uses, and methods involving the inventive compounds for the treatment and/or prevention of an infectious disease (e.g., bacterial infection (e.g., tuberculosis, methicillin- resistant Staphylococcus aureus)).
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- Direct Intramolecular Aminoboration of Allenes
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Direct intramolecular aminoboration of sulfonamidoallenes was realized using BCl3 as a boron source. The reactions benefited from the interaction between BCl3 and sulfonamides and provided a variety of borylvinyl heterocycles in good isolated yields. When chiral substrates were involved in the reactions, high stereoselectivity was observed, as can be ascertained by single-crystal X-ray diffraction experiments. Derivatization of the thus-obtained borylvinyl compounds proceeded readily, and different functionalities could be obtained via oxidation, halogenation, and Suzuki coupling reactions.
- Yang, Chun-Hua,Han, Meng,Li, Wenyan,Zhu, Ningning,Sun, Zhenzhen,Wang, Junjie,Yang, Zhantao,Li, Yue-Ming
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p. 5090 - 5093
(2020/07/15)
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- Structure-Based Design, Synthesis, and Biological Evaluation of Non-Acyl Sulfamate Inhibitors of the Adenylate-Forming Enzyme MenE
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N-Acyl sulfamoyladenosines (acyl-AMS) have been used extensively to inhibit adenylate-forming enzymes that are involved in a wide range of biological processes. These acyl-AMS inhibitors are nonhydrolyzable mimics of the cognate acyl adenylate intermediates that are bound tightly by adenylate-forming enzymes. However, the anionic acyl sulfamate moiety presents a pharmacological liability that may be detrimental to cell permeability and pharmacokinetic profiles. We have previously developed the acyl sulfamate OSB-AMS (1) as a potent inhibitor of the adenylate-forming enzyme MenE, an o-succinylbenzoate-CoA (OSB-CoA) synthetase that is required for bacterial menaquinone biosynthesis. Herein, we report the use of computational docking to develop novel, non-acyl sulfamate inhibitors of MenE. A m-phenyl ether-linked analogue (5) was found to be the most potent inhibitor (IC50 = 8 μM; Kd = 244 nM), and its X-ray co-crystal structure was determined to characterize its binding mode in comparison to the computational prediction. This work provides a framework for the development of potent non-acyl sulfamate inhibitors of other adenylate-forming enzymes in the future.
- Evans, Christopher E.,Si, Yuanyuan,Matarlo, Joe S.,Yin, Yue,French, Jarrod B.,Tonge, Peter J.,Tan, Derek S.
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p. 1918 - 1930
(2019/04/03)
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- Synthesis method of biological orthogonal experiment aromatic eight-membered ring marker
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The invention relates to a synthesis method of a biological orthogonal experiment aromatic eight-membered ring marker. The synthesis method comprises the following steps: (a) after mixing benzenedimethanol, dichloromethane, imidazole and tert-butyldimethylsilane, reacting; carrying out chromatographic column purification to obtain a compound II; (b) adding toluenesulfonyl methyl carbamate, triphenylphosphine and diethyl azodicarboxylate and reacting; after concentrating, carrying out column purification to obtain a compound III; (c) dissolving the compound III in methanol and cooling until thetemperature is less than or equal to 0 DEG C; then adding potassium carbonate and reacting; adding water and quenching; (d) after extracting with ethyl acetate for a plurality of times, combining organic phases and purifying to obtain a compound V; (e) concentrating and carrying out chromatographic column purification to obtain a compound VI; (f) after concentrating, carrying out chromatographiccolumn purification to obtain a compound VII; (g) after concentrating, carrying out chromatographic column purification to obtain a compound I. By adopting the synthesis method, a redesign of a synthesis route of the aromatic eight-membered ring marker is realized.
