- Various located urea and schiff-base bifunctional derivatives: Their gelation and Zn2+ sensing behaviors
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The efficient combination of various moieties is helpful to develop organic functional molecules. Herein, three of urea and Schiff-base bifunctional derivatives (OG, MG and PG) were prepared from o/m/p-diaminobenzene respectively. Benefitting from the urea and Schiff-base, these derivatives revealed satisfactory gelation capacity. However, the various locations of urea and imine paved them markedly different assembly performances during the gel formation. Additionally, these functional molecules displayed obvious “off-on” fluorescence sensing behaviors towards Zn2+ in solution ascribing to the imine and neighbor phenolic hydroxyl, among which the MG displayed the best Zn2+ selectivity. Crucially, the MG also realized Zn2+ probing at cellular level and its gel gave a visual detection via the gel-sol transition.
- Chen, Yu,Lei, Zhimei,Liu, Jie,Sun, He-Lue,Xing, Li-Juan,Yu, Haitao,Zhang, Xin
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- Secondary Sphere Hydrogen Bonding in Monocopper Complexes of Potentially Dinucleating Bis(carboxamide) Ligands
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Reaction of a macrocyclic ligand precursor comprising two bis(carboxamido)pyridine units (H4L4) connected by ethylene linkers with NMe4OH and CuX2 (X = Cl, OAc, or OTf) yielded monocopper complexes [NMe4][(Hsub
- Neisen, Benjamin D.,Solntsev, Pavlo V.,Halvagar, Mohammad R.,Tolman, William B.
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- Synthesis of tert-butyl (substituted benzamido)phenylcarbamate derivatives: anti-inflammatory activity and docking studies
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A series of new tert-butyl 2-(substituted benzamido) phenylcarbamate (4a–4j) were synthesized by the condensation of tert-butyl 2-amino phenylcarbamate (3) with various substituted carboxylic acid in the presence of EDCI and HOBt as coupling reagent, obta
- Bhookya, Shankar,Pochampally, Jalapathi,Valeru, Anil,Sunitha, Vianala,Balabadra, Saikrishna,Manga, Vijjulatha,Kudle, Karunakar rao
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- Chemoselective modifications for the traceless ligation of thioamide-containing peptides and proteins
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Thioamides are single-atom substitutions of canonical amide bonds, and have been proven to be versatile and minimally perturbing probes in protein folding studies. Previously, our group showed that thioamides can be incorporated into proteins by native chemical ligation (NCL) with Cys as a ligation handle. In this study, we report the expansion of this strategy into non-Cys ligation sites, utilizing radical initiated desulfurization to "erase" the side chain thiol after ligation. The reaction exhibited high chemoselectivity against thioamides, which can be further enhanced with thioacetamide as a sacrificial scavenger. As a proof-of-concept example, we demonstrated the incorporation of a thioamide probe into a 56 amino acid protein, the B1 domain of Protein G (GB1). Finally, we showed that the method can be extended to β-thiol amino acid analogs and selenocysteine.
- Wang, Yanxin J.,Szantai-Kis, D. Miklos,Petersson, E. James
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- Heli(aza)cene: A Helical Molecular Tweezer with Tunable Intra- and Intermolecular Charge Transfer
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Non-planar fluorophores offer unique avenues of intra- and intermolecular energy transfer not available in their planar counterparts. We have rationally designed a molecular tweezer based on the pyridine-2,6-dicarboxamide framework having two structurally
- Kumar, Rajesh,Semwal, Shrivats,Choudhury, Joyanta,Srivastava, Aasheesh
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- A live bacteria SERS platform for the: In situ monitoring of nitric oxide release from a single MRSA
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A simple and unique surface-enhanced Raman spectroscopy (SERS) platform is developed for the precise and sensitive in situ monitoring of nitric oxide (NO) release from an individual bacterium. Using this live bacteria SERS platform, NO release from MRSA u
- Zhang, Zhijun,Han, Xuemei,Wang, Zhimin,Yang, Zhe,Zhang, Wenmin,Li, Juan,Yang, Huanghao,Ling, Xing Yi,Xing, Bengang
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- Nitrogen Bridged Diazocines: Photochromes Switching within the Near-Infrared Region with High Quantum Yields in Organic Solvents and in Water
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Diazocines are bridged azobenzenes with superior photophysical properties. In contrast to azobenzenes the Z configuration is thermodynamically stable and the E isomer is metastable. We present a new class of nitrogen bridged diazocines with bathochromically shifted switching wavelengths and remarkably high quantum yields (-NH-CH2- bridged diazocine: φZ→E = 0.57, φE→Z = 0.8). Z to E isomerization is induced by irradiation with blue light, whereas switching back to the Z isomer is accomplished with light in the near-infrared window (up to 740 nm), which is important for medical applications like photopharmacology (deep tissue penetration). Furthermore, substitution at the bridging nitrogen should provide access to widely applicable tricyclic, photoswitchable pharmacophores. The -NAc-CH2- bridged derivative is soluble in water, and all photophysical properties (conversion rates, quantum yields, and thermal half-lives) are largely retained. Hence, this diazocine is an ideal photoswitch for applications in biochemical systems and in photopharmacology.
