- An Isosteric and Fluorescent DNA Base Pair Consisting of 4-aminophthalimide and 2,4-diaminopyrimidine as C-Nucleosides
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A 13mer DNA duplex containing the artificial 4-aminophthalimide:2,4-diaminopyrimidine (4AP:DAP) base pair in the central position was characterized by optical and NMR spectroscopy. The fluorescence of 4AP in the duplex has a large Stokes shift of Δλ=124 nm and a quantum yield of ΦF=24 %. The NMR structure shows that two interstrand hydrogen bonds are formed and confirms the artificial base pairing. In contrast, the 4-N,N-dimethylaminophthalimide moiety prefers the syn conformation in DNA. The fluorescence intensity of this chromophore in DNA is very low and the NMR structure shows no significant interaction with DAP. Primer-extension experiments with DNA polymerases showed that not only is the 4AP C nucleotide incorporated at the desired position opposite DAP in the template, but also that the polymerase is able to progress past this position to give the full-length product. The observed selectivity supports the NMR results.
- Merkel, Marcus,Dehmel, Lars,Ernsting, Nikolaus P.,Wagenknecht, Hans-Achim
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Read Online
- In pursuit of a selective hepatocellular carcinoma therapeutic agent: Novel thalidomide derivatives with antiproliferative, antimigratory and STAT3 inhibitory properties
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Advanced stage liver cancer is predominantly treated with the multi-kinase inhibitor sorafenib; however, this therapeutic agent lacks selectivity in its cytotoxic actions and is associated with poor survival outcomes. Herein we report the design and preparation of several thalidomide derivatives, including a variety of novel thioether-containing forms that are especially rare in the literature. Importantly, two of the derivatives described are potent antiproliferative agents with dose-dependent selectivity for tumorigenic liver progenitor cells (LPC) growth inhibition (up to 36% increase in doubling time at 10 μM) over non-tumorigenic cells (no effect at 10 μM). Furthermore, these putative anti-liver cancer agents were also found to be potent inhibitors of tumorigenic LPC migration. This report also describes these derivatives’ effects on several key signalling pathways in our novel liver cell lines by immunofluorescence and AlphaLISA assays. Aryl thioether derivative 7f significantly reduced STAT3 phosphorylation (23%) and its nuclear localisation (16%) at 10 μM in tumorigenic LPCs, implicating the IL-6/JAK/STAT3 axis is central in the mode of action of our derivatives.
- Nutt, Michael J.,Yee, Yeung Sing,Buyan, Amanda,Andrewartha, Neil,Corry, Ben,Yeoh, George C.T.,Stewart, Scott G.
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- COMPOUNDS AND USES THEREOF
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The present disclosure features compounds and methods useful for the treatment of BAF complex-related disorders.
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Page/Page column 316
(2021/08/06)
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- Synthesis method of 4-halogenated phthalic anhydride and derivative thereof
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The invention relates to a synthetic method of 4-halogenated phthalic anhydride and a derivative of the 4-halogenated phthalic anhydride, and solves the technical problems of low product purity, poorproduct performance, complex synthetic process and low utilization ratio of monohalide isomers and polyhalides in the existing production process. The method specifically comprises the following steps: dissolving phthalic anhydride in an organic solvent, and introducing a halogenating reagent under the action of iron powder and a Lewis acid catalyst to prepare a halogenated phthalic anhydride mixture; rectifying and purifying the polyhalogenated phthalic anhydride mixture to obtain a 4-halogenated phthalic anhydride pure product; and continuing subjecting residual halogenated phthalic anhydride mixture to halogenation reaction under the action of fuming sulfuric acid and the catalyst to prepare tetrahalogenated phthalic anhydride, and to realize comprehensive utilization of the raw materials. The method is widely applied to the technical field of flame retardant synthesis.
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Paragraph 0024-0027; 0029-0032; 0034-0037; 0039-0042; 0044-0
(2020/12/30)
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- Dihydroxyphenyl Sulfonylisoindoline Derivatives
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Provided are compounds that are inhibitors of pyruvate dehydrogenase kinase (PDK), and pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition.