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Paragraph 0022
(2018/12/02)
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- Synthetic method for ring formation intermediate of aromatic octatomic ring through biological orthogonal experiment
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The invention relates to a synthetic method for a ring formation intermediate of an aromatic octatomic ring through a biological orthogonal experiment. The synthetic method comprises the following steps: (a) mixing o-benzenedicarbinol, dichloromethane, imidazole and tert-butyldimethylsilyl chloride for reaction, and purifying by virtue of a chromatographic column, so as to obtain a compound II; (b) adding methyl toluenesulfonyl carbamate, triphenylphosphine and diethyl azodicarboxylate, concentrating, and carrying out column purification, so as to obtain a compound III; (c) dissolving the compound III into methanol, cooling to the temperature less than or equal to 0 DEG C, adding potassium carbonate for reaction, and adding water for quenching; (d) carrying out extraction for several timesby virtue of ethyl acetate, combining organic phases, drying by virtue of anhydrous sodium sulfate, concentrating, and purifying by virtue of the chromatographic column, so as to obtain a compound V;(e) concentrating, and purifying by virtue of the chromatographic column, so as to obtain a compound VI; and (f) concentrating, and purifying by virtue of the chromatographic column, so as to obtaina compound VII. According to the synthetic method, the redesign of a synthetic route for the ring formation intermediate of the aromatic octatomic ring is realized.
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Paragraph 0019-0021; 0028-0031
(2019/01/06)
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- A biological orthogonal experiment mark [...] intermediate hydroxy derivative synthesis method (by machine translation)
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The invention relates to a biological orthogonal experiment mark [...] intermediate hydroxy derivative synthesis method, comprising the following steps: (a) the O-methanol, dichloromethane, imidazole-butyl dimethylchlorosilane mixed for reaction; over the chromatographic column purification to obtain compound II; (b) adding toluene sulfonyl amino methyl formate, triphenylphosphine and azo-phthalic acid diethyl ester reaction, after concentrating column purification to obtain compound III; (c) the compound III is dissolved in the methanol, lowering the temperature to ≤ 0 °C, adding potassium carbonate by the reaction of, water quenching; (d) and condensing the chromatographic column purification to obtain compound V; (e) the compound V soluble in tetrahydrofuran, add tetrabutyl ammonium fluoride solution reaction, water quenching; and condensing the chromatographic column purification to obtain compound VI. The aromatic eight-membered ring mark [...] intermediate of the synthetic route re-design. (by machine translation)
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Paragraph 0014; 0018-0020
(2018/10/19)
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- Flexible synthesis of anthracycline aglycone mimics via domino carbopalladation reactions
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A synthesis of anthracycline aglycone derivatives is described. The key step utilizes a powerful domino carbopalladation approach and subsequent ring closure. During this process two of the four rings of the anthracycline scaffold are formed. Differently substituted carbohydrates and dialkyne chains serve as versatile and simple starting materials for the reaction sequence. Diverse building blocks lead to a variety of different products and a broad range of structural diversity.
- Leibeling, Markus,Werz, Daniel B.
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p. 2194 - 2201
(2013/11/19)
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- Synthetic studies on the solanacol ABC ring system by cation-initiated cascade cyclization: Implications for strigolactone biosynthesis
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We report a new method for constructing the ABC ring system of strigolactones, in a single step from a simple linear precursor by acid-catalyzed double cyclization. The reaction proceeds with a high degree of stereochemical control, which can be qualitatively rationalized using DFT calculations. Our concise synthetic approach offers a new model for thinking about the (as yet) unknown chemistry that is employed in the biosynthetic pathways leading to this class of plant hormones.
- Chojnacka, Kinga,Santoro, Stefano,Awartani, Radi,Richards, Nigel G. J.,Himo, Fahmi,Aponick, Aaron
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supporting information; experimental part
p. 5350 - 5353
(2011/09/13)
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- Efficient synthesis of the spiroacetal core of paecilospirone via oxidative radical cyclisation
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The spiroacetal core of the microtubule assembly inhibitor paecilospirone has been prepared using two separate oxidative cyclisation methods. Georg Thieme Verlag Stuttgart - New York.