- Brahms, Arne,Gescheidt, Georg,Gr?bner, Jens,Herges, Rainer,Lentes, Pascal,R?hricht, Fynn,S?nnichsen, Frank D.,Stadler, Eduard
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- Pojamide: An HDAC3-Selective Ferrocene Analogue with Remarkably Enhanced Redox-Triggered Ferrocenium Activity in Cells
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A ferrocene containing o-aminoanilide, N1-(2-aminophenyl)-N8-ferrocenyloctanediamide (2b, Pojamide) displayed nanomolar potency vs HDAC3. In comparison to RGFP966, a potent and selective HDAC3 inhibitor, Pojamide displayed superior a
- Ocasio, Cory A.,Sansook, Supojjanee,Jones, Rhiannon,Roberts, Justin M.,Scott, Thomas G.,Tsoureas, Nikolaos,Coxhead, Peter,Guille, Matthew,Tizzard, Graham J.,Coles, Simon J.,Hochegger, Helfrid,Bradner, James E.,Spencer, John
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- Rhenium(I) polypyridine diamine complexes as intracellular phosphorogenic sensors: Synthesis, characterization, emissive behavior, biological properties, and nitric oxide sensing
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We report the development of a series of rhenium(I) polypyridine complexes appended with an electron-rich diaminoaromatic moiety as phosphorogenic sensors for nitric oxide (NO). The diamine complexes [Re(N^N)(CO)3(py-DA)] [PF6] (py-DA=3-(N-(2-amino-5-methoxyphenyl)aminomethyl)pyridine; N^N=1,10-phenanthroline (phen) (1a), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4-phen) (2a), 4,7-diphenyl-1,10-phenanthroline (Ph 2-phen) (3a)) have been synthesized and characterized. In contrast to common rhenium(I) diimines, these diamine complexes were very weakly emissive due to quenching of the triplet metal-to-ligand charge-transfer ( 3MLCT) emission by the diaminoaromatic moiety through photoinduced electron transfer (PET). Upon treatment with NO, the complexes were converted into the triazole derivatives [Re(N^N)(CO)3(py-triazole)][PF 6] (py-triazole=3-((6-methoxybenzotriazol-1-yl)methyl)pyridine; N^N=phen (1b), Me4-phen (2b), Ph2-phen (3b)), resulting in significant emission enhancement (I/I0≈60). The diamine complexes exhibited high reaction selectivity to NO, and their emission intensity was found to be independent on pH. Also, these complexes were effectively internalized by HeLa cells and RAW264.7 macrophages with negligible cytotoxicity. Additionally, the use of complex 3a as an intracellular phosphorogenic sensor for NO has been demonstrated. Emission turned ON for NO: A series of rhenium(I) polypyridine complexes functionalized with an electron-rich diaminoaromatic moiety has been developed as a new class of phosphorogenic sensors for NO. Upon treatment with NO, the weakly emissive complexes were converted into the strongly emissive triazole derivatives, resulting in significant emission enhancement (I/I0≈60; see figure). Experiments showed that the diamine complexes can sense NO that is 1) generated exogenously by NOC-7 in HeLa cells and 2) produced endogenously in RAW264.7 macrophages.
- Choi, Alex Wing-Tat,Yim, Vicki Man-Wai,Liu, Hua-Wei,Lo, Kenneth Kam-Wing
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- Synthesis of novel acyclic and multiple phenyl iron tetraamino ligand catalysts and its catalytic activity for degradation of dye wastewater by H2O2
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We need a practical, inexpensive, and green way to reduce the environmental pollutants, especially for dye wastewater. The discharge of industrial wastewater such as organic dyes will cause serious pollution to water bodies, thereby affecting people's liv
- Li, Shun-Lai,Zhou, Run,Zhao, Wei-Jing,Du, Hong-Guang
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- HDAC DEGRADER
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The disclosure provides compounds of formula (I). The compounds may be used to degrade the Histone Deacetylase (HDAC) family of enzymes, particularly HDAC1, 2 and 3 that exist in corepressor complexes. Accordingly, the compounds may
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Page/Page column 37; 41
(2021/07/31)
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- Calculated oxidation potentials predict reactivity in Baeyer-Mills reactions
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Azobenzenes are widely used as dyes and photochromic compounds, with the Baeyer-Mills reaction serving as the most common method for their preparation. This transformation is often plagued by low yields due to the formation of undesired azoxybenzene. Here, we explore electronic effects dictating the formation of the azoxybenzene side-product. Using calculated oxidation potentials, we were able to predict reaction outcomes and improve reaction efficiency simply by modulating the oxidation potential of the arylamine component.
- Gingrich, Phillip W.,Olson, David E.,Tantillo, Dean J.,Tombari, Robert J.,Tuck, Jeremy R.,Yardeny, Noah
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supporting information
p. 7575 - 7580
(2021/09/22)
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- Sulfated tungstate: A highly efficient, recyclable and ecofriendly catalyst for chemoselective N-tert butyloxycarbonylation of amines under the solvent-free conditions
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Sulfated tungstate catalyzed an efficient and ecofriendly protocol has been described for the chemoselective N-tert-butyloxycarbonylation of amines under the solvent-free conditions at room temperature. The variety of functionalized aliphatic, aromatic and heteroaromatic amines efficiently undergoes the N-tert-butyloxycarbonylation under the developed protocol. The aminoalcohol, aminophenol, aminoester as well as various chiral amines underwent the chemoselective N-Boc protection under the optimized reaction condition. The rapid reaction rate, mild conditions, very good functional group tolerance, excellent yield, solvent-free, easy recovery products and excellent catalyst recyclability are the advantages of this protocol. This makes the protocol feasible, economical and environmentally benign.
