- Alkene–Azide 1,3-Dipolar Cycloaddition as a Trigger for Ultrashort Peptide Hydrogel Dissolution
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An alkene–azide 1,3-dipolar cycloaddition between trans-cyclooctene (TCO) and an azide-capped hydrogel that promotes rapid gel dissolution is reported. Using an ultrashort aryl azide-capped peptide hydrogel (PhePhe), we have demonstrated proof-of-concept where upon reaction with TCO, the hydrogel undergoes a gel–sol transition via 1,2,3-triazoline degradation and 1,6-self-immolation of the generated aniline. The potential application of this as a general trigger in sustained drug delivery is demonstrated through release of encapsulated cargo (doxorubicin). Administration of TCO resulted in 87 % of the cargo being released in 10 h, compared to 13–14 % in the control gels. This is the first example of a potential bioorthogonal-triggered hydrogel dissolution using a traditional click-type reaction. This type of stimulus could be extended to other aryl azide-capped hydrogels.
- Dadhwal, Sumit,Fairhall, Jessica M.,Goswami, Shailesh K.,Hook, Sarah,Gamble, Allan B.
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Read Online
- A Dual-Response Fluorescent Probe for the Detection of Viscosity and H2S and Its Application in Studying Their Cross-Talk Influence in Mitochondria
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Intracellular viscosity is an essential microenvironmental parameter and H2S is a critical gaseous signaling molecule, which are both related to various physiological processes. It is reported that the change of viscosity and an imbalance of H2S production in the mitochondria are both associated with overexpression of amyloid betapeptide (Aβ), which is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, to our best knowledge, no fluorescent probe is found for dual detection of mitochondrial viscosity and H2S. Herein, a dual-response fluorescent probe (Mito-VS) is designed and synthesized to monitor the level of viscosity and H2S, respectively. Mito-VS itself is nonfluorescent due to a free intramolecular rotation between dimethylaniline and pyridine. After the increase of viscosity, the rotation is prohibited and an intense red fluorescence is released. Upon the addition of H2S, the probe can react with H2S to form compound 3 and a strong green fluorescence can be observed. Moreover, the probe possesses a good mitochondrion-targeting ability and is applied for imaging the change of viscosity on the red channel and visualizing the variation of exogenous and endogenous H2S concentration on the green channel in mitochondria. Most importantly, the probe is capable of studying the cross-talk influence of viscosity and H2S in mitochondria, which is very beneficial for knowing the pathogenesis of AD.
- Li, Song-Jiao,Li, Yong-Fei,Liu, Hong-Wen,Zhou, Dong-Ye,Jiang, Wen-Li,Ou-Yang, Juan,Li, Chun-Yan
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- Molecular isomerization triggered by H2S to an NIR accessible first direct visualization of Ca2+-dependent production in living HeLa cells
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Few studies determined the role of intracellular labile Ca2+ in H2S homeostasis. Undoubtedly, fluorescent probes are powerful tools for exploring the question because of their unique advantages: non-destruction, visualization, and mu
- Wen, Ying,Huo, Fangjun,Wang, Junping,Yin, Caixia
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Read Online
- Photocrosslinking and Click Chemistry Enable the Specific Detection of Proteins Interacting with Phospholipids at the Membrane Interface
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New lipid analogs mimicking the abundant membrane phospholipid phosphatidylcholine were developed to photocrosslink proteins interacting with phospholipid headgroups at the membrane interface. In addition to either a phenylazide or benzophenone photoactiv
- Gubbens, Jacob,Ruijter, Eelco,de Fays, Laurence E.V.,Damen, J. Mirjam A.,de Kruijff, Ben,Slijper, Monique,Rijkers, Dirk T.S.,Liskamp, Rob M.J.,de Kroon, Anton I.P.M.
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Read Online
- Synthesis and antitumor activity of 1-substituted 1,2,3-triazole-mollugin derivatives
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A new series of mollugin-1,2,3-triazole derivatives were synthesized using a copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of corresponding O-propargylated mollugin with aryl azides. All the compounds were evaluated for their cytotoxicity on five human cancer cell lines (HL-60, A549, SMMC-7721, SW480, and MCF-7) using MTS assays. Among the synthesized series, most of them showed cytotoxicity and most of all, compounds 14 and 17 exhibited significant cytotoxicity of all five cancer cell lines.
- Hu, Jiang-Miao,Li, Hong-Mei,Liu, Shou-Jin,Luo, Han,Lv, Yong-Feng,Zhang, Hong
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- Nucleophilic transformations of azido-containing carbonyl compoundsviaprotection of the azido group
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Nucleophilic transformations of azido-containing carbonyl compounds are discussed. The phosphazide formation from azides and di(tert-butyl)(4-(dimethylamino)phenyl)phosphine (Amphos) enabled transformations of carbonyl groups with nucleophiles such as lithium aluminum hydride and organometallic reagents. The good stability of the phosphazide moiety allowed us to perform consecutive transformations of a diazide through triazole formation and the Grignard reaction.