- Jay-Smith, Morgan,Furkert, Daniel P.,Sperry, Jonathan,Brimble, Margaret A.
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scheme or table
p. 1395 - 1398
(2011/08/03)
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- Synthesis of novel isochromene derivatives by tandem Ugi reaction/ nucleophilic substitution
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Unprecedented 3-amino-4-amido-lH-isochromenes have been prepared in three steps from protected ortho-(hydroxymethyl)benzaldehyde, with the introduction of three diversity inputs, through a Ugi reaction followed by intramolecular nucleophilic substitution. Georg Thieme Verlag Stuttgart.
- Banfi, Luca,Basso, Andrea,Casuscelli, Francesco,Guanti, Giuseppe,Naz, Farah,Riva, Renata,Zito, Paola
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scheme or table
p. 85 - 88
(2010/07/16)
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- NOVEL CURCUMIN DERIVATIVE
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The present invention provides a novel compound that is structurally similar to curcumin and has a suppressive effect on Aβ aggregation, a degradative effect on Aβ aggregates, an inhibitory effect on β-secretase, and a protective effect on neurons. The novel compound is a compound represented by the following general formula (Ia) or a salt thereof: wherein R1 represents a 4-hydroxy-3-methoxyphenyl group or the like, and R2 represents a 1H-indol-6-yl group or the like.
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Page/Page column 79
(2009/12/07)
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- A palladium-catalyzed alkylation/direct arylation synthesis of nitrogen-containing heterocycles
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(Chemical Equation Presented) A norbornene-mediated palladium-catalyzed sequence is described in which an alkyl-aryl bond and an aryl-heteroaryl bond are formed in one reaction vessel. The aryl-heteroaryl bond-forming step occurs via a direct arylation re
- Blaszykowski, Christophe,Aktoudianakis, Evangelos,Alberico, Dino,Bressy, Cyril,Hulcoop, David G.,Jafarpour, Farnaz,Joushaghani, Arash,Laleu, Benoit,Lautens, Mark
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p. 1888 - 1897
(2008/09/18)
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- A rhodium-catalyzed C-H activation/cycloisomerization tandem
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A reaction cascade comprising a rhodium-catalyzed C-H activation, a subsequent hydrometalation of an alkylidene cyclopropane in vicinity, regioselective C-C bond activation of the flanking cyclopropane ring, followed by reductive elimination of the result
- Aeissa, Christophe,Fuerstner, Alois
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p. 14836 - 14837
(2008/09/18)
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- METHODS FOR TREATING ARTHRITIS USING TRIHETEROCYCLIC COMPOUNDS
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The present invention relates to methods for treating or preventing arthritis comprising administering a Triheterocyclic Compound. In one embodiment, the present invention relates to methods of using Triheterocyclic Compounds for treating or preventing rh
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Page/Page column 114
(2008/06/13)
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- Triheterocyclic compounds, compositions, and methods for treating cancer or viral diseases
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The present invention relates to novel Triheterocyclic Compounds, compositions comprising a Triheterocyclic Compound, and methods useful for treating or preventing cancer or a neoplastic disorder comprising administering a Triheterocyclic Compound. The compounds, compositions, and methods of the invention are also useful for inhibiting the growth of a cancer cell or neoplastic cell, treating or preventing a viral infection, or inhibiting the replication and/or infectivity of a virus.
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Page/Page column 49-50
(2010/02/14)
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- TRIHETEROCYCLIC COMPOUNDS, COMPOSITIONS, AND METHODS FOR TREATING CANCER OR VIRAL DISEASES
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The present invention relates to novel Triheterocyclic Compounds, formula (I): and pharmaceutically acceptable salts thereof, where in: Q1 is -O-, -S- or -N(R1)-; Q2 is -C(R3)- or -N-; Q3 is -C (Rsub
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- Direct lactonization of alkenols via osmium tetroxide-mediated oxidative cleavage
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(Matrix presented) A highly efficient, mild, and simple protocol is presented for the tandem OsO4-mediated oxidative cleavage/oxidative lactonization of alkenols to lactones. The protocol couples the OsO 4-catalyzed oxidative cleavage of olefins with Oxone as the co-oxidant with the direct oxidation of aldehydes in alcoholic solvents to their corresponding esters.