- Ingale, Ajit P.,Shinde, Sandeep V.,Thorat, Nitin M.
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supporting information
p. 2528 - 2543
(2021/07/02)
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- Cannabinoid receptor light-operated ligand and preparation method and application thereof
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The invention relates to the technical field of biology, in particular to a novel cannabinoid receptor light-operated ligand and a preparation method and application thereof. Disclosed is the cannabinoid receptor light-operated ligand or the isomer prodrug, the solvate and the pharmaceutically acceptable salt of the cannabinoid receptor light-operated ligand, wherein the structural formula of thecannabinoid receptor light-operated ligand is A-linker-B; A is a transmembrane domain ligand structure, and B is a light-operated element; Linker is a subunit which is linear and has no activity on acannabinoid receptor light-operated ligand. According to the invention, the cannabinoid receptor ligand is integrated with azobenzene through a proper connector, so that the ligand configuration is changed under an illumination condition, and the activation or inhibition state of the cannabinoid receptor is regulated and controlled.
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Paragraph 0066; 0073-0078
(2021/01/24)
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- Rational Remodeling of Atypical Scaffolds for the Design of Photoswitchable Cannabinoid Receptor Tools
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Azobenzene-embedded photoswitchable ligands are the widely used chemical tools in photopharmacological studies. Current approaches to azobenzene introduction rely mainly on the isosteric replacement of typical azologable groups. However, atypical scaffolds may offer more opportunities for photoswitch remodeling, which are chemically in an overwhelming majority. Herein, we investigate the rational remodeling of atypical scaffolds for azobenzene introduction, as exemplified in the development of photoswitchable ligands for the cannabinoid receptor 2 (CB2). Based on the analysis of residue-type clusters surrounding the binding pocket, we conclude that among the three representative atypical arms of the CB2 antagonist, AM10257, the adamantyl arm is the most appropriate for azobenzene remodeling. The optimizing spacer length and attachment position revealed AzoLig 9 with excellent thermal bistability, decent photopharmacological switchability between its two configurations, and high subtype selectivity. This structure-guided approach gave new impetus in the extension of new chemical spaces for tool customization for increasingly diversified photo-pharmacological studies and beyond.
- Hu, Tao,Hua, Tian,Li, Fei,Liu, Zhi-Jie,Makriyannis, Alexandros,Stevens, Raymond C.,Tao, Houchao,Tian, Cuiping,Xie, Linshan,Xu, Yueming,Xue, Dongxiang,Zhao, Fei,Zhao, Simeng,Zhao, Suwen,Zheng, Guoxun,Zhong, Guisheng,Zhou, Fang
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p. 13752 - 13765
(2021/09/20)
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- Copper-mediated ortho C–H primary amination of anilines
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We report herein a copper-mediated ortho C–H primary amination of anilines by using cheap and commercially available benzophenone imine as the amination reagent. The protocol show good functional group tolerance and heterocyclic compatibility. Late-stage diversification of drugs demonstrate the synthetic utility of this protocol.
- Cheng, Tai-Jin,Wang, Xing,Xu, Hui,Dai, Hui-Xiong
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supporting information
(2021/05/10)
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- Synthesis and structure-activity relationships of new 2-phenoxybenzamides with antiplasmodial activity
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The 2-phenoxybenzamide 1 from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of P. falciparum. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of P. falciparum. Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D7.4 and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The tert-butyl-4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against P. falciparum NF54 (PfNF54 IC50 = 0.2690 μM) and very low cytotoxicity (L-6 cells IC50 = 124.0 μM) resulting in an excellent selectivity index of 460. Compared to the lead structure 1 the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters.
- Dolensky, Johanna,Hermann, Theresa,Hochegger, Patrick,Kaiser, Marcel,M?ser, Pascal,Pferschy-Wenzig, Eva-Maria,Saf, Robert,Seebacher, Werner,Weis, Robert
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- A Greener Approach for the Chemoselective Boc Protection of Amines Using Sulfonated Reduced Graphene Oxide as a Catalyst in Metal- And Solvent-Free Conditions
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Sulfonated reduced graphene oxide (SrGO) has displayed great potential as a solid acid catalyst due to its efficiency, cost-effectiveness, and reliability. In this study, SrGO was synthesized by the introduction of sulfonic acid-containing aryl radicals onto chemically reduced graphene oxide using ultrasonication. The SrGO catalyst was characterized by Fourier Transform Infrared (FTIR) spectroscopy, Raman spectroscopy, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and transmission electron microscopy (TEM). Further, SrGO was effectively utilized as a metal-free and reusable solid acid catalyst for the chemoselective N - t -Boc protection of various aromatic and aliphatic amines under solvent-free conditions. The N - t -Boc protection of amines was easily achieved under ambient conditions affording high yields (84-95percent) in very short reaction times (5 min-2 h). The authenticity of the approach was confirmed by a crystal structure. The catalyst could be easily recovered and was reused up to seven consecutive catalytic cycles without any substantial loss in its activity.