- Aimi, Takahiro,Meguro, Tomohiro,Kobayashi, Akihiro,Hosoya, Takamitsu,Yoshida, Suguru
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supporting information
p. 6062 - 6065
(2021/06/21)
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- Rapid Broad Spectrum Detection of Carbapenemases with a Dual Fluorogenic-Colorimetric Probe
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Carbapenems stand as one of the last-resort antibiotics; however, their efficacy is threatened by the rising number and rapid spread of carbapenemases. Effective antimicrobial stewardship thus calls for rapid tests for these enzymes to aid appropriate prescription and infection control. Herein, we report the first effective pan-carbapenemase reporter CARBA-H with a broad scope covering all three Ambler classes. Using a chemical biology approach, we demonstrated that the absence of the 1β-substituent in the carbapenem core is key to pan-carbapenemase recognition, which led to our rational design and probe development. CARBA-H provides a dual colorimetric-fluorogenic response upon carbapenemase-mediated hydrolysis. A clear visual readout can be obtained within 15 min when tested against a panel of carbapenemase-producing Enterobacteriaceae (CPE) clinical isolates that notably includes OXA-48 and OXA-181-producing strains. Furthermore, CARBA-H can be applied to the detection of carbapemenase activity in CPE-spiked urine samples.
- Ma, Chi-Wang,Ng, Kenneth King-Hei,Yam, Bill Hin-Cheung,Ho, Pak-Leung,Kao, Richard Yi-Tsun,Yang, Dan
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p. 6886 - 6894
(2021/05/29)
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- BIOPROBES FOR LYSYL OXIDASES AND USES THEREOF
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The present invention relates to novel bioprobes which are capable of binding to certain amine oxidase enzymes. These bioprobes are useful in methods of detecting and determining the concentration of certain amine oxidase enzymes in a sample as well as in methods for the quantitative assessment of inhibition of certain amine oxidases.
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Paragraph 00222; 00223; 00269; 00271
(2021/08/14)
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- SELECTIVE DRUG RELEASE FROM INTERNALIZED CONJUGATES OF BIOLOGICALLY ACTIVE COMPOUNDS
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The invention relates to conjugates of biologically active compounds, wherein such a conjugate is comprised of a sequence of amino acids containing a tripeptide that confers selective cleavage by tumor tissue homogenate for release of free drug and/or imp
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Paragraph 0609-0610
(2021/04/01)
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- A curcumin-analogous fluorescent sensor for cysteine detection with a bilateral-response click-like mechanism
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A novel curcumin-analogous fluorescent sensor, DNP, was developed for cysteine detection with a bilateral-response click-like mechanism. DNP indicated high selectivity and practical sensitivity. It could recognize Cys from other biologically relevant molecules, especially, from GSH and Hcy. The most interesting point was that, with typical azide groups for sensing, DNP indicated a covalent binding procedure with Cys instead of a presupposed simple reduction for reductive sulfide. Moreover, the recognition occurred at both sides of the sensor. DNP could be utilized into the detection of endogenous and exogenous Cys in living cells. Though the specific optical performances of DNP still need optimization, this work supplied novel information for broadening the vision on fluorophores and mechanisms, for the monitoring of Cys and even other sulfur-containing species.
- Fan, Xiang-Jun,Fang, Fang,Li, Zhen,Liu, Sheng-Jin,Yang, Yu-shun
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supporting information
(2020/09/16)
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- Small Molecule Control of Morpholino Antisense Oligonucleotide Function through Staudinger Reduction
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Conditionally activated, caged morpholino antisense agents (cMOs) are tools that enable the temporal and spatial investigation of gene expression, regulation, and function during embryonic development. Cyclic MOs are conformationally gated oligonucleotide analogs that do not block gene expression until they are linearized through the application of an external trigger, such as light or enzyme activity. Here, we describe the first examples of small molecule-responsive cMOs, which undergo rapid and efficient decaging via a Staudinger reduction. This is enabled by a highly flexible linker design that offers opportunities for the installation of chemically activated, self-immolative motifs. We synthesized cyclic cMOs against two distinct, developmentally relevant genes and demonstrated phosphine-triggered knockdown of gene expression in zebrafish embryos. This represents the first report of a small molecule-triggered antisense agent for gene knockdown, adding another bioorthogonal entry to the growing arsenal of gene knockdown tools.
- Chen, James K.,Darrah, Kristie,Deiters, Alexander,Lukasak, Bradley,Tsang, Michael,Wesalo, Joshua
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supporting information
p. 18665 - 18671
(2021/11/16)
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- BETA-LACTAM COMPOUNDS AND METHODS OF USE THEREOF
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Beta-lactam compounds to detect carbapenemases or microbial carbapenem resistance are disclosed. The compounds contain a chemical probe. Upon hydrolysis by carbapenemases, the compounds undergo intramolecular rearrangement and release the chemical probe. Detection of the released chemical probe indicates the presence of carbapenemases and the presence of microbial carbapenem resistance.