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Paragraph 058; 060; 0116
(2018/06/12)
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- PROCESS FOR THE PREPARATION OF ORGANIC BROMIDES
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The present invention provides a process for the preparation of organic bromides, by a radical bromodecarboxylation of carboxylic acids with a bromoisocyanurate.
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Paragraph 00139; 00141; 00162
(2017/07/28)
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- Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors
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Pyruvate dehydrogenase kinases 1-4 (PDK1-4) negatively control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure, and cancer. We reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] (1) and PS10 [2-((2,4-dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] (2) that targeted the ATP-binding pocket in PDKs. Here, we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in 1 and 2 to the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor (S)-3-amino-4-(4-((2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)-4-oxobutanamide (17) shows a ～8-fold lower IC50 (58 nM) than 2 (456 nM). In the crystal structure, the asparagine moiety in 17 provides additional interactions with Glu-262 from PDK2. Treatment of diet-induced obese mice with 17 resulted in significant liver-specific augmentation of PDC activity, accompanied by improved glucose tolerance and drastically reduced hepatic steatosis. These findings support 17 as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes.
- Tso, Shih-Chia,Lou, Mingliang,Wu, Cheng-Yang,Gui, Wen-Jun,Chuang, Jacinta L.,Morlock, Lorraine K.,Williams, Noelle S.,Wynn, R. Max,Qi, Xiangbing,Chuang, David T.
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supporting information
p. 1142 - 1150
(2017/02/19)
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- Industrial preparation method of 5-bromophthalide
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The invention relates to a preparation method of 5-bromophthalide and mainly solves such production technical problems of an existing preparation method as expensive raw material, dangerous and complex operation, relatively low yield, high quantity of generated three wastes and etc. The technical scheme of the invention is as follows: an industrial preparation method of 5-bromophthalide is characterized in that 5-bromophthalide is obtained through three step reactions of bromination, ammoniation and reduction by taking a conventional and easily available ammoniation as a raw material. The chemical reaction formula is as shown in the description. The method provided by the invention is mainly used for industrial preparation of 5-bromophthalide.
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- Preparation method of 4-bromo phthalic anhydride
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The invention belongs to the field of chemical engineering, and relates to a preparation method of 4-bromo phthalic anhydride. The preparation method includes the following steps that sodium hydroxide is dissolved in water, phthalic anhydride and a phase transfer catalyst are added and evenly mixed, a reaction is performed in the mode that programmed temperature control is performed in three stages and reactants are added in three times, 20% fuming sulphuric acid is added for acidification, a sodium bisulfite aqueous solution is added after cooling for removing excessive bromine, an organic solvent is added for extraction, the organic solvent is removed through distillation, then temperature is increased to obtain a crude 4-bromo phthalic anhydride product, rectification dehydration is performed under the vacuum condition, fraction is collected, and the finished 4-bromo phthalic anhydride product is obtained. Compared with a multi-step reaction in the prior art, the process steps are simplified, the product yield is high, the production energy consumption is reduced, the three-waste emission is greatly reduced, the energy consumption and wastewater treatment cost for extraction of 4-bromophthalic acid crystals are reduced, production cost is reduced, and environmental protection pressure is relieved.
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Paragraph 0025
(2016/12/01)
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- Synthesis and biological evaluation of novel aromatic imide-polyamine conjugates
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Three types of conjugates in which aromatic imide scaffolds were coupled to diverse amine/polyamine motifs were synthesized, and their antitumor activities were evaluated in vitro and in vivo. Results showed that the conjugate 11e of 1,8-naphthilimide with spermine had pronounced effects on inhibiting tumor cell proliferation and inducing tumor cell apoptosis via ROS-mediated mitochondrial pathway. The in vivo assays on three H22 tumor transplant models revealed that compound 11e exerted potent ability in preventing lung cancer metastasis and extending lifespan. Furthermore, the efficacy of 11e in inhibiting tumor growth and improving body weight index were better than that of positive control, amonafide. Our study demonstrates that compound 11e is a valuable lead compound for further investigation.