- Awasthi, Satish K.,Mishra, Anupam,Mittal, Rupali
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p. 591 - 601
(2020/02/13)
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- PROTAC-mediated degradation of class i histone deacetylase enzymes in corepressor complexes
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We have identified a proteolysis targeting chimera (PROTAC) of class I HDACs 1, 2 and 3. The most active degrader consists of a benzamide HDAC inhibitor, an alkyl linker, and the von Hippel-Lindau E3 ligand. Our PROTAC increased histone acetylation levels and compromised colon cancer HCT116 cell viability, establishing a degradation strategy as an alternative to class I HDAC inhibition.
- Adams, Grace E.,Cowley, Shaun Michael,Hodgkinson, James T.,Millard, Christopher J.,Norris, James K. S.,Schwabe, John W. R.,Smalley, Joshua P.,Song, Yun
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supporting information
p. 4476 - 4479
(2020/05/13)
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- Synthesis of a simplified iron(III) tetraamido macrocyclic ligand (FeIII-TAML) catalyst and its catalytic activity for degradation of dye wastewater by H2O2
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To reduce the cost of water treatment reagents, a simplified iron(III) tetraamido macrocyclic ligand compound (FeIII-TAML) was synthesized with a total yield of 53.3%. For comparison, two second generation FeIII-TAML catalysts were s
- Li, Shunlai,Wang, Liaoyuan,Zhou, Run,Zhou, Cheng,Du, Hongguang
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p. 217 - 228
(2020/01/22)
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- Discovery of novel indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase 1 (HDAC1) dual inhibitors derived from the natural product saprorthoquinone
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The discovery of IDO1 and HDAC1 dual inhibitors may provide a novel strategy for cancer treatment by taking advantages of both immunotherapeutic and epigenetic drugs. In this paper, saprorthoquinone (1) and 13 of its analogues from Salvia prionitis Hance were investigated for their SAR against IDO1, the results demonstrated the ortho-quinone was a key pharmacophore. Then a series of IDO1 and HDAC dual inhibitors connected by appropriate linkers were designed, synthesized, and evaluated from the hit compound saprorthoquinone (1). Among them, compound 33d showed balanced activity against both IDO1 (IC50 = 0.73 μM) and HDAC1 (IC50 = 0.46 μM). Importantly, the structure of 33d suggested that an ortho-quinone pharmacophore and a N-(2- aminophenyl) amide pharmacophore were necessary for the IDO inhibition and HDAC inhibition respectively. Meanwhile, these two pharmacophore groups should be combined by a pentane linker. Moreover, the binding modes of 33d to the enzyme active site showed that the hydrogen bond with Leu234 of IDO1 appeared to confer increased potency to this class of inhibitors, which may explain the higher activity of 33d. This study provides a new strategy for future IDO1/HDAC dual inhibitors with synergistic antitumor activity started from lead compound 33d.
- Lin, Yang,Zhang, Heyanhao,Niu, Tong,Tang, Mei-Lin,Chang, Jun
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- N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN-γ induced PD-L1 expression
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Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC50 values in nanomolar range with Compound 20 (HDAC IC50 = 194 nM; HSP90α IC50 = 153 nM) and compound 26 (HDAC IC50 = 360 nM; HSP90α IC50 = 77 nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for cancer treatment in the future.
- Mehndiratta, Samir,Lin, Mei-Hsiang,Wu, Yi-Wen,Chen, Chun-Han,Wu, Tung-Yun,Chuang, Kuo-Hsiang,Chao, Min-Wu,Chen, Yi-Ying,Pan, Shiow-Lin,Chen, Mei-Chuan,Liou, Jing-Ping
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- Tert-Butyl(3-cyano-4,6-dimethylpyridin-2-yl)carbonate as a green and chemoselective N-tert-butoxycarbonylation reagent
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The use of tert-butyl(3-cyano-4,6-dimethylpyridin-2-yl)carbonate as a chemoselective tert-butoxycarbonylation reagent for aromatic and aliphatic amines has been demonstrated. To gain insight into this reaction, in situ React IR technology was used to confirm the effectivity and chemoselectivity of this novel Boc reagent. The reaction was carried out chemoselectively in high yield under mild, environment-friendly conditions and was completed quickly within 1 hour. Simultaneously, the Boc carrier was easily recyclable, and has great application prospects for industrial production.
