- Design, synthesis and biological evaluation of LpxC inhibitors with novel hydrophilic terminus
-
Abstract In order to develop novel LpxC inhibitors with good activities and metabolic stability, two series of compounds with hydrophilic terminus have been synthesized and their in vitro antibacterial activities against Escherichial coli and Pseudomonas aeruginosa were evaluated. Especially, compounds 22b and c exhibited comparable antibacterial activities to CHIR-090 and better metabolic stability than CHIR-090 and LPC-011 in liver microsomes (rat and mouse), which indicated the terminal methylsulfone may be a preferred structure in the design of LpxC inhibitors and worthy of further investigations.
- Ding, Shi,Wang, Wen-Ke,Cao, Qiao,Chu, Wen-Jing,Lan, Le-Fu,Hu, Wen-Hao,Yang, Yu-She
-
-
Read Online
- Thermal solid state polymerization of p-ethynylbenzoic acid
-
While p-ethynylbenzoic acid (EBA) has been suggested to be reactive in the solid state, the structure-reactivity relationships and the nature of the product(s) have remained unknown. Crystallized from toluene, EBA is a monoclinic crystal, space group P21/n, a = 3.8684(4), b = 6.2329(4), c = 30.190(3) A; β= 90.281(8)°; V = 727.90 A3. The crystal structure contains linear chains and short intermolecular contacts between acetylene moieties, which provide a structural basis for initiation of topochemical reactivity. Heating of EBA leads to an amorphous poly(phenylacetylene) (PPA) derivative. The absorption and emission spectral characteristics of the polymer are discussed. Analogous to PPA, a subsequent thermal process leads to a cyclic trimer. Differential scanning calorimetry of EBA exhibits at least four exothermic processes, and these are discussed in terms of the polymerization and subsequent processes that ultimately lead to the cyclotrimer.
- Njus, Jeffrey M.,Sandman, Daniel J.,Yang, Lin,Foxman, Bruce M.
-
-
Read Online
- Control of the helicity of poly(phenylacetylene)s: From the conformation of the pendant to the chirality of the backbone
-
(Figure Presented) Helix sense selection: Tuning the conformational equilibrium of the pendants of poly(phenylacetylene)s allows selection of the helicity of the polymer in a reversible way. Complexation with appropriate metal cations (e.g. Ba2+) or changing the polarity of the solvent permits the reversible selection of the desired helix sense. A full picture of the mechanism explaining this phenomenon is presented.
- Louzao, Iria,Seco, Jose M.,Quinoa, Emilio,Riguera, Ricardo
-
-
Read Online
- Synthesis and properties of substituted polyacetylenes containing pyrene moieties in the side group
-
A novel phenylacetylene derivative containing a pyrene group was synthesized and polymerized with various Rh complex catalysts. The obtained polymers were soluble in common organic solvents such as chloroform and THF. The Mw and Mw/Mn were estimated as ca. 12000-18000 and 1.31.7 respectively, and the polymer yields were estimated as around 5772%. The characteristic absorptions of ≡ C-H (3200 cm-1) and C≡C (2100 cm-1) stretchings seen in the monomer spectra have completely disappeared in the polymer spectra from IR spectrum. 1HNMR analysis confirmed that the acetylene triple bonds transformed to polyene double bonds. These polymers were found to be thermally stable based on TGA data. The synthesized polymers exhibited blue fluorescence. The fluorescence quantum yield in solution was high at 0.37-0.41. Furthermore, the obtained polymer had a long fluorescence lifetime.
- Sugano, Shou,Kouzai, Hiroaki
-
-
Read Online
- Water-soluble nano-fluorogens fabricated by self-assembly of bolaamphiphiles bearing AIE moieties: Towards application in cell imaging
-
Nano-fluorogens with a mono-molecule layered structure are fabricated by self-assembly of a new bolaamphiphile bearing a tetraphenylethene moiety. The nano-fluorogens show good water-solubility, biocompatibility, and strong emission with a quantum yield as high as 15%. The nano-fluorogens, as prepared, are successfully applied to label and map HeLa cells. The images obtained have high contrast and resolution, showing a promising potential for fluorescence detection in bio-related systems.