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- COMPOSITIONS COMPRISING ENZYME CLEAVABLE LINKER PLATFORMS AND CONJUGATES THEREOF
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The present invention relates to a cleavable linker platform. In particular, the invention relates to construction of an enzyme cleavable linker platform conjugated to a drug or a diagnostically relevant compound, a biomolecule, and an enzyme cleavable group, for which cleavage of the enzyme cleavable group leads to release of the drug or diagnostically relevant compound.
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Page/Page column 69
(2021/01/23)
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- Polymer-Based Bioorthogonal Nanocatalysts for the Treatment of Bacterial Biofilms
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Bioorthogonal catalysis offers a unique strategy to modulate biological processes through the in situ generation of therapeutic agents. However, the direct application of bioorthogonal transition metal catalysts (TMCs) in complex media poses numerous challenges due to issues of limited biocompatibility, poor water solubility, and catalyst deactivation in biological environments. We report here the creation of catalytic "polyzymes", comprised of self-assembled polymer nanoparticles engineered to encapsulate lipophilic TMCs. The incorporation of catalysts into these nanoparticle scaffolds creates water-soluble constructs that provide a protective environment for the catalyst. The potential therapeutic utility of these nanozymes was demonstrated through antimicrobial studies in which a cationic nanozyme was able to penetrate into biofilms and eradicate embedded bacteria through the bioorthogonal activation of a pro-antibiotic.
- He, Luke D.,Huang, Rui,Li, Cheng-Hsuan,Makabenta, Jessa Marie,Rotello, Vincent M.,Yu, Erlei,Zhang, Xianzhi,Cao-Milán, Roberto
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supporting information
p. 10723 - 10729
(2020/07/04)
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- Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries
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Cell division cycle 25 (Cdc25) protein phosphatases play key roles in the transition between the cell cycle phases and their association with various cancers has been widely proven, which makes them ideal targets for anti-cancer treatment. Though several Cdc25 inhibitors have been developed, most of them displayed low activity and poor subtype selectivity. Therefore, it is extremely important to discover novel small molecule inhibitors with potent activities and significant selectivity for Cdc25 subtypes, not only served as drugs to treat cancer but also to probe its mechanism in transitions. In this study, miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening were used to discover selective Cdc25 inhibitors. The bioassay results showed that compound M2N12 proved to be the most potent Cdc25 inhibitor, which also act as a highly selective Cdc25C inhibitor and was about 9-fold potent than that of NSC 663284. Moreover, M2N12 showed remarkable anti-growth activity against the KB-VIN cell line, equivalent to that of PXL and NSC 663284. An all-atom molecular dynamics (MD) simulation approach was further employed to probe the significant selectivity of M2N12 for Cdc25C relative to its structural homologs Cdc25A and Cdc25B. Overall, above results make M2N12 a promising lead compound for further investigation and structural modification.
- Jing, Lanlan,Wu, Gaochan,Hao, Xia,Olotu, Fisayo A.,Kang, Dongwei,Chen, Chin Ho,Lee, Kuo-Hsiung,Soliman, Mahmoud E.S.,Liu, Xinyong,Song, Yuning,Zhan, Peng
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- Novel near-infrared rate fluorescent probe for detecting hydrogen sulphide and preparation method and application of novel near-infrared rate fluorescent probe
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The invention discloses a novel near-infrared rate fluorescent probe for detecting hydrogen sulphide and a preparation method and application of the novel near-infrared rate fluorescent probe. The probe is a 2-[2-[2-(4-benzylazide carbobenzoxy) benzylamine-3-[(1,3-dihydrogen-1,3,3-trimethyl-2H-indole-2-idene) ethylidene]-1-cyclohexene-1-base]vinyl]-1,3,3-trimethyl-indole-onium iodide. The preparation method comprises the following steps of enabling 1,2,3,3-tetramethyl-3H-iodination indole and 2-chlorine-1-formyl-3-hydroxymethyl cyclohexene to have a dehydration and condensation reaction; enabling the obtained 2-[2-[2-chlorine-3-[(1,3-dihydrogen-1,3,3-trimethyl-2H-indole-2-idene)ethylidene]-1-cyclohexene-1-base]vinyl]-1,3,3-trimethyl indole-onium iodide and benzylamine to a reaction; and enabling the obtained 2-[2-[2-benzylamino-3-[(1,3-dihydrogen-1,3,3-trimethyl-2H-indole-2-idene) ethylidene]-1-cyclohexene-1-base]vinyl ]-1,3,3-trimethyl indole-onium iodide and chloroformic acid to havea reaction on azide base benzyl ester so as to obtain the fluorescent probe. The probe shows higher selectivity on detection of the hydrogen sulphide.