- Li, Ming,Wang, Yuxia,Zhang, Jianying,Xie, Songqiang,Wang, Chaojie,Wu, Yingliang
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- Design, synthesis and structure-activity relationship studies of morpholino-1H-phenalene derivatives that antagonize Mcl-1/Bcl-2
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We report herein characteristic studies of Mcl-1 and Bcl-2 dual inhibitors. It was found that a protruding carbonyl group forming hydrogen bond with R263 plays a predominant role compared with the hydrophobic group that occupies the p2 pocket. A series of dual inhibitors representing different parts of the morpholino-1H-phenalene were designed, synthesized and evaluated.
- Li, Xiangqian,Liang, Xiaomeng,Song, Ting,Su, Pengchen,Zhang, Zhichao
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p. 5738 - 5746
(2015/02/02)
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- An anthraquinone scaffold for putative, two-face bim BH3 α-helix mimic
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Bim BH3 peptide features an α-helix with hotspot residues on multiple faces. Compound 5 (6-bromo-2,3-dihydroxyanthracene-9,10-dione), which adopts a rigid-plan amphipathic conformation, was designed and evaluated as a scaffold to mimic two faces of Bim α-helix. It reproduced the functionalities of both D67 and I65 on two opposing helical sides. Moreover, it maintained the two-faced binding mode during further evolution. A putative BH3 α-helix mimic and nanomolar Bcl-2/Mcl-1 dual inhibitor, 6, was obtained based on the structure of 5.
- Zhang, Zhichao,Li, Xiangqian,Song, Ting,Zhao, Yan,Feng, Yingang
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p. 10735 - 10741
(2013/02/23)
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- HISTAMINE H3 INVERSE AGONISTS AND ANTAGONISTS AND METHODS OF USE THEREOF
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Provided herein are fused imidazolyl compounds, methods of synthesis, and methods of use thereof. The compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, such as neurological disorders and metabolic disorders. Compounds provided herein inhibit the activity of histamine H3 receptors and modulate the release of various neurotransmitters, such as histamine, acetylcholine, norepinephrine, and dopamine (e.g. at the synapse). Pharmaceutical formulations containing the compounds and their methods of use are also provided herein.
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Page/Page column 109
(2010/08/18)
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- Anticonvulsant and neurotoxicity evaluation of new bromophthalimidobutyryl amide derivatives
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A series of 4-(5-bromo-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-butyryl N-(substituted phenyl) amides (3a-l) were synthesized and evaluated for their anticonvulsant activity in MES test according to the protocols of Antiepileptic Drug Development (ADD) programme of National Institutes of Health (NIH, Bethesda, USA).The most active compounds of the series were 3a, 3c, 3d, 3f, 3g, 3i and 3k at the dose of 30 mg/kg (i.p.) 0.5 h and 4 h after administration. In neurotoxic screen (NT), 3d, 3i and 3k were less toxic when compared with the other compounds.
- Khan, Suroor A.,Siddiqui, Nadeem,Kamal, Mehnaz,Alam, Ozair,Jawaid, Talha
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experimental part
p. 65 - 68
(2009/06/06)
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- Asymmetric dihydroxylations using immobilized alkaloids with an anthraquinone core
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In osmium-catalyzed dihydroxylations use of polymer-supported alkaloids with an anthraquinone core allows to obtain optically active diols with high enantioselectivities. Soluble as well as insoluble polymers have been tested for immobilization.
- Bolm,Maischak
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- Kinetics and mechanism of the formation of mono- and di-phthalate esters catalysed by titanium and tin alkoxides
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The kinetics and mechanism of the formation of phthalate mono-esters and phthalate di-esters from phthalic anhydride and a variety of mono- and di-hydric alcohols are reported and discussed. The kinetic work is extended to a mechanistic study of the same reactions using titanium tetra-n-butoxide and tri-n-butyltin ethoxide as catalysts. The results support a mechanism involving alkoxy ligand exchange at the metal as a crucial step in the catalysis.