- Xia, Yijun,Dong, Lin,Jin, Yingzhi,Wang, Shuai,Yan, Li,Yin, Shouchun,Zhou, Shixin,Song, Bo
-
-
Read Online
- Two- and three-dimensional silver(I)-organic networks generated from mono- and dicarboxylphenylethynes
-
Three phenylethynes bearing methyl carboxylate (HL1), monocarboxylate (H2L2), and dicarboxylate (H2L3) groups were utilized as ligands to synthesize a new class of organometallic silver(I)-ethynide complexes as bifunctional building units to assemble silver(I)-organic networks. X-ray crystallographic studies revealed that in [Ag2(L1) 2?AgNO3]∞ (1) (L1= 4-C 2C6H4CO2CH3), one ethynide group interacts with three silver ions to form a complex unit. These units aggregate by sharing silver ions with the other three units to afford a silver column, which are further linked through argentophilic interaction to generate a two-demensional (2D) silver(I) network. In [Ag2(L2) ?3AgNO3?H2O]∞ (2) (L2 = 4-CO2C6H4C2), the ethynide group coordinates to four silver ions to form a building unit (Ag4C 2C6H4CO2), which interacts through silver(I)-carboxylate coordination bonds to generate a wave-like 2D network and is subsequently connected by nitrate anions as bridging ligands to afford a three-demensional (3D) network. In [Ag3(L3)?AgNO 3]∞ (3) (L3 = 3,5-(CO2)2C 6H3C2), the building unit (Ag4C 2C6H3(CO2)2) aggregates to form a dimer [Ag8(L3)2] through argentophilic interaction. The dimeric units interact through silver(I)-carboxylate coordination bonds to directly generate a 3D network. The obtained results showed that as a building unit, silver(I)-ethynide complexes bearing carboxylate groups exhibit diverse binding modes, and an increase in the number of carboxylate groups in the silver(I)-ethynide complex unit leads to higher level architectures. In the solid state, all of the complexes (1, 2, and 3) are photoluminescent at room temperature.
- Zhao, Ying,Zhang, Peng,Li, Bao,Meng, Xianggao,Zhang, Tianle
-
-
Read Online
- Ribosome Rescue Inhibitors Kill Actively Growing and Nonreplicating Persister Mycobacterium tuberculosis Cells
-
The emergence of Mycobacterium tuberculosis (MTB) strains that are resistant to most or all available antibiotics has created a severe problem for treating tuberculosis and has spurred a quest for new antibiotic targets. Here, we demonstrate that trans-translation is essential for growth of MTB and is a viable target for development of antituberculosis drugs. We also show that an inhibitor of trans-translation, KKL-35, is bactericidal against MTB under both aerobic and anoxic conditions. Biochemical experiments show that this compound targets helix 89 of the 23S rRNA. In silico molecular docking predicts a binding pocket for KKL-35 adjacent to the peptidyl-transfer center in a region not targeted by conventional antibiotics. Computational solvent mapping suggests that this pocket is a druggable hot spot for small molecule binding. Collectively, our findings reveal a new target for antituberculosis drug development and provide critical insight on the mechanism of antibacterial action for KKL-35 and related 1,3,4-oxadiazole benzamides.
- Alumasa, John N.,Manzanillo, Paolo S.,Peterson, Nicholas D.,Lundrigan, Tricia,Baughn, Anthony D.,Cox, Jeffery S.,Keiler, Kenneth C.
-
-
Read Online
- Chirality assignment of amines and amino alcohols based on circular dichroism induced by helix formation of a stereoregular poly((4- carboxyphenyl)acetylene) through acid-base complexation
-
An optically inactive polyacetylene, poly((4-carboxyphenyl)acetylene) (poly-l), exhibits an induced circular dichroism (ICD) in the UV-visible region upon complexation with chiral amines and amino alcohols in DMSO and in the film, the sign of which reflects the stereochemistry including bulkiness, type (primary, secondary, or tertiary), and absolute configuration of the amines. Therefore, the polyacetylene can be used as a novel probe for determining the chirality of amines. Most primary amines and amino alcohols of the same configuration gave the same sign for the induced Cotton effect; however, secondary and/or tertiary amines used in the present study tended to show Cotton effect signs opposite to those of the primary amines and amino alcohols of the same configuration. The magnitude of the ICD likely increases with an increase in the bulkiness of the chiral amines. The complexation dynamics during the formation of the helical structure of poly-1 with chiral amines were investigated on the basis of the spin-spin relaxation behavior and 1H NMR, CD, and optical rotatory dispersion (ORD) titrations. The complex formation of poly-1 with chiral amines such as 1-(l- naphthyl)ethylamine and 2-amino-l-propanol exhibits a positive nonlinear effect between the enantiomeric excess of the chiral amines and amino alcohols and the observed ellipticity of the Cotton effects. The excess enantiomer bound to poly-1 may induce an excess of a single-handed helix (rightor left-handed helix), which may result in a more intense ICD than that expected from the ee of the amine. Moreover, it was found that the coexistence of achiral amines such as l-aminoethanol also induced an excess of one helical sense of poly-1.