- Du, Fangyu,Zhou, Qifan,Fu, Yang,Zhao, Hanqi,Chen, Yuanguang,Chen, Guoliang
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supporting information
p. 6549 - 6554
(2019/05/04)
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- Structurally Diverse Histone Deacetylase Photoreactive Probes: Design, Synthesis, and Photolabeling Studies in Live Cells and Tissue
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Histone deacetylase (HDAC) activity is modulated in vivo by post-translational modifications and formation of multiprotein complexes. Novel chemical tools to study how these factors affect engagement of HDAC isoforms by HDAC inhibitors (HDACi) in cells and tissues are needed. In this study, a synthetic strategy to access chemically diverse photoreactive probes (PRPs) was developed and used to prepare seven novel HDAC PRPs 9–15. The class I HDAC isoform engagement by PRPs was determined in biochemical assays and photolabeling experiments in live SET-2, HepG2, HuH7, and HEK293T cell lines and in mouse liver tissue. Unlike the HDAC protein abundance and biochemical activity against recombinant HDACs, the chemotype of the PRPs and the type of cells were key in defining the engagement of HDAC isoforms in live cells. Our findings suggest that engagement of HDAC isoforms by HDACi in vivo may be substantially modulated in a cell- and tissue-type-dependent manner.
- Aboukhatwa, Shaimaa M.,Hanigan, Thomas W.,Taha, Taha Y.,Neerasa, Jayaprakash,Ranjan, Rajeev,El-Bastawissy, Eman E.,Elkersh, Mohamed A.,El-Moselhy, Tarek F.,Frasor, Jonna,Mahmud, Nadim,McLachlan, Alan,Petukhov, Pavel A.
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supporting information
p. 1096 - 1107
(2019/04/17)
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- Chemoselective: N-tert -butyloxycarbonylation of amines in glycerol
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A catalyst-free, efficient and green protocol has been developed for the chemoselective N-Boc protection of amines by using glycerol as a solvent at room temperature. A variety of functionalized amines, such as aliphatic, aromatic as well as heteroaromatic were protected using the developed protocol. N-tert-Butyloxycarbonylation derivatives were formed without the formation of isocyanate, urea, N,N-di-t-Boc, or oxazolidinone as side products. The operational simplicity, cleaner reaction, rapid reaction convergence, functional group tolerance, excellent yield, high selectivity, catalyst-free feature and solvent recyclability are the distinct advantages of this protocol. Owing to these merits, this protocol is feasible, economical and environmentally benign.
- Ingale, Ajit P.,More, Vishal K.,Gangarde, Uddhav S.,Shinde, Sandeep V.
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supporting information
p. 10142 - 10147
(2018/06/18)
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- Schiff-base appended polymers for phosphate removal
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The remediation of phosphate-contaminated water bodies and the effective treatment of hyperphosphatemia are two big challenges in which phosphate recognition could play a useful role. Here, we summarise briefly the state of the art in phosphate removal. Next, we present findings from synthetic and phosphate extraction studies that involve polymeric materials with pendent Schiff-base macrocycles designed to function as phosphate anion receptors.
- Deliomeroglu, Murat K.,Lynch, Vincent M.,Sessler, Jonathan L.
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p. 807 - 821
(2017/09/25)
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- Design, synthesis and biological screening of 2-aminobenzamides as selective HDAC3 inhibitors with promising anticancer effects
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Histone deacetylases (HDACs) have been found as a potential target for anticancer therapy. A number of HDAC inhibitors have been used pre-clinically and clinically as anticancer agents. In the current study, we have designed and synthesized compound 12a by combining the scaffolds of CI-994 and BG45. Moreover, the structure of compound 12a was optimized and a series of 2-aminobenzamide derivatives were synthesized further. These compounds were tested for their HDAC inhibitory activity and found to be efficient HDAC inhibitors. Compound 26c showed 11.68-fold HDAC3 selectivity over pan HDACs, better than the prototype HDAC3 inhibitor BG45. Most of these compounds exhibited antiproliferative activity in both B16F10 and HeLa cell lines. Particularly, compound 26c exhibited better antitumor efficacy in the cell lines compared to the prototype inhibitors CI-994 and BG45. It was also found to promote apoptosis as well as induced significant cell growth arrest in the G2/M phase of cell cycle in B16F10 melanoma cells. This work may provide significant insight regarding structural information to design newer small molecule HDAC3 inhibitors to fight against the target specific malignancies in future.
- Trivedi, Prakruti,Adhikari, Nilanjan,Amin, Sk. Abdul,Jha, Tarun,Ghosh, Balaram
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p. 165 - 181
(2018/09/12)
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- An anion receptor that facilitates transmembrane proton-anion symport by deprotonating its sulfonamide N-H proton
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Indole-based amide-sulfonamide derivatives were synthesized. The X-ray crystal structure and chloride binding studies in solution showed a 1?:?1 stoichiometry. The ion transport efficiency directly correlated to the pKa of the sulfonamide N-H p
- Shinde, Sopan Valiba,Talukdar, Pinaki
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p. 10351 - 10354
(2018/09/21)
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- HISTONE DEACETYLASE INHIBITORS
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Provided herein are compounds and methods for inhibiting histone deacetylase ("HDAC") enzymes (e.g., HDAC1, HDAC2, and HDAC3).
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Paragraph 00317; 00324
(2018/07/29)
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- Development of a novel protocol for chemoselective deprotection of N/O-benzyloxycarbonyl (Cbz) at ambient temperature
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Abstract: A novel protocol for the deprotection of N-benzyloxycarbonyl and O-benzyloxycarbonyl groups by nickel boride generated in situ from NaBH4 and NiCl2·6H2O in methanol at room temperature has been developed to give the corresponding amines and phenols. This protocol is chemoselective as groups like chloro, bromo, amide, ester, pyridine, and tert-butyloxycarbonyl moiety are unaffected under these conditions. The deprotection has also been validated in gram scale reactions, to establish the wider appropriateness of this protocol. Graphical abstract: [Figure not available: see fulltext.].