- Hinde, Nicholas J.,Hall, C. Dennis
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p. 1249 - 1256
(2007/10/03)
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- Conformationally restricted analogues of remoxipride as potential antipsychotic agents
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Several conformationally restricted derivatives of (S)-3-bromo-N-((1- ethyl-2-pyrrolidinyl)methyl)-2,6-dimethoxybenzamide (remoxipride) were synthesized and evaluated in vitro for their ability to inhibit [3H]raclopride binding at the dopamine D-2 receptor. The cyclic benzamides designed to mimic the intramolecular hydrogen bonding of desmethylremoxipride (4, FLA-797) included 2,3-dihydro-4H-1,3-benzoxazin-4-ones, 2,3-dihydro-4H- 1,3-benzthiazin-4-ones, phthalimides, 1-isoindolinones, 1,2-benzisothiazol- 3(2H)-ones, and 1,2-benzisothiazol-3(2H)-one 1,1-dioxides. In this series, enhanced affinities to the dopamine D-2 receptor were not observed. The phthalimidine analogue 24b ((S)-6-chloro-2-(1-ethylpyrrolidinyl)-1- isoindolinone) exhibited the highest affinity to the dopamine D-2 receptor with an IC50 of 1.3 μM, which was equipotent to remoxipride.
- Norman,Kelley,Hollingsworth
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p. 3417 - 3423
(2007/10/02)
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- Process for the preparation of 4-bromophthalic anhydride
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A process for the production of 4-bromophthalic anhydride which comprises the reaction of 4-chlorotetrahydrophthalic anhydride with elemental bromine, in the presence of a catalytically effective amount of iron or an iron salt is disclosed.
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- Light stabilizing flame retardants
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This invention provides novel hindered amine light stabilizers with flame retardant properties. The compounds of this invention protect polymeric compositions against the degradative effects of heat and light and simultaneously improve the flammability rating of the polymeric composition, while also contributing antioxidant and metal deactivation properties to the polymeric compositions. The compositions of this invention are prepared by reacting halogenated flame retardant containing a cyclic anhydride group with hindered amine light stabilizers containing primary amino or reactive hydrazido functional groups. The preparation of the novel compositions may be carried out in inert solvents or in inert polymeric compositions in a melt blending step.
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- Flame retardant for polymeric compositions
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An additive flame retardant bisimide containing halogen atoms and ammonium acid tetrahalophthalate, e.g. N,N'-bis(2-ethylene tetrabromophthalimide) ammonium acid tetrabromophthalate. These compounds are useful in a variety of polymeric compositions and demonstrate increased thermal stability. They also foam on decomposition with the evolution of gas thus readily lending themselves to the preparation of flame retardant coatings.
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- Benzocyclobutenes. Part 4. Synthesis of Benzocyclobutene-1,2-diones by Pyrolytic Methods
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Oxidation of the cyclic hydrazides prepared from phthalic anhydrides in the presence of anthracene gives the corresponding Diels-Alder adducts which, on flash vacuum pyrolysis, give benzocyclobutene-1,2-dione (BBD) and its 4-chloro, 3,6- and 4,5-dichloro, 4,5-dibromo, and 4,5-dimethyl derivatives in 75-98percent yield.Cyclobuta- and cyclobuta-naphthalene-1,2-dione as well as cyclobuta- and cyclobuta-pyridine-1,2-dione have been prepared similarly; the last three of these diones are very unstable.Cyclobutanaphthalene-1,2-dione has also been made by pyrolysis of benzindene-1,2,3-trione.Attempts to make thiophen and furan analogues of BBD from appropriate anthracene adducts failed as did attempts to make tetrachloro- and tetrabromo-derivatives of BBD by the pyrolysis of tetrahalogenophthalimidosulphoximides.
- Gould, Ken J.,Hacker, Nigel P.,McOmie, John F. W.,Perry, David H.
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p. 1834 - 1840
(2007/10/02)
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