- Yashima, Eiji,Matsushima, Teruyuki,Okamoto, Yoshio
-
-
Read Online
- Polyacetylene derivatives in perovskite solar cells: From defect passivation to moisture endurance
-
The last decade has witnessed the exploration of exceptional optoelectronic and photovoltaic properties of perovskite solar cells (PSCs) at the laboratory scale. Unfortunately, their sensitivity to moisture causes bulk degradation, hindering the commercialization of PSC devices. Despite the numerous strategies that have been developed to date in this field, effective passivation against moisture remains highly challenging. Here, we report a novel approach based on the incorporation of polyacetylene derivatives into the perovskite active layer to yield perovskite films with larger grains, lower defect density, and excellent robustness with respect to moisture. Moreover, it is revealed that the reduced trap-state density of these films is most likely due to the efficient coordination between the carboxylate moieties in the polymer and the undercoordinated Pb2+ in the perovskite. Upon adopting the polymer-doped perovskite as an active layer in inverted planar heterojunction PSCs with all-inorganic charge extraction layers, the power conversion efficiency (PCE) is improved to 20.41%, which is the highest value reported to date for this type of PSC to the best of our knowledge. Most importantly, the optimized device retained 90% of its initial PCE after aging in ambient air for 60 days due to its dual mechanism of moisture resistance. This work highlights an approach for developing high-performance PSCs with improved moisture stability and paves the way for their potential commercialization. This journal is
- Faheem, M. Bilal,Jiang, Jiexuan,Lang, Xianhua,Li, Yanbo,Rong, Shanshan,Zeng, Qiugui,Zhao, Hui
-
-
Read Online
- Nesting complexation of C60 with large, rigid D2 symmetrical macrocycles
-
A series of four chiral D2 symmetrical macrocycles, in which two 3,3′-disubstituted Binol units are bridged by conjugated organic spacers of differing lengths and/or electronic properties, have been synthesized and characterized. The four different bridges consist of either ether or ester linkages in combination with either short biphenyl spacers or long diethynylphenyl spacers. NMR, CD spectroscopy, and molecular modeling help rationalize the shape of the cyclic scaffolds and even subtle modifications in the bridging units lead to drastic changes in conformation. The three macrocycles with longer bridging units and/or ester linkages form stable 1:1 complexes with C60 in toluene. The one with a short spacer and ether linkage does not. The binding constants have been determined with a high degree of accuracy via equilibrium-restricted factor analysis; with long spacers and ester linkages log Ka = 4.37(2); with short spacers and ester linkages log Ka = 3.498(4); with long spacers and ether linkages log Ka = 3.509(2). The Royal Society of Chemistry 2010.
- Caricato, Marco,Coluccini, Carmine,Dondi, Daniele,Vander Griend, Douglas A.,Pasini, Dario
-
-
Read Online
- Acetylenic Replacement of Albicidin's Methacrylamide Residue Circumvents Detrimental E/Z Photoisomerization and Preserves Antibacterial Activity
-
The natural product albicidin is a highly potent inhibitor of bacterial DNA gyrase. Its outstanding activity, particularly against Gram-negative pathogens, qualifies it as a promising lead structure in the search for new antibacterial drugs. However, as we show here, the N-terminal cinnamoyl moiety of albicidin is susceptible to photochemical E/Z isomerization. Moreover, the newly formed Z isomer exhibits significantly reduced antibacterial activity, which hampers the development and biological evaluation of albicidin and potent derivatives thereof. Hence, we synthesized 13 different variants of albicidin in which the vulnerable para-coumaric acid moiety was replaced; this yielded photostable analogues. Biological activity assays revealed that diaryl alkyne analogues exhibited virtually undiminished antibacterial efficacy. This promising scaffold will therefore serve as a blueprint for the design of a potent albicidin-based drug.
- Behroz, Iraj,Kleebauer, Leonardo,Hommernick, Kay,Seidel, Maria,Gr?tz, Stefan,Mainz, Andi,Weston, John B.,Süssmuth, Roderich D.
-
p. 9077 - 9086
(2021/05/27)
-
- RET INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
-
Provided herein are a RET inhibitor, a pharmaceutical composition thereof and uses thereof. In particular, provided is a compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. Provided is a pharmaceutical composition comprising the compound, and uses of the compound and pharmaceutical composition thereof for the preparation of a medicament, in particular for treatment and prevention of RET-related diseases and conditions, including cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
- -
-
Paragraph 00230; 00291
(2020/07/05)
-
- Directed polymorphism and mechanofluorochromism of conjugated materials through weak non-covalent control
-
Understanding and manipulating crystal polymorphism can provide novel strategies for materials discovery in organic optoelectronics. In this paper, a series of seven ester-terminated three-ring phenylene ethynylenes (PEs) exhibit structure-dependent polymorphism wherein alkyl chain length modulates the propensity to form violet or green fluorescent solid phases, as well as tunable thermal and mechanofluorochromic (MFC) transitions. These compounds harness "soft" non-covalent control to achieve polymorphism: the electronic substituent effect of the ester groups weakens the fluoroarene-arene (ArF-ArH) interactions that typically direct crystal packing of this class of compounds, increasing competitiveness of other interactions. Small structural modifications tip this balance and shift the prevalence of violet- or green-emitting polymorphs. Compounds with short alkyl chain lengths show both violet and various green fluorescent polymorphs, while the violet fluorescent form dominates with alkyl lengths longer than butyl. Further, thermally induced green-to-violet fluorescent crystal-to-crystal transitions occur for single crystals of two derivatives. Finally, the PEs show reversible violet-to-green mechanofluorochromism (MFC), with temperature required for reversion of this MFC decreasing with alkyl chain length. We therefore present this design of directional but weak interactions as a strategy to access polymorphs and tunable stimuli-responsive behavior in solids.