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Paragraph 0056; 0086-0090
(2019/01/23)
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- Methylene blue derivative as well as synthesis method and application thereof
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The invention provides a methylene blue derivative as well as a synthesis method and application thereof. The methylene blue derivative is as follows: 4-azidobenzyl-3,7-bis(dimethylamino)-10H-phenothiazine-10-carboxylate. A detection method comprises the
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Paragraph 0023-0025
(2019/04/04)
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- A2B Adenosine Receptor Antagonists with Picomolar Potency
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The A2B adenosine receptor (A2BAR) was proposed as a novel target for the (immuno)therapy of cancer since A2BAR blockade results in antiproliferative, antiangiogenic, antimetastatic, and immunostimulatory effects. In this study, we explored the structure-activity relationships of xanthin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established, which facilitated the synthesis of the target compounds. Many of the new compounds exhibited subnanomolar affinity for the A2BAR combined with high selectivity. Functional groups were introduced, which will allow the attachment of dyes and other reporter groups. 8-(4-((4-(4-Bromophenyl)piperazin-1-yl)sulfonyl)phenyl)-1-propylxanthine (34, PSB-1901) was the most potent A2B-antagonist (Ki 0.0835 nM, KB 0.0598 nM, human A2BAR) with >10 000-fold selectivity versus all other AR subtypes. It was similarly potent and selective at the mouse A2BAR, making it a promising tool for preclinical studies. Computational studies predicted halogen bonding to contribute to the outstanding potency of 34.
- Jiang, Jie,Seel, Catharina Julia,Temirak, Ahmed,Namasivayam, Vigneshwaran,Arridu, Antonella,Schabikowski, Jakub,Baqi, Younis,Hinz, Sonja,Hockemeyer, J?rg,Müller, Christa E.
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supporting information
p. 4032 - 4055
(2019/05/06)
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- Mechanistic Evaluation of Bioorthogonal Decaging with trans-Cyclooctene: The Effect of Fluorine Substituents on Aryl Azide Reactivity and Decaging from the 1,2,3-Triazoline
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Bioorthogonal prodrug activation/decaging strategies need to be selective, rapid and release the drug from the masking group upon activation. The rates of the 1,3-dipolar cycloaddition between a trans-cyclooctene (TCO) and a series of fluorine-substituted
- Matikonda, Siddharth S.,Fairhall, Jessica M.,Fiedler, Franziska,Sanhajariya, Suchaya,Tucker, Robert A. J.,Hook, Sarah,Garden, Anna L.,Gamble, Allan B.
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p. 324 - 334
(2018/02/28)
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- Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal-Cell Carcinoma to Topotecan
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Chemical probes of microRNA (miRNA) function are potential tools for understanding miRNA biology that also provide new approaches for discovering therapeutics for miRNA-associated diseases. MicroRNA-21 (miR-21) is an oncogenic miRNA that is overexpressed in most cancers and has been strongly associated with driving chemoresistance in cancers such as renal cell carcinoma (RCC). Using a cell-based luciferase reporter assay to screen small molecules, we identified a novel inhibitor of miR-21 function. Following structure-activity relationship studies, an optimized lead compound demonstrated cytotoxicity in several cancer cell lines. In a chemoresistant-RCC cell line, inhibition of miR-21 via small molecule treatment rescued the expression of tumor-suppressor proteins and sensitized cells to topotecan-induced apoptosis. This resulted in a >10-fold improvement in topotecan activity in cell viability and clonogenic assays. Overall, this work reports a novel small molecule inhibitor for perturbing miR-21 function and demonstrates an approach to enhancing the potency of chemotherapeutics specifically for cancers derived from oncomir addiction.
- Naro, Yuta,Ankenbruck, Nicholas,Thomas, Meryl,Tivon, Yaniv,Connelly, Colleen M.,Gardner, Laura,Deiters, Alexander
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p. 5900 - 5909
(2018/08/04)
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- BODIPY-based high-sensitivity fluorescent probe and synthesis method and application thereof
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The invention relates to a BODIPY-based high-sensitivity fluorescent probe and a synthesis method and application thereof. A structural general formula of the probe is shown as (I), wherein Trigger is stimulant triggering groups, R1 and R2 are groups for regulating and controlling fluorescent transmission wavelength of the probe and introducing organelle targeting, and R1 and R2 are defined in the description. By the probe, detection of different substrates can be realized without changing mother nucleus structure of the probe by only changing different Trigger groups. In addition, according to different needs on wavelength and targeting, the mother nucleus structure of the probe can be quickly modified. By changing R1 and R2, maximum fluorescent emission wavelength of the probe can be changed, and the probe can target mitochondrion to realize detection of active substances in the mitochondrion. The probe has good biocompatibility, thereby being applicable to detecting biological systems. Application value of the fluorescent probe in the aspect of detecting bioactive molecules and protease over-expressed in inflammatory or tumor tissue has potential social benefit and economic benefit.
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- Zinc-Mediated Efficient and Selective Reduction of Carbonyl Compounds
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We herein describe for the first time that an optimized combination of Zn and NH4Cl can be used for the selective reduction of aldehydes and ketones to the corresponding alcohols. The aldehyde and keto groups are selectively reduced in the presence of azide, cyano, epoxy, ester, and carbon–carbon double-bond functional groups. A broad functional-group compatibility, chemoselective reduction of aldehydes in the presence of ketones, and selective reduction of isatins at the C3 carbonyl group are the highlights of the present method.