- Saroha, Mohit,Aggarwal, Komal,Bartwal, Gaurav,Khurana, Jitender M.
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p. 2231 - 2235
(2018/10/02)
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- Efficient and expeditious chemoselective BOC protection of amines in catalyst and solvent-free media
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A green and eco-friendly route for the almost quantitative BOC protection of a large variety of aliphatic and aromatic amines, amino acids, and amino alcohols is reported in catalyst and solvent-free media under mild reaction conditions. The products were confirmed by 1H, 13C NMR, IR spectroscopy, and in some cases, elemental analysis. This protocol does not require any water quenches, solvent separations, and purification steps, such as recrystallization and column chromatography.
- Viswanadham, Balaga,Mahomed, Abdul S.,Friedrich, Holger B.,Singh, Sooboo
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p. 1355 - 1363
(2017/02/15)
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- Copper nanoparticles catalyzed N-H functionalization: An efficient solvent-free N-tert-butyloxycarbonylation strategy
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A chemoselective transformation of amines to their tert-butyloxycarbonyl (Boc) protected derivatives (NBoc) is described using Cu-NPs under solvent-free conditions. Simple method, rapid reaction rate, mild conditions, tolerance of a wide range of functional groups, excellent yield, ease recovery and high catalytic turnover are the salient features of this approach. tert-Butyloxycarbonylation of chiral amino acid esters and amino alcohols were performed without racemization.
- Deb, Barnali,Debnath, Sudipto,Deb, Anindita,Maiti, Dilip K.,Majumdar, Swapan
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supporting information
p. 629 - 633
(2017/01/25)
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- Sustainable and chemoselective N-Boc protection of amines in biodegradable deep eutectic solvent
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Abstract: A green and practical approach for the chemoselective N-tert-butyloxycarbonylation of structurally diverse amines with di-tert-butyl dicarbonate (Boc2O) is described. Selective N-Boc protection was achieved in excellent yields in urea-choline chloride deep eutectic solvent (DES) as the most promising environmentally benign and cost-effective solvent under mild reaction condition. DES can protect various aromatic and aliphatic amines using Boc2O in good to excellent yields in short reaction times without any side products. Graphical abstract: [Figure not available: see fulltext.].
- Azizi, Najmedin,Shirdel, Fatemeh
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p. 1069 - 1074
(2017/05/12)
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- Stable and Rapid Thiol Bioconjugation by Light-Triggered Thiomaleimide Ring Hydrolysis
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Maleimide-mediated thiol-specific derivatization of biomolecules is one of the most efficacious bioconjugation approaches currently available. Alarmingly, however, recent work demonstrates that the resulting thiomaleimide conjugates are susceptible to breakdown via thiol exchange reactions. Herein, we report a new class of maleimides, namely o-CH2NHiPr phenyl maleimides, that undergo unprecedentedly rapid ring hydrolysis after thiol conjugation to form stable thiol exchange-resistant conjugates. Furthermore, we overcome the problem of low shelf lives of maleimide reagents owing to their propensity to undergo ring hydrolysis prior to bioconjugation by developing a photocaged version of this scaffold that resists ring hydrolysis. UV irradiation of thiol bioconjugates formed with this photocaged maleimide unleashes rapid thiomaleimide ring hydrolysis to yield the desired stable conjugates within 1 h under gentle, ice-cold conditions.
- Kalia, Dimpy,Pawar, Sharad P.,Thopate, Jyoti S.
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supporting information
p. 1885 - 1889
(2017/02/05)
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- Emedastine hydrochloride intermediate compound and preparation method thereof
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The invention provides an antihistamine medicine emedastine hydrochloride intermediate and a preparation method thereof, and is used for solving the problems of many reaction steps, operation complexity and high production cost in the preparation process
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Paragraph 0045; 0046; 0090; 0091
(2017/09/01)
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- FAR SUPERIOR OXIDATION CATALYSTS BASED ON MACROCYCLIC COMPOUNDS
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An especially robust compound and its derivative metal complexes that are approximately one hundred-fold superior in catalytic performance to the previously invented TAML analogs is provided having the formula (I) wherein Y1, Y2, Y3 and Y4 are oxidation resistant groups which are the same or different and which form 5- or 6-membered rings with a metal, M, when bound to D; at least one Y incorporates a group that is significantly more stable towards nucleophilic attack than the organic amides of TAML activators; D is a metal complexing donor atom, preferably N; each X is a position for addition of a labile Lewis acidic substituent such as (i) H, deuterium, (ii) Li, Na, K, alkali metals, (iii) alkaline earth metals, transition metals, rare earth metals, which may be bound to one or more than one D, (iv) or is unoccupied with the resulting negative charge being balanced by a nonbonded counteraction; at least one Y may contain a site that is labile to acid dissociation, providing a mechanism for shortening complex lifetime. The new complexes deliver catalytic performances that promise to revolutionize multiple oxidation technology spaces including water purification.