- Sharber, Seth A.,Mann, Arielle,Shih, Kuo-Chih,Mullin, William J.,Nieh, Mu-Ping,Thomas, Samuel W.
-
supporting information
p. 8316 - 8324
(2019/07/17)
-
- Fluoroboron pyrrole liquid crystal compound containing 8-(diphenylethinyl)-ester group flexible multi-element rings, preparation method and application thereof
-
The invention relates to fluoroboron pyrrole liquid crystal dye containing 8-(diphenylethinyl)-ester group flexible multi-element rings, a preparation method and application thereof. According to theinvention, boron fluoride complex dipyrrole methine is used as a matrix, a diphenylacetylene rigid structure is introduced into a No. 8 position through a Sonogashira coupling reaction, a series of BODIPY-type dichroic dye of the 8-methyl-(diphenylethinyl)-ester group flexible multi-element rings is designed and synthetized by connecting bicyclohexyl, cholesterol and other flexible multi-element rings with a diphenyl acetenyl group through an esterification reaction. The maximum emission wavelength of the compound in dichloromethane is all concentrated at about 525nm, so that the compound presents green fluorescence, and a good dichroic ratio and ordered parameters are shown in liquid crystal E7; the liquid crystal compound has a liquid crystal intermediate phase in the temperature range of 100-280 DEG C, and can be used for manufacturing liquid crystal display products, particularly, the liquid crystal compound is used as a guest dye for a guest host mode liquid crystal display; whenthe compound is added to E7 liquid crystal and used in a guest host display mode, the response time can be improved, and the effect of quick response can be achieved.
- -
-
-
- Benzophenanthrene benzoyloxy benzene bridged perylene bisimide diester synthetic method
-
The invention provides a benzophenanthrene benzoyloxy benzene bridged perylene bisimide diester synthetic method. A synthesis route is characterized in that 1) p-acetenyl benzoic acid is synthesized; monohydroxy pentahexyloxy benzophenanthrene is generated; a benzophenanthrene derivative containing terminal alkyne is finally prepared; 2) N-(4-iodophenyl)perylene imine dioctyl phthalate diester is generated; and 3) an intermediate obtained by the above two parts, and a benzophenanthrene benzoyloxy benzene bridged perylene bisimide diester binary compound is obtained through a reaction by a Sonogashira cross-coupling reaction. The benzophenanthrene and its derivative are most widely discotic liquid crystal material in the prior art, have good photoelectric property, and can easily form a cylindrical liquid crystalline phase, a perylene imide derivative has strong electronic capacity, has high electronic affinity, has strong absorption capacity at a visible light zone, and is an excellent n-type organic semiconductor material. The discotic liquid crystal binary compound with an electron donor (D)-bridge (B)-acceptor (A) structure is designed and synthesized, and can be used for molecule devices of an organic photovoltaic material, a liquid crystal material, an organic solar energy cell, and an organic light-emitting diode.
- -
-
Paragraph 0017; 0018
(2017/09/01)
-
- Synthesizing method of benzophenanthrene benzoyloxy alkynylphenyl alkynylphenyl bridged perylene mono-imide dihexyl ester
-
The invention aims at providing a synthesizing method of benzophenanthrene benzoyloxy alkyne benzyne benzene bridged perylene mono-imide dihexyl ester. A synthesizing path of the synthesizing comprises the first part of synthesizing iodine-containing phenyl ethynyl benzoyloxy penta-hexyloxy benzophenanthrene, the second part of utilizing 3,4,9,10-perylene tetracarboxylic acid anhydride as a raw material and synthesizing alkyne-containing phenyl perylene bisimide diester derivative and the third part of synthesizing intermediates obtained through the first part and the second part into benzophenanthrene oxycarbonyl phenylalkynylphenyl alkynylphenyl bridged perylene mono-imide dihexyl ester binary compound through Sonogashira cross coupling reaction. Benzophenanthrene and derivative of the benzophenanthrene are disc-shaped liquid crystal materials which are most extensively utilized currently, and perylene bisimide derivative is an excellent n type organic semiconductor material. The synthesizing method disclosed by the invention designs and synthesizes disc-shaped liquid crystal binary compound containing an electron donor-bridge-receptor structure, and the compound can be applied to molecular devices of organic solar cells, organic light emitting diodes and the like.