- Mandal, Tirtha,Jana, Snehasish,Dash, Jyotirmayee
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p. 4972 - 4983
(2017/09/13)
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- QUINOLIN-2-ONE DERIVATIVES
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Compounds of the formula (I) in which X1, X2, X3, X4, R1, R2, R3, Q and Y have the meanings indicated in Claim 1, are inhibitors of c-Kit kinase, and can be employed for the treatment of cancer.
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Page/Page column 56; 57
(2017/08/07)
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- Synthesis of photophore and fluorophore modified o-benzylserine derivatives
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O-Benzylation of serine is one of the important protection methods for solid phase peptide synthesis. The utilities of the protection group may be indicated that chemical modifications for O-benzylserine will be utilized to make functional peptides on sol
- Hashimoto, Makoto,Yoshida, Takuma,Tachrim, Zetryana Puteri,Sakihama, Yasuko,Hashidoko, Yasuyuki,Hatanaka, Yasumaru,Kanaoka, Yuichi
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p. 462 - 473
(2019/05/21)
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- Application of polymer microspheres to Raman detection
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The invention discloses application of polymer microspheres to Raman detection. Methacrylate/amide polymer monomers or styrene polymer monomers containing alkynyl, cyano, azido or a carbon-deuterium bond group are prepared into the polymer microspheres with the particle diameter from a nanometer grade to a micron grade through an emulsion polymerization or dispersion polymerization method; the polymer microspheres have a remarkable Raman signal under the condition of no metal sensitization structure; and a Raman characteristic peak signal is located in a Raman quiet zone (1800cm to 2800cm) in a living organism and can be used as a marker for biological imaging.
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Paragraph 0188-0189
(2018/03/13)
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- Based on tubulin azido - β - lactam small molecular probe and its preparation method and application (by machine translation)
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The invention discloses a based on tubulin azido - β - lactam small molecular probe and its preparation method and application, which belongs to the field of pharmaceutical chemistry. The invention will be β - lactam nucleus with the azido active unit is combined, simple and efficient. It has the following general structure: The type of probe molecule anticancer activity in vitro experiments show that a variety of tumor cells MCF - 7, MGC - 803, A549 has a certain inhibition effects. In particular the azido - β - lactam probe molecule I - 9 to the MGC - 803 cell activity of the 85 nm. On the other hand, the compounds of the invention with the microtubule protein binding, inhibiting tubulin polymerization, can be used as potential microtubule protein small molecular probe. The invention solves the azido type of microtubule protein probe of less variety, synthetic complex, the problem of high cost, helps to inhibit tubulin polymerization for drug development. (by machine translation)
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Page/Page column 7
(2017/09/01)
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- Synthesis of α-santonin derived acetyl santonous acid triazole derivatives and their bioevaluation for T and B-cell proliferation
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A new series of α-santonin derived acetyl santonous acid 1,2,3-triazole derivatives were synthesised using Huisgen 1,3-dipolar cyclo-addition reaction (click chemistry approach) and evaluated for their in vitro inhibition activity on concanavalin A (ConA) induced T cell proliferation and lipopolysaccharide (LPS) induced B cell proliferation. Among the synthesised series, compounds 2-10 and 19 exhibited significant inhibition against ConA and LPS stimulated T-cell and B-cell proliferation in a dose dependent manner. More significantly compounds 4, 9-10 and 19 exhibited potent inhibition activity with remarkably lower cytotoxicity on the mitogen-induced T cell and B cell proliferation at 1 μM concentration. The compound 6 displayed potent immunosuppressive effects with ~89% against LPS induced B-cell and ~83% against ConA stimulated T-cell proliferation at 100 μM concentration without cytotoxicity. Compound 10 was more selective against B cell proliferation and exhibited 81% and 69% suppression at 100 and 1 μM concentration respectively. The present study led to the identification of several santonin analogs with reduced cytotoxicity and strong inhibition activity against the cell proliferation induced by the mitogens.
- Dangroo, Nisar A.,Singh, Jasvinder,Dar, Alamgir A.,Gupta, Nidhi,Chinthakindi, Praveen K.,Kaul, Anpurna,Khuroo, Mohmmed A.,Sangwan, Payare L.
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p. 160 - 169
(2016/05/24)
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- Design and synthesis of peptide conjugates of phosphoramide mustard as prodrugs activated by prostate-specific antigen
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A series of Glutaryl-Hyp-Ala-Ser-Chg-Gln-4-aminobenzyl phosphoramide mustard conjugates (1a-e) was designed and synthesized as potential prodrugs for site-specific activation by PSA in prostate cancer cells. All conjugates were found to be substrates of PSA with cleavage occurring between Gln and the para-aminobenzyl (PAB) linker. Structure-activity relationship studies on these conjugates indicated that introduction of electron-withdrawing fluorine(s) on the phenyl ring in the PAB linker uniformly improved the chemical stability of the conjugates while the position of substitution affected differently the self-immolative process of conjugates upon proteolysis. Introduction of a fluorine at ortho position to benzylic phosphoramide as in 1b results in better stability of the conjugate prior to activation while maintaining its antiproliferative activity upon activation by PSA. The conjugate 1b with 2-fluoro substitution was identified as a promising lead for further evaluation and optimization in the development of prostate cancer-targeted prodrugs.