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Page/Page column 86; 87
(2017/04/11)
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- 2-Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors
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A series of 2-aminopyrimidine derivatives were designed and synthesized as highly selective FGFR4 inhibitors. One of the most promising compounds 2n tightly bound FGFR4 with a Kd value of 3.3 nM and potently inhibited its enzymatic activity with an IC50 value of 2.6 nM, but completely spared FGFR1/2/3. The compound selectively suppressed proliferation of breast cancer cells harboring dysregulated FGFR4 signaling with an IC50 value of 0.38 μM. Furthermore, 2n exhibited extraordinary target specificity in a Kinome-wide screen against 468 kinases, with S(35) and S(10) selectivity scores of 0.01 and 0.007 at 1.0 μM, respectively.
- Mo, Cheng,Zhang, Zhang,Guise, Christopher P.,Li, Xueqiang,Luo, Jinfeng,Tu, Zhengchao,Xu, Yong,Patterson, Adam V.,Smaill, Jeff B.,Ren, Xiaomei,Lu, Xiaoyun,Ding, Ke
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supporting information
p. 543 - 548
(2017/05/19)
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- Synthesis of 2-Alkoxy/Thioalkoxy Benzo[d]imidazoles and 2-Thione Benzo[d]imidazoles via a Phase-Based, Chemoselective Reaction
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2-Alkoxy/thioalkoxy benzo-[d]-imidazole and 2-thione benzo-[d]-imidazole libraries were constructed in solution phase and on solid phase, respectively. The key step in this work is the phase-based chemoselective reaction of the 2-mercaptobenzo-[d]-imidazole intermediate with benzyl chloride (solution phase) and Merrifield resin (solid phase). In the solution-phase case, benzyl chloride reacted with the thiol group of 2-mercaptobenzo-[d]-imidazole, whereas in the solid-phase case, Merrifield resin was introduced at an internal amine group of benzo-[d]-imidazole. To afford the desired 2-alkoxy/thioalkoxy benzo-[d]-imidazole analogues, we used various alkyl halides, alcohols, and thiols in solution phase, and to obtain 2-thione benzo-[d]-imidazole derivatives on solid phase, we used diverse alkyl halides and boronic acids. Finally, to measure the drug potential to be orally active and the molecular diversity in three-dimensional (3D) space, we calculated physicochemical properties and displayed energy-minimized 3D structures. As a result, the libraries from solution phase and solid phase show distinct features in physicochemical properties and skeletal diversities in 3D space.
- Yoon, Hyo-Jeong,Yang, Seung-Ju,Gong, Young-Dae
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supporting information
p. 738 - 747
(2017/12/18)
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- Heterobimetallic dinuclear lanthanide alkoxide complexes as acid-base bifunctional catalysts for synthesis of carbamates under solvent-free conditions
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Heterobimetallic dinuclear lanthanide alkoxide complexes Ln2Na8(OCH2CH2NMe2)12(OH)2 [Ln: I (Nd), II (Sm), III (Yb) and IV (Y)] were used as efficient acid-base bifunctional catalysts for the synthesis of carbamates from dialkyl carbonates and amines as well as the N-Boc protection of amines. The cooperative catalysts showed high catalytic activity and a wide scope of substrates with good to excellent yields under solvent-free conditions. The systems have shown higher catalytic activities due to the noteworthy synergistic interactions of Lewis acid center-Br?nsted basic center. The comparison of catalytic efficiency between mono- and dinuclear heterobimetallic lanthanide alkoxide analogues was also investigated.
- Zeng, Ruijie,Bao, Linquan,Sheng, Hongting,Sun, Lili,Chen, Man,Feng, Yan,Zhu, Manzhou
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p. 78576 - 78584
(2016/09/09)
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- Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening
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Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.
- Kilchmann, Falco,Marcaida, Maria J.,Kotak, Sachin,Schick, Thomas,Boss, Silvan D.,Awale, Mahendra,G?nczy, Pierre,Reymond, Jean-Louis
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supporting information
p. 7188 - 7211
(2016/09/09)
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- A hybrid of thiazolidinone with the hydroxamate scaffold for developing novel histone deacetylase inhibitors with antitumor activities
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A series of novel histone deacetylase (HDAC) inhibitors were designed, synthesized and evaluated based on the strategies of a hybrid of the classic pharmacophore of HDAC inhibitors with the thiazolidinone scaffold. Some of the compounds showed potent HDAC1 inhibition with nM IC50 values, more importantly, compound 12i displayed much better anti-metastatic effects than vorinostat (SAHA) against migration of the A549 cell line. Further mechanism exploration implied that compound 12i may inhibit tumor metastasis via modulating the epithelial-mesenchymal transition (EMT) and upregulating the acetylation of α-tubulin.