- -
-
Paragraph 0017; 0018
(2017/09/01)
-
- Synthesis method of triphenylene benzoyloxy alkynyl biphenyl alkynyl benzene bridged perylene monoimine dihexyl ester
-
The invention aims at providing a synthesis method of triphenylene oxycarbonyl phenylacetylenic biphenyl alkyne benzene bridged perylene monoimine dihexyl ester. The synthesis method comprises the synthesis routes: firstly, synthesizing iodine-containing biphenylyl acetenyl benzoyloxy pentaoctoxytriphenylene; secondly, synthesizing an alkyne-containing phenyl perylene imide diester derivative by taking perylene tetracarboxylic anhydride as a raw material; and thirdly, carrying out Sonogashira cross-coupling reaction on an intermediate obtained by the two steps to synthesize a triphenylene oxycarbonyl phenylacetylenic biphenyl alkyne benzene bridged perylene monoimine dihexyl ester binary compound. Triphenylene and a derivative thereof are discoid liquid crystal materials most extensively applied at present, while a perylene imide derivative is a favorable N-type organic semiconductor material. The invention designs and synthesizes a discoid liquid crystal binary compound with an electron donor-bridge-receptor structure, and the compound can be applied to molecular devices such as organic solar cells and organic light-emitting diodes.
- -
-
Paragraph 0017; 0018
(2017/12/29)
-
- Reagents and methods for sirtuin capture
-
The invention provides a method of preparing a sirtuin complex, a method for detecting a sirtuin in a sample, and a method of screening for compounds which inhibit the deacetylase activity of a sirtuin. The method includes (a) providing a sirtuin substrate having the formula: (b) providing NAD+ or an NAD+ analog having the formula: and (c) providing a sirtuin, wherein R1-R4, A1, A2, and n are as defined herein.
- -
-
-
- Natural-Product-Inspired Aminoepoxybenzoquinones Kill Members of the Gram-Negative Pathogen Salmonella by Attenuating Cellular Stress Response
-
Gram-negative bacteria represent a challenging task for antibacterial drug discovery owing to their impermeable cell membrane and restricted uptake of small molecules. We herein describe the synthesis of natural-product-derived epoxycyclohexenones and explore their antibiotic activity against several pathogenic bacteria. A compound with activity against Salmonella Typhimurium was identified, and the target enzymes were unraveled by quantitative chemical proteomics. Importantly, two protein hits were linked to bacterial stress response, and corresponding assays revealed an elevated susceptibility to reactive oxygen species upon compound treatment. The consolidated inhibition of these targets provides a rationale for antibacterial activity and highlights epoxycyclohexenones as natural product scaffolds with suitable properties for killing Gram-negative Salmonella.
- Mandl, Franziska A.,Kirsch, Volker C.,Ugur, Ilke,Kunold, Elena,Vomacka, Jan,Fetzer, Christian,Schneider, Sabine,Richter, Klaus,Fuchs, Thilo M.,Antes, Iris,Sieber, Stephan A.
-
p. 14852 - 14857
(2016/11/23)
-
- Using the same hydroxamic acid derivative and HDAC8 inhibitor (by machine translation)
-
Disclosed are: a compound which is capable of inhibiting the function of HDAC8; and an HDAC8 inhibitor. Specifically disclosed is a hydroxamic acid derivative which is characterized by being composed of a compound represented by general formula (1) (wherein X represents an aromatic substituent or an optionally substituted 3-8 membered ring, and n represents an integer of 0-20), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
- -
-
Paragraph 0031; 0036; 0039
(2016/10/09)
-
- Differential Targeting of Human Topoisomerase II Isoforms with Small Molecules
-
(Chemical Equation Presented). The TOP2 poison etoposide has been implicated in the generation of secondary malignancies during cancer treatment. Structural similarities between TOP2 isoforms challenge the rational design of isoform-specific poisons to further delineate these processes. Herein, we describe the synthesis and biological evaluation of a focused library of etoposide analogues, with the identification of two novel small molecules exhibiting TOP2B-dependent toxicity. Our findings pave the way toward studying isoform-specific cellular processes by means of small molecule intervention.
- Mariani, Angelica,Bartoli, Alexandra,Atwal, Mandeep,Lee, Ka C.,Austin, Caroline A.,Rodriguez, Rapha?l
-
supporting information
p. 4851 - 4856
(2015/06/25)
-
- RAFAMYCIN ANALOGS AND METHODS FOR MAKING SAME
-
A semi-synthetic rapamycin analog with a triazole moiety or a pharmaceutically acceptable salt or prodrug thereof, is a broad-spectrum cytostatic agent and a mTOR inhibitor, and is useful in the treatment of various cancers, or tumors in organs such as kidney, liver, breast, head and neck, lung, prostate, and restenosis in coronary arteries, peripheral arteries, and arteries in the brain, immune and autoimmune diseases. Also disclosed are fungal growth-, restenosis-, post-transplant tissue rejection- and immune- and autoimmune disease-inhibiting compositions and a method of inhibiting cancer, fungal growth, restenosois, post-transplant tissue rejection, and immune and autoimmune disease in a mammal. One particular preferred application of such triazole-moiety containing rapamycin analog is in treating renal carcinoma, lung cancer, colon cancer, and breast cancers wherein potency of the drug, its half-life, tissue distribution properties, and its pharmacokinetic properties including bioavailability through oral and intravenous routes are essential to the clinical outcomes.