- Wu, Xinghua,Hu, Longqin
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p. 2697 - 2706
(2016/06/08)
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- Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents
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Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated, leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl A ring and 4-phenyl B ring for potent antiproliferative activity and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC50 values of 38 and 19 nM, respectively, in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular structure in MCF-7 cells as visualized by confocal microscopy, and caused G2/M arrest and apoptosis. Compound 90b possessed a mean GI50 value of 22 nM in the NCI60 cell line screen, displayed minimal cytotoxicity, and was shown to interact at the colchicine-binding site on β-tubulin. Phosphate and amino acid prodrugs of both 78b and 90b were synthesized, of which the alanine amide 102b retained potency and is a promising candidate for further clinical development.
- Greene, Thomas F.,Wang, Shu,Greene, Lisa M.,Nathwani, Seema M.,Pollock, Jade K.,Malebari, Azizah M.,McCabe, Thomas,Twamley, Brendan,OBoyle, Niamh M.,Zisterer, Daniela M.,Meegan, Mary J.
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- A colorimetric and ratiometric fluorescent probe with a large stokes shift for detection of hydrogen sulfide
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Developing probes for selective and sensitive detection of hydrogen sulfide (H2S) has received much research attention, because H2S is an environmental toxin as well as an important signaling molecule to regulate physiological and pathological processes. In this work, a new colorimetric and ratiometric fluorescent probe (Probe 1) for H2S detection was synthesized by employing dicyanoisophorone based fluorescence dye as a fluorophore and azide group as the response unit. The synthesized Probe 1 showed a long emission wavelength (λem = 643 nm) and large stokes shift (λem - λabs = 163 nm). Based on the H2S-induced reduction of azide group to amino group, Probe 1 showed high response speed, sensitivity, and selectivity toward HS- under room temperature. Moreover, Probe 1 can ratiometrically respond to HS- and the detection limit is as low as 0.13 μM. It was proved that Probe 1 is suitable for quantitatively detecting HS- ions in river water samples. The numerous advantages of Probe 1 make it be potentially used for quantitative detection of H2S in environment and living organisms.
- Xiang, Kaiqiang,Liu, Yunchang,Li, Changjiang,Tian, Baozhu,Tong, Tianzhong,Zhang, Jinlong
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- The rational design of a peptide-based hydrogel responsive to H2S
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The development of hydrogels that are responsive to external stimuli in a well-controlled manner is important for numerous biomedical applications. Herein we reported the first example of a hydrogel responsive to hydrogen sulphide (H2S). H
- Peltier, Raoul,Chen, Ganchao,Lei, Haipeng,Zhang, Mei,Gao, Liqian,Lee, Su Seong,Wang, Zuankai,Sun, Hongyan
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p. 17273 - 17276
(2015/12/08)
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- Bioorthogonal prodrug activation driven by a strain-promoted 1,3-dipolar cycloaddition
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Due to the formation of hydrolysis-susceptible adducts, the 1,3-dipolar cycloaddition between an azide and strained trans-cyclooctene (TCO) has been disregarded in the field of bioorthogonal chemistry. We report a method which uses the instability of the adducts to our advantage in a prodrug activation strategy. The reaction of trans-cyclooctenol (TCO-OH) with a model prodrug resulted in a rapid 1,3-dipolar cycloaddition with second-order rates of 0.017 M-1 s-1 and 0.027 M-1 s-1 for the equatorial and axial isomers, respectively, resulting in release of the active compound. 1H NMR studies showed that activation proceeded via a triazoline and imine, both of which are rapidly hydrolyzed to release the model drug. Cytotoxicity of a doxorubicin prodrug was restored in vitro upon activation with TCO-OH, while with cis-cyclooctenol (CCO-OH) no activation was observed. The data also demonstrates the potential of this reaction in organic synthesis as a mild orthogonal protecting group strategy for amino and hydroxyl groups.
- Matikonda, Siddharth S.,Orsi, Douglas L.,Staudacher, Verena,Jenkins, Imogen A.,Fiedler, Franziska,Chen, Jiayi,Gamble, Allan B.
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p. 1212 - 1218
(2015/02/19)
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- Structure-activity relationship of semicarbazone EGA furnishes photoaffinity inhibitors of anthrax toxin cellular entry
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EGA, 1, prevents the entry of multiple viruses and bacterial toxins into mammalian cells by inhibiting vesicular trafficking. The cellular target of 1 is unknown, and a structure-activity relationship study was conducted in order to develop a strategy for target identification. A compound with midnanomolar potency was identified (2), and three photoaffinity labels were synthesized (3-5). For this series, the expected photochemistry of the phenyl azide moiety is a more important factor than the IC50 of the photoprobe in obtaining a successful photolabeling event. While 3 was the most effective reversible inhibitor of the series, it provided no protection to cells against anthrax lethal toxin (LT) following UV irradiation. Conversely, 5, which possessed weak bioactivity in the standard assay, conferred robust irreversible protection vs LT to cells upon UV photolysis.