- Yang, Feifei,Peng, Shihong,Li, Yunqi,Su, Liqiang,Peng, Yangrui,Wu, Jing,Chen, Huang,Liu, Mingyao,Yi, Zhengfang,Chen, Yihua
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p. 1727 - 1735
(2016/02/10)
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- Treatment of small molecules and their VLCFAE [...] control
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Disclosed are methods and compositions for modulating the function of transcription factors, especially transcription factors that recruit epigenetic regulators (histone modifying enzymes) to specific DNA promoters. The targeted transcription factors incl
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Paragraph 0119; 0121
(2016/10/08)
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- Synthesis and thermal reactivity of thiazolo[3,4-a]benzimidazole-2,2-dioxides: Approach to 1H-benzo[d]imidazoles via novel benzo-2,5-diazafulvenium methides
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Abstract The generation and reactivity of novel benzo-2,5-diazafulvenium methides was explored. Thiazolo[3,4-a]benzimidazole-2,2-dioxides have been prepared and used as precursors of benzo-2,5-diazafulvenium methides, whose pericyclic reactions led to the
- Soares, Maria I.L.,Pinho e Melo, Teresa M.V.D.
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p. 4227 - 4235
(2015/06/02)
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- OPIOID AGONISTS AND USES THEREOF
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Provided are compounds, including those of Formula I; and pharmaceutically acceptable salts and solvates thereof. The compounds described herein relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry.
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Paragraph 00238
(2015/06/11)
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- INHIBITORS OF HISTONE DEACETYLASE
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The present invention relates to compounds which inhibit histone deacetylase activity and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing these compounds. The present invention also rel
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Paragraph 000392-000393
(2015/05/26)
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- INHIBITORS OF HISTONE LYSINE SPECIFIC DEMETHYLASE (LSD1) AND HISTONE DEACETYLASES (HDACS)
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A series of phenelzine analogs comprising a phenelzine scaffold linked to an aromatic moiety and their use as inhibitors of lysine-specific demethylase 1 (LSD1) and/or one or more histone deacetylases (HDACs) is provided. The presently disclosed phenelzine analogs exhibit potency and selectivity for LSD1 versus MAO and LSD2 enzymes and exhibit bulk, as well as, gene specific histone methylation changes, anti-proliferative activity in several cancer cell lines, and neuroprotection in response to oxidative stress. Accordingly, the presently disclosed phenelzine analogs can be used to treat diseases, conditions, or disorders related to LSD1 and/or HDACs, including, but not limited to, cancers and neurodegenerative diseases.
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Page/Page column 129
(2015/09/28)
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- An "all-water" strategy for regiocontrolled synthesis of 2-aryl quinoxalines
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A new synthetic strategy of tandem N-aroylmethylation-nitro reduction-cyclocondensation has been developed for the first and generalized regioselective synthesis of 2-aryl quinoxalines adopting "all water chemistry." Water plays the critical role through
- Tanwar, Babita,Purohit, Priyank,Raju, Banothu Naga,Kumar, Dinesh,Kommi, Damodara N.,Chakraborti, Asit K.
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p. 11873 - 11883
(2015/02/19)
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- NOVEL TRANSCRIPTION FACTOR MODULATORS
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The present disclosure provides novel compounds capable of functioning as transcription factor modulators, as well as compositions, pharmaceutical formulations, and kits. Also provided are methods of treating a condition regulatable by a transcription factor and/or cofactor using the compounds, compositions, pharmaceutical formulations, and kits provided herein.
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Paragraph 0178; 0185; 0186
(2014/09/29)
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- Delayed and prolonged histone hyperacetylation with a selective HDAC1/HDAC2 inhibitor
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The identification and in vitro and in vivo characterization of a potent SHI-1:2 are described. Kinetic analysis indicated that biaryl inhibitors exhibit slow binding kinetics in isolated HDAC1 and HDAC2 preparations. Delayed histone hyperacetylation and
- Methot, Joey L.,Hoffman, Dawn Mampreian,Witter, David J.,Stanton, Matthew G.,Harrington, Paul,Hamblett, Christopher,Siliphaivanh, Phieng,Wilson, Kevin,Hubbs, Jed,Heidebrecht, Richard,Kral, Astrid M.,Ozerova, Nicole,Fleming, Judith C.,Wang, Hongmei,Szewczak, Alexander A.,Middleton, Richard E.,Hughes, Bethany,Cruz, Jonathan C.,Haines, Brian B.,Chenard, Melissa,Kenific, Candia M.,Harsch, Andreas,Secrist, J. Paul,Miller, Thomas A.
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p. 340 - 345
(2014/05/06)
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- Solvent free N-Boc protection of amines using amberlystr a 21 solid base resin as a reusable heterogeneous catalyst
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An efficient, environmentally benign, highly facile and convenient synthetic protocol for the selective t-butyl carboxylation of aliphatic, aromatic and heterocyclic amines using AmberlystR A 21 catalyst; a mild basic solid resin under solvent free conditions is reported. This method explores several advantages such as reusability of the heterogeneous catalyst, cleaner reaction profile, mild and solvent free system, short reaction time, operational simplicity, high conversions , excellent product yields and low cost of the catalyst. Furthermore since the catalyst is mild basic, decomposition of the carbamate formed is not observed if the reaction is continued for prolonged time as in the case of Lewis acid catalyzed N-Boc protection. This makes the present protocol a useful and attractive for N-Boc protection of amines.
- Tekale, Sunil U.,Kauthale, Sushama S.,Pawar, Rajendra P.
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p. 1619 - 1623
(2013/09/12)
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