- -
-
-
- Design, Synthesis, and Evaluation of Triazole Derivatives That Induce Nrf2 Dependent Gene Products and Inhibit the Keap1-Nrf2 Protein-Protein Interaction
-
The transcription factor Nrf2 regulates the expression of a large network of cytoprotective and metabolic enzymes and proteins. Compounds that directly and reversibly inhibit the interaction between Nrf2 and its main negative regulator Keap1 are potential pharmacological agents for a range of disease types including neurodegenerative conditions and cancer. We describe the development of a series of 1,4-diphenyl-1,2,3-triazole compounds that inhibit the Nrf2-Keap1 protein-protein interaction (PPI) in vitro and in live cells and up-regulate the expression of Nrf2-dependent gene products.
- Bertrand, Hélène C.,Schaap, Marjolein,Baird, Liam,Georgakopoulos, Nikolaos D.,Fowkes, Adrian,Thiollier, Clarisse,Kachi, Hiroko,Dinkova-Kostova, Albena T.,Wells, Geoff
-
p. 7186 - 7194
(2015/10/05)
-
- RAFAMYCIN ANALOGS AND METHODS FOR MAKING SAME
-
A semi-synthetic rapamycin analog with a triazole moiety or a pharmaceutically acceptable salt or prodrug thereof, is a broad-spectrum cytostatic agent and a m TOR inhibitor, and is useful in the treatment of various cancers, or tumors in organs such as kidney, liver, breast, head and neck, lung, prostate, and restenosis in coronary arteries, peripheral arteries, and arteries in the brain, immune and autoimmune diseases. Also disclosed are fungal growth-, restenosis-, post- transplant tissue rejection- and immune- and autoimmune disease- inhibiting compositions and a method of inhibiting cancer, fungal growth, restenosois, post-transplant tissue rejection, and immune and autoimmune disease in a mammal. One particular preferred application of such triazole-moiety containing rapamycin analog is in treating renal carcinoma, lung cancer, colon cancer, and breast cancers wherein potency of the drug, its half-life, tissue distribution properties, and its pharmacokinetic properties including bioavailability through oral and intravenous routes are essential to the clinical outcomes.
- -
-
-
- Peripherally and axially carboxylic acid substituted subphthalocyanines for dye-sensitized solar cells
-
A series of subphthalocyanines (SubPcs) bearing a carboxylic acid group either at the peripheral or axial position have been designed and synthesized to investigate the influence of the COOH group positions on the dye-sensitized solar cell (DSSC) performance. The DSSC devices based on SubPcs with axially substituted carboxylic acid groups showed low photovoltaic performance, whereas peripherally substituted one exhibited higher power conversion efficiency owing to improved injection from LUMO of SubPcs to the TiO2 conduction band.
- Ince, Mine,Medina, Anais,Yum, Jun-Ho,Yella, Aswani,Claessens, Christian G.,Martinez-Diaz, M. Victoria,Graetzel, Michael,Nazeeruddin, Mohammad K.,Torres, Tomas
-
supporting information
p. 2016 - 2021
(2014/03/21)
-
- REAGENTS AND METHODS FOR SIRTUIN CAPTURE
-
The invention provides a method of preparing a sirtuin complex. The invention also provides a method of detecting a sirtuin in a sample comprising use of the aforesaid sirtuin complex.
- -
-
Page/Page column
(2013/03/28)
-
- ANTIBACTERIAL AGENTS
-
Antibacterial compounds of formula (I) are provided, as well as stereoisomers and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of such compounds.
- -
-
-
- Rapid discovery of highly potent and selective inhibitors of histone deacetylase 8 using click chemistry to generate candidate libraries
-
To find HDAC8-selective inhibitors, we designed a library of HDAC inhibitor candidates, each containing a zinc-binding group that coordinates with the active-site zinc ion, linked via a triazole moiety to a capping structure that interacts with residues on the rim of the active site. These compounds were synthesized by using click chemistry. Screening identified HDAC8-selective inhibitors including C149 (IC50 = 0.070 μM), which was more potent than PCI-34058 (6) (IC50 = 0.31 μM), a known HDAC8 inhibitor. Molecular modeling suggested that the phenylthiomethyl group of C149 binds to a unique hydrophobic pocket of HDAC8, and the orientation of the phenylthiomethyl and hydroxamate moieties (fixed by the triazole moiety) is important for the potency and selectivity. The inhibitors caused selective acetylation of cohesin in cells and exerted growth-inhibitory effects on T-cell lymphoma and neuroblastoma cells (GI50 = 3-80 μM). These findings suggest that HDAC8-selective inhibitors have potential as anticancer agents.