- Jung, Michael E.,Chamberlain, Brian T.,Ho, Chi-Lee C.,Gillespie, Eugene J.,Bradley, Kenneth A.
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p. 363 - 367
(2014/05/06)
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- Ratiometric two-photon fluorescent probes for mitochondrial hydrogen sulfide in living cells
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Hydrogen sulfide (H2S) is an important signaling molecule with diverse biological roles. Various fluorescent probes for H2S with biological application have been developed. However, two-photon ratiometric imaging of mitochondrial Hs
- Liu, Xiu-Ling,Du, Xiao-Jiao,Dai, Chun-Guang,Song, Qin-Hua
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p. 9481 - 9489
(2015/02/19)
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- Chemoselective reduction and self-immolation based FRET probes for detecting hydrogen sulfide in solution and in cells
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Hydrogen sulfide (H2S) has been regarded as the third gaseous transmitter. Based on the mechanism of chemoselective azido reduction and self-immolation, five fluorescence resonance energy transfer (FRET) probes for the detection of H2S were designed and synthesized. The effect of functional substitution of the self-immolative moiety on azido reduction and quinone-methide rearrangement were investigated. Their fluorescence responses and chemoselectivity for H2S detection were evaluated in solutions and in cells. This strategy may provide a general route for designing H 2S probes with many commercially available FRET pairs. the Partner Organisations 2014.
- Chen, Bifeng,Wang, Peng,Jin, Qingqing,Tang, Xinjing
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supporting information
p. 5629 - 5633
(2014/07/22)
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- Click chemistry inspired synthesis and bioevaluation of novel triazolyl derivatives of osthol as potent cytotoxic agents
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A new series of diverse triazoles linked through the hydroxyl group of lactone ring opened osthol (1) were synthesized using click chemistry approach. All the derivatives were subjected to 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) cytot
- Farooq, Saleem,Shakeel-U-Rehman,Hussain, Aashiq,Hamid, Abid,Qurishi, Mushtaq A.,Koul, Surrinder
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p. 545 - 554
(2015/03/14)
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- Ln[N(SiMe3)2]3-catalyzed cycloaddition of terminal alkynes to azides leading to 1,5-disubstituted 1,2,3-triazoles: New mechanistic features
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The first example of rare earth metal-catalyzed cycloaddition of terminal alkynes to azides resulting in the formation of 1,5-disubstituted 1,2,3-triazoles is described. Preliminary studies revealed that the present cycloaddition shows unprecedented mecha
- Hong, Longcheng,Lin, Weijia,Zhang, Fangjun,Liu, Ruiting,Zhou, Xigeng
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supporting information
p. 5589 - 5591
(2013/07/25)
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- A red emission fluorescent probe for hydrogen sulfide and its application in living cells imaging
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Hydrogen sulfide has emerged as an important biological messenger and much attention has been paid to the design of fluorescent probes for H2S to meet the requirement of accurate measurement of H2S. In this work, a new red emission fluorescent probe for H2S was developed based on the reduction reaction of azide with H2S to amine with the fluorophore of dicyanomethylenedihydrofuran because of its long excitation and emission wavelength. The probe has a high selectivity for H2S over competitive anions and sulfide-containing analytes. Finally, the probe was applied to sense H2S in living cells.
- Chen, Tao,Zheng, Yi,Xu, Zhaochao,Zhao, Miao,Xu, Yongnan,Cui, Jingnan
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supporting information
p. 2980 - 2982
(2013/07/05)
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- A near-infrared fluorescent probe for hydrogen sulfide in living cells
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Fluorescent probes for hydrogen sulfide have received considerable attention because of the biological significance of H2S recognized recently. However, near-infrared fluorescent probes for H2S are still rare. In this work, a new near-infrared fluorescent probe for H2S was developed based on the reduction reaction of azide with H2S to amine based on the fluorophore of dicyanomethylene-4H-chromene because of its long excitation and emission wavelength. The probe has a high selectivity for H2S over competitive anions and sulfide-containing analytes. Finally, the probe was applied to sense H2S in living cells.
- Zheng, Yi,Zhao, Miao,Qiao, Qinglong,Liu, Huiying,Lang, Haijing,Xu, Zhaochao
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p. 367 - 371
(2013/07/19)
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- Cell-based proteome profiling using an affinity-based probe (AfBP) derived from 3-deazaneplanocin A (DzNep)
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3-Deazaneplanocin A (DzNep), a global histone methylation inhibitor, has attracted significant interest in epigenetic research in recent years. The molecular mechanism of action and the cellular off-targets of DzNep, however, are still not well-understood
- Tam, Eric K. W.,Li, Zhengqiu,Goh, Yi Ling,Cheng, Xiamin,Wong, Sze Yue,Santhanakrishnan, Sridhar,Chai, Christina L. L.,Yao, Shao Q.