- Schomaker, Jennifer M.,Travis, Benjamin R.,Borhan, Babak
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p. 3089 - 3092
(2007/10/03)
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- Fused imidazopyridine derivatives as antihyperlipidemic agents
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A novel compound of the formula: wherein ring Q is an optionally substituted pyridine ring; One of R0, R1and R2is —Y0—Z0, and the other tow groups are a hydrogen, a halogen, an optionally substituted hydroxy group, a hydrocarbon group that may be an optionally substituted hydrocarbon group or an acyl group; Y0is a bond or an optionally substituted bivalent hydrocarbon group; Z0is a basic group which may be bonded via oxygen, nitrogen, —CO—, —CS—, —SO2N(R3)— (where R3is hydrogen or an optionally substituted hydrocarbon group), or S(O)n(wherein n is to 0, 1 or 2); .........is a single bond or a double bond, or a salt thereof, which has an excellent LDL receptor up-regulating, blood-lipids lowering, blood-sugar lowering and diabetic complication-ameliorating activity.
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- Development of dual-acting agents for thromboxane receptor antagonism and thromboxane synthase inhibition. 2. Design, synthesis, and evaluation of a novel series of phenyl oxazole derivatives
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Synthesis and initial in vitro evaluation of a novel series of phenyl oxazole derivatives are described. An SAR study of the novel dual-acting TRA/TSI agent has revealed that the lipophilicity of the oxazole amide substituents greatly influences the TRA activity but not the TSI. The chain length of the alkenoic acid side chain affects both TRA and TSI. The optimal chain length for the combined activities was found to be n = 4 (heptenoic acid).
- Takeuchi, Kumiko,Kohn, Todd J.,Mais, Dale E.,True, Timothy A.,Wyss, Virginia L.,Jakubowski, Joseph A.
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p. 1943 - 1948
(2007/10/03)
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- (Carboxyalkyl)benzyl propargyl ethers as selective inhibitors of leukocyte-type 12-lipoxygenases
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A series of (carboxyalkyl)benzyl propargyl ethers was synthesized and tested as inhibitors of 12-lipoxygenase (12-LO) from porcine leukocyte cytosol. Optimum activity was displayed by 3-[4-[(2- tridecynyloxy)methyl]phenyl]propanoic acid. Altering the length of the alkyl side chain attached to the acetylenic group reduced activity. Changing the substitution pattern in the (carboxyalkyl)benzyl group from para to meta or ortho also reduced activity. Analogs in which the triple bond was replaced by a double bond or an allene displayed reduced activity, whereas fully saturated analogs were inactive. High concentrations (10 μM) of the most potent acetylenic (carboxylalkyl)benzyl ethers did not inhibit human platelet 12-LO, human neutrophil 5-LO, rabbit reticulocyte 15-LO, or soybean 15-LO. Thus, this class of compounds represents the first example of isoform specific LO inhibitors.
- Gorins, Gilles,Kuhnert, Lethea,Johnson, Carl R.,Marnett, Lawrence J.