- Suzuki, Takayoshi,Ota, Yosuke,Ri, Masaki,Bando, Masashige,Gotoh, Aogu,Itoh, Yukihiro,Tsumoto, Hiroki,Tatum, Prima R.,Mizukami, Tamio,Nakagawa, Hidehiko,Iida, Shinsuke,Ueda, Ryuzo,Shirahige, Katsuhiko,Miyata, Naoki
-
p. 9562 - 9575
(2013/01/16)
-
- Polyacetylenes as enantiodifferentiating alignment media
-
Orientation help: Valine-derived polyacetylenes are introduced as enantiomer-differentiating alignment media. The F2-coupled HSQC-type NMR spectra of both enantiomers of isopinocampheol (IPC) display narrow line widths allowing for the precise extraction of residual dipolar couplings (black contour plot: (+)-IPC in an isotropic phase, blue: (-)-IPC in an anisotropic phase, and red: (+)-IPC in an anisotropic phase; J=coupling constant). Copyright
- Meyer, Nils-Christopher,Krupp, Alexis,Schmidts, Volker,Thiele, Christina M.,Reggelin, Michael
-
supporting information; experimental part
p. 8334 - 8338
(2012/09/08)
-
- UV-induced fluorescence recovery and solubility modulation of photocaged conjugated oligomers
-
This article describes photoactivatable conjugated oligomers that show both increased fluorescence quantum yield and pH-dependant solubility upon irradiation with UV light. Sonogashira coupling between ester-substituted phenylacetylenes and alkoxy-substituted diiodo phenylene-vinylenes yielded conjugated phenylene-ethynylene/phenylene-vinylene oligomers. Oligomers with nitrobenzyl ester moieties had quenched fluorescence in polar solvents; UV irradiation restored their quantum yield of fluorescence to that of corresponding alkyl ester-substituted oligomers. These photocaged oligomers also exhibited UV-induced changes in solubility consistent with photogeneration of carboxylic acids. This approach is therefore effective at tuning the properties of conjugated organics with light after traditional synthetic operations, and has potential for use in photoactivatable fluorophores or solution-processable multilayer devices.
- Pawle, Robert H.,Eastman, Victoria,Thomas, Samuel W.
-
supporting information; experimental part
p. 14041 - 14047
(2012/06/01)
-
- Synthesis of 3-tert-butyl-5-(4-vinylphenyl)-1,2,4-oxadiazole using two different pathways
-
3-tert-butyl-5-(4-vinylphenyl)-1,2,4-oxadiazole (1) has been synthesized in two different ways, using 3-tert-butyl-5-(4-ethynylphenyl)-1,2,4-oxadiazole (2) or 4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)benzaldehyde (3) as intermediates. The structure of compound 3 was confirmed by X-ray diffraction. 1,2,4-Oxadiazoles have been prepared using 1,1-carbonyldiimidazole (CDI) as a reagent for both formation and cyclodehydration of O-acyl-amidoximes. The use of CDI facilitates parallel purification of the oxadiazole products by simple liquid-liquid extraction and filtration. The heterocycles were obtained in good yields and in relatively short reaction times.
- Maftei, Catalin-Vasile,Fodor, Elena,Mangalagiu, Ionel,Jones, Peter G.,Daniliuc, Constantin-Gabriel,Franz, Heiko M.,Neda, Ion
-
p. 989 - 994
(2012/01/19)
-
- Smectic aggregates of sheet-like side-chain liquid crystalline polyacetylenes directly formed during solution polymerization
-
We have successfully synthesized two side-chain liquid crystalline polyacetylenes (denoted as P3-5 and P2-5) with the mesogenic units based on a "phenyl-ester-phenyl" motif directly linked to the semirigid polyacetylene backbone in a terminal-on mode without flexible spacer. During the polymerization catalyzed by Rh(nbd)[B(C6H5)4] in toluene, the resultant polymers (or oligomers) automatically precipitate out of the polymerization solution as red solids, which cannot be dissolved in common organic solvents. Wide-angle X-ray diffraction results confirm that the polymer precipitates possess a smectic (or sanidic) structure, suggesting that the molecules without flexible spacers are sheet-like and can stack parallel to each other during polymerization. We in situ monitored the solution polymerization and the aggregation processes using UV-visible and 1H NMR spectroscopy methods. The experimental results indicate that after reaching a critical molecular weight the P3-5 and P2-5 molecules self-aggregate in solution and that the smectic aggregation proceeds during the solution polymerization. An apparent first-order polymerization kinetics can be obtained after the polymerization and aggregation slowed down. The resultant polymers are cis-rich with the main-chain absorption at ~455 nm. This implies that a considerably long effective conjugation length is achieved in the sheet-like cis-rich polyacetylene derivatives.