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p. 1818 - 1828
(2013/09/02)
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- 18F-LABELED AZIDE COMPOUND, REAGENT FOR 18F-LABELING AND METHOD FOR 18F-LABELING OF ALKYNE COMPOUND USING SAME
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[OBJECT] The present invention provides an 18F-labeled azide compound usable in the Huisgen reaction which enables 18F-labeling although only a small quantity of alkyne compound is available as a counterpart substrate, more specifica
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Page/Page column 5
(2012/05/04)
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- DNA-templated release of functional molecules with an azide-reduction- triggered immolative linker
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Nucleic acid templated reactions have attracted significant attention for nucleic acid sensing. Herein we report a general design which extends the potential of nucleic acid templated reactions to unleash the function of a broad diversity of small molecules such as a transcription factor agonist, a cytotoxic or a fluorophore.
- Gorska, Katarzyna,Manicardi, Alex,Barluenga, Sofia,Winssinger, Nicolas
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p. 4364 - 4366
(2011/06/19)
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- Organocatalytic synthesis of 1,2,3-triazoles from unactivated ketones and arylazides
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Organo-click reaction: A new and complementary method to Huisgen's metal-catalyzed triazole synthesis is described using unactivated ketones and arylazides as the substrates and proline as an organocatalyst. Dramatic acceleration was observed for this reaction using microwave activation and high regio- and chemoselectivities were obtained for a wide range of ketones and arylazides (see scheme). Copyright
- Belkheira, Mokhtaria,El Abed, Douniazad,Pons, Jean-Marc,Bressy, Cyril
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supporting information; experimental part
p. 12917 - 12921
(2011/12/04)
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- Copper(II)-catalyzed conversion of aryl/heteroaryl boronic acids, boronates, and trifluoroborates into the corresponding azides: Substrate scope and limitations
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We report the copper(II)-catalyzed conversion of organoboron compounds into the corresponding azide derivatives. A systematic series of phenylboronic acid derivatives is evaluated to examine the importance of steric and electronic effects of the sub-stituents on reaction yield as well as functional group compatibility. Heterocyclic substrates are also shown to participate in this mild reaction while compounds incorporating B-C(sp3) bonds are unreactive under the reaction conditions. The copper(II)-catalyzed boronic acid-azide coupling reaction is further extended to both boronate esters and potassium organotrifluoroborate salts. The method described herein complements existing procedures for the preparation of aryl azides from the respective amino, triazene, and halide derivatives and we expect that it will greatly facilitate copper- and ruthenium-catalyzed azide-alkyne cycloaddition reactions for the preparation of diversely functionalized 1-aryl- or 1-heteroaryl-1,2,3- triazoles derivatives. Georg Thieme Verlag Stuttgart.
- Grimes, Kimberly D.,Gupte, Amol,Aldrich, Courtney C.
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experimental part
p. 1441 - 1448
(2010/10/03)
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- Synthesis and evaluation of novel 3,4-epoxypiperidines as efficient DNA alkylating agents
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3,4-Epoxypiperidine derivatives are novel DNA alkylating agents based on an active site of the antitumor antibiotics azinomycins A and B. A 3,4-epoxypiperidine library was constructed containing derivatives with a variety of functional groups at C5 via Huisgen reaction, and DNA cleavage activity was examined. Results revealed a more active derivative than any 3,4-epoxypiperidines previously reported.
- Kawada, Yuji,Kodama, Tetsuya,Miyashita, Kazuyuki,Imanishi, Takeshi,Obika, Satoshi
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experimental part
p. 1249 - 1265
(2010/10/18)
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- Modified Bovine G-CSF Polypeptides And Their Uses
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Modified bovine G-CSF polypeptides and uses thereof are provided.
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- Exploring a pocket for polycycloaliphatic groups in the CXCR3 receptor with the aid of a modular synthetic strategy
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A CXCR3 pocket capable of accommodating polycycloaliphatics was explored using a modular synthetic strategy. The systematic studies reveal that the tricyclic 2-adamantane and bicyclic (iso)bornyl group are efficiently recognized by CXCR3.
- Wijtmans, Maikel,Verzijl, Dennis,van Dam, Cindy M.E.,Bosch, Leontien,Smit, Martine J.,Leurs, Rob,de Esch, Iwan J.P.
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supporting information; scheme or table
p. 2252 - 2257
(2009/12/03)
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- Click chemistry for photonic applications: Triazole-functionalized platinum(ii) acetylides for optical power limiting
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Three different triazole-containing platinum(ii) acetylide compounds were synthesized by click chemistry and evaluated for their use in optical power limiting (OPL) applications. The triazole unit was incorporated at three different positions within, or a
- Westlund, Robert,Glimsdal, Eirik,Lindgren, Mikael,Vestberg, Robert,Hawker, Craig,Lopes, Cesar,Malmstroem, Eva
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p. 166 - 175
(2008/12/21)
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- Click-connected ligand scaffolds: macrocyclic chelates for asymmetric hydrogenation
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Click chemistry is used to construct ligand scaffolds for a series of chiral diphosphites. Enantioselectivity as high as 97% ee is obtained using these click ligands in rhodium-catalyzed asymmetric hydrogenation. Control experiments and spectroscopic data suggest that a 16-membered P,P-macrocyclic Rh(1) chelate is formed.
- Qing, Zhang,Takacs, James M.
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p. 545 - 548
(2008/09/17)
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