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p. 4871 - 4878
(2007/10/03)
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- Benzoate derivatives of taxol
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This invention relates to a compound of formula I STR1 or a pharmaceutically acceptable salt thereof, in which R2 is a radical of the formula STR2 in which Ra and Rb are independently hydrogen or C1-6 alkyl, said C1-6 alkyl being optionally substituted with hydroxy, phosphono, phosphonooxy, carboxy or di(C1-6 alkyl) amino; or NRa Rb together represents a radical of the formula STR3 in which y is one to three, and Ra is as defined above; Rp and Rr are independently same or different C1-6 alkyl; R1 is hydrogen or a radical Z of the formula STR4 in which Q is --(CH2)f --, optionally substituted with one to six same or different C1-6 alkyl or C3-6 cycloalkyl, or a carbon atom of said --(CH2)f -- radical may also be a part of C3-6 cycloalkylidene; R3 and R4 are independently hydrogen or C1-6 alkyl, or R3 and R4 taken together with the carbon atom to which they are attached form C3-6 cycloalkylidene; R5 is --OC(=O)R, --OP=O(OH)2 or --CH2 OP=O(OH)2, in which R is C1-6 alkyl; R6, R7, R8 and R9 are independently halogen, C1-6 alkyl, C1-6 alkoxy or hydrogen, but when R5 is --OC(=O)R, one of R6, R7, R8 or R9 is --OP=O(OH)2 ; f is 2 to 6; n is O, and m is 1 or 0 when R5 is --CH2 OP=O(OH)2 ; and n is 1 or 0, and m is 1 when R5 is --OC(=O)R or --OP=O(OH)2. Also provided by this invention are pharmaceutical formulations and a method for treating mammalian tumors with a compound of formula I.
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- Phosphonooxy and carbonate derivatives of taxol
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The present invention is directed to novel taxol derivatives useful as anti-tumor agents. Also provided by this invention is pharmaceutical formulations and methods of treating mammalian tumors with the compounds of this invention.
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- Synthesis, molecular modeling, 2-D NMR, and biological evaluation of ILV mimics as potential modulators of protein kinase C
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To study the structural determinants required for protein kinase C (PKC) activation by indolactam V (ILV) for purposes of arriving at simpler versions of this PKC activator, four simplified analogues of ILV (4a-c and 14a) were synthesized. These analogues contain a benzene ring in place of the indole group of ILV and were designed for synthesis because molecular modeling studies revealed these simplified structures to possess readily accessible [ILV]-sofa-like conformations, thus mimicking the literature-reported bioactive conformation of ILV. During the course of designing these analogues, a more rigorous conformational search program (SysSearch) was developed to analyze the highly functionalized nine-membered lactam ring system present in ILV. The results of the molecular modeling studies using the SysSearch program on which the design of these analogues was based were confirmed by 2-D NMR and X-ray studies. The compounds of this series were constructed by use of the Mitsunobu reaction to generate the unique nine-membered lactam ring present in these structures. Two routes to compound 4a are presented, one of which utilizes the amino acid building blocks, L-valine and L-phenylalanine, to fix the stereochemistry of its two asymmetric centers. The biological studies reveal that these new analogues fail to modulate PKC activity, and thus they exclude the possibility that a benzene ring can serve as a surrogate of the indole ring of ILV. The present work therefore indicates that the nine-membered lactam ring moiety of ILV in an [ILV]sofa conformation is not a sufficient structural determinant for PKC activation.
- Kozikowski, Alan P.,Ma, Dawei,Pang, Yuan-Ping,Shum, Patrick,Likic, Vladimir,Mishra, Prasanna K.,Macura, Slobodan,Basu, Alakananda,Lazo, John S.,Ball, Richard G.
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p. 3957 - 3965
(2007/10/02)
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- Synthesis of 3,9b-Dihydro-5H-pyrroloisoindoles and 3,5,6,10b-Tetrahydropyrroloisoquinolines with 1,3-Dipolar Cycloaddition Reactions.
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The title classes of compounds have been prepared using a sequence of two ring-forming reactions.Initial 1,3-dipolar cycloaddition with an azomethine ylide gave N-acylated 3-pyrrolines which were further elaborated to the target compounds by a tandem deprotection/cyclization reaction.
- Anderson, Wayne K.,Kinder, Frederick R.
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p. 975 - 979
(2007/10/02)
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