- Liu, Lu-Mei,Liu, Kai-Peng,Dong, Yu-Ping,Chen, Er-Qiang,Tang, Ben Zhong
-
experimental part
p. 6014 - 6023
(2011/10/19)
-
- A suite of activity-based probes for human cytochrome P450 enzymes
-
Cytochrome P450 (P450) enzymes regulate a variety of endogenous signaling molecules and play central roles in the metabolism of xenobiotics and drugs. We recently showed that an aryl alkyne serves as an effective activity-based probe for profiling mouse liver microsomal P450s in vitro and in vivo. However, individual P450s display distinct substrate and inhibitor specificities, indicating that multiple probe structures may be required to achieve comprehensive coverage of this large and diverse enzyme family. Here, we have synthesized a suite of P450-directed, activity-based protein profiling (ABPP) probes that contain: (1) varied chemical architectures validated as mechanism-based inhibitors of the P450 enzyme family, and (2) terminal alkyne groups for click chemistry conjugation of reporter tags. This set of probes was screened against a wide cross-section of human P450s, leading to the discovery of an optimal set of probes that provide broad coverage of this enzyme family. We used these probes to profile the effects on P450 activity of aromatase inhibitors in current clinical use for the treatment of breast cancer. We describe the surprising discovery that one of these aromatase inhibitors, anastrozole, significantly increases probe-labeling of P450 1A2, indicative of a heterotypic cooperativity effect on a central P450 isozyme involved in metabolizing numerous drugs and xenobiotics. The results presented herein greatly expand the suite of ABPP probes for profiling P450s and illuminate new applications for these tools to understand P450-drug interactions.
- Wright, Aaron T.,Song, Joongyu D.,Cravatt, Benjamin F.
-
scheme or table
p. 10692 - 10700
(2009/12/08)
-
- Silica- and polymer-supported platinum(II) polypyridyl complexes: Synthesis and application in photosensitized oxidation of alkenes
-
Square-planar polypyridine platinum(II) complexes have been introduced into a silica/polymer matrix by covalent ligand modification. The photophysical properties of the supported matrices are well retained as their model complexes, and the quantum yields for singlet oxygen (1O2) generation are comparable with that of TPP (tetraphenylporphyrin) under similar conditions. A preliminary application in photosensitized oxidation indicates the silica/polymer-supported matrices are promising, which can be reused without loss of reactivity by a simple filtration. Moreover, the polymer-supported matrix exhibits excellent compatibility in various solvents. The Royal Society of Chemistry 2009.
- Feng, Ke,Peng, Ming-Li,Wang, Deng-Hui,Zhang, Li-Ping,Tung, Chen-Ho,Wu, Li-Zhu
-
experimental part
p. 9794 - 9799
(2010/03/04)
-
- Sonogashira coupling applied in the synthesis of 1,2,4-oxadiazole-based nonsymmetrical liquid crystals
-
A series of highly π-conjugated nonsymmetrical liquid crystals, based on the core 3,5-(disubstituted)-1,2,4-oxadiazole with a shape similar to a hockey stick, were successfully synthesized by convergent Sonogashira coupling reaction between the building blocks of aryl iodides and the corresponding terminal arylacetylenes, using 3-[4-(decyloxy)phenyl]-5-(haloaryl)-1,2,4-oxadiazoles or decyl 4-iodobenzoate (10) and terminal arylacetylenes. This versatile synthetic route yielded luminescent mesogens with smectic and nematic phases, typical of calamitic compounds. Georg Thieme Verlag Stuttgart.
- Gallardo, Hugo,Cristiano, Rodrigo,Vieira, Andre A.,Neves Filho, Ricardo A. W.,Srivastava, Rajendra M.
-
p. 605 - 609
(2008/12/21)
-
- Evidence for the assembly of carboxyphenylethynyl zinc porphyrins on nanocrystalline TiO2 surfaces
-
UV-visible absorption and AFM studies suggest that carboxyphenylethynyl zinc porphyrins aggregate on nanocrystalline TiO2 surfaces in an H-type fashion. The Royal Society of Chemistry 2006.
- Lo, Chen-Fu,Luo, Liyang,Diau, Eric Wei-Guang,Chang, I.-Jy,Lin, Ching-Yao
-
p. 1430 - 1432
(2008/02/03)
-
- Diminished helical character in para-substituted cis-transoidal polyphenylacetylenes due to intramolecular cyclization
-
The cis-transoidal PPA helix undergoes irreversible structural changes related to 6π electrocyclization of 1,3-cis-5-hexatriene sequences in the polymer backbone. The dynamics of the helical conformation is evaluated by optical rotation or circular dichroism (CD) spectra at various temperatures. Helical cis- and trans-poly(alkylacetylenes) exhibit different CD spectra in solutions. In the solution, 1,3-cis-5-hexatriene sequences in PPA and its substituted analogues undergo electrocyclization to form cyclohaxadiene repeat units. The results show that literature data on helical PPA are only qualitative as no complete structural analysis was reported in any previous studies.
- Percec, Virgil,Rudick, Jonathan G.,Aqad, Emad
-
p. 7205 - 7206
(2007/10/03)
-
- AN IMPROVED PROCEDURE FOR THE GENERATION AND SELECTIVE TRAPPING OF 2,4'-DILITHIOPHENYLETHYNE
-
2,4'-Dilithiophenylethyne, prepared by treatment of 4-bromophenylethyne with two equivalents of butyllithium, reacts selectively with electrophilic reagents at the 4'-position provided the correct temperature and solvent combination are employed.The successive addition of two different electrophiles gives the 2,4'-dialkylated product in a regioselective manner.
- Furber, Mark,Taylor, Richard J. K.,Burford, S. Cliff
-
p. C35 - C38
(2007/10/02)
-