- Conjugation of an oligonucleotide to Tat, a cell-penetrating peptide, via click chemistry
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Uptake of diagnostic and therapeutic oligonucleotides that specifically target disease can be enhanced by attachment of a cell-penetrating peptide. Here, we describe the covalent attachment of an oligonucleotide to Tat, a biologically important cell-penetrating peptide, via click chemistry.
- Brown, Sarah D.,Graham, Duncan
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- Linear-Dendritic Alternating Copolymers
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Herein, the design, synthesis, and characterization of an unprecedented copolymer consisting of alternating linear and dendritic segments is described. First, a 4th-generation Hawker-type dendron with two azide groups was synthesized, followed by a step-growth azide-alkyne “click” reaction between the 4th-generation diazido dendron and poly(ethylene glycol) diacetylene to create the target polymers. Unequal reactivity of the functional groups was observed in the step-growth polymerization. The resulting copolymers, with alternating hydrophilic linear and hydrophobic dendritic segments, can spontaneously associate into a unique type of microphase-segregated nanorods in water.
- Sun, Haotian,Haque, Farihah M.,Zhang, Yi,Commisso, Alex,Mohamed, Mohamed Alaa,Tsianou, Marina,Cui, Honggang,Grayson, Scott M.,Cheng, Chong
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- Preliminary evaluation of 18F-labeled LLP2A-trifluoroborate conjugates as VLA-4 (α4β1 integrin) specific radiotracers for PET imaging of melanoma
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Introduction: The transmembrane α4β1 integrin receptor, or very-late antigen 4 (VLA-4), is associated with tumor metastasis and angiogenesis, the development of chemotherapeutic drug resistance, and is overexpressed in multiple myelomas, osteosarcomas, lymphomas, leukemias, and melanomas. The peptidomimetic, LLP2A, is a high-affinity ligand with specificity for the extracellular portion of VLA-4 and several conjugates have been evaluated in vivo by NIR-fluorescence, 111In-SPECT and 68Ga- and 64Cu-PET imaging, but to date, not with 18F-PET. Methods: Using two highly stable organotrifluoroborate prosthetic groups: ammoniumdimethyl-trifluoroborate (AMBF3) and a new N-pyridinyl-para-trifluoroborate (N-Pyr-p-BF3), both capable of facile aqueous 18F-labeling by isotope exchange (IEX), we present the first PET imaging evaluations of two [18F]R-BF3 ?–PEG2-LLP2A tracers using VLA-4 overexpressing B16-F10 murine melanoma tumor mouse models. Results: Here, we demonstrate successful one-step 18F-labeling of both conjugates with wet NCA [18F]F? in radiochemical yields of up to 11.6% within 75 min at molar activities of 40–100 GBq/μmol. Average tumor uptake values based on ex vivo biodistribution values were 4.4%ID/g (11) and 2.8%ID/g (12) using 18F-labeled LLP2A-conjugates with the two prosthetic groups: N-Pyr-p-BF3 (5) and alkyl-N,N-dimethylammonio-BF3 (AMBF3) (7), respectively, and was found to be target-specific as evidenced by in vivo blocking controls. Dynamic PET scanning and biodistribution studies revealed slow clearance of the [18F]R-BF3 ?–PEG2-LLP2A tracers from the tumors, and also substantial uptake in the intestines, gall bladder, liver and bladder. Observed bone uptake was blockable, consistent with known VLA-4 expression in hematopoietic stem cells found in bone marrow. Conclusions: These studies show that these [18F]R-BF3 ?–PEG2-LLP2A conjugates (11 and 12) are promising VLA-4 targeting radiotracers, yet, further optimization will be required to reduce uptake in the gastro-intestinal tract.
- Roxin, áron,Zhang, Chengcheng,Huh, Sungjoon,Lepage, Mathieu L.,Zhang, Zhengxing,Lin, Kuo-Shyan,Bénard, Fran?ois,Perrin, David M.
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- Click chemistry to construct fluorescent oligonucleotides for DNA sequencing
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"Click chemistry" 1,3-dipolar cycloaddition between alkynyl 6-carboxyfluorescein (FAM) and azido-labeled single-stranded (ss) DNA was carried out under aqueous conditions to produce FAM-labeled ssDNA in quantitative yield. The FAM-labeled ssDNA was succes
- Seo, Tae Seok,Li, Zengmin,Ruparel, Hameer,Ju, Jingyue
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- Hypervalent Iodine Based Reversible Covalent Bond in Rotaxane Synthesis
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Reversible covalent bonds play a significant role in achieving the high-yielding synthesis of mechanically interlocked molecules. Still, only a handful of such bonds have been successfully employed in synthetic procedures. Herein, we introduce a novel app
- Kandrnálová, Markéta,Kokan, Zoran,Havel, Václav,Ne?as, Marek,?indelá?, Vladimír
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- Rapid formation of a supramolecular polypeptide-DNA Hydrogel for in situ three-dimensional multilayer bioprinting
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A rapidly formed supramolecular polypeptide-DNA hydrogel was prepared and used for in situ multilayer three-dimensional bioprinting for the first time. By alternative deposition of two complementary bio-inks, designed structures can be printed. Based on their healing properties and high mechanical strengths, the printed structures are geometrically uniform without boundaries and can keep their shapes up to the millimeter scale without collapse. 3D cell printing was demonstrated to fabricate live-cell-containing structures with normal cellular functions. Together with the unique properties of biocompatibility, permeability, and biodegradability, the hydrogel becomes an ideal biomaterial for 3D bioprinting to produce designable 3D constructs for applications in tissue engineering.
- Li, Chuang,Faulkner-Jones, Alan,Dun, Alison R.,Jin, Juan,Chen, Ping,Xing, Yongzheng,Yang, Zhongqiang,Li, Zhibo,Shu, Wenmiao,Liu, Dongsheng,Duncan, Rory R.
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- Modulation of the Passive Permeability of Semipeptidic Macrocycles: N- And C-Methylations Fine-Tune Conformation and Properties
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Incorporating small modifications to peptidic macrocycles can have a major influence on their properties. For instance, N-methylation has been shown to impact permeability. A better understanding of the relationship between permeability and structure is of key importance as peptidic drugs are often associated with unfavorable pharmacokinetic profiles. Starting from a semipeptidic macrocycle backbone composed of a tripeptide tethered head-to-tail with an alkyl linker, we investigated two small changes: peptide-to-peptoid substitution and various methyl placements on the nonpeptidic linker. Implementing these changes in parallel, we created a collection of 36 compounds. Their permeability was then assessed in parallel artificial membrane permeability assay (PAMPA) and Caco-2 assays. Our results show a systematic improvement in permeability associated with one peptoid position in the cycle, while the influence of methyl substitution varies on a case-by-case basis. Using a combination of molecular dynamics simulations and NMR measurements, we offer hypotheses to explain such behavior.
- Boudreault, Pierre-Luc,Comeau, Christian,Derbali, Rabeb Mouna,Grandbois, Michel,Poulet, Sylvain,Ries, Benjamin,Riniker, Sereina,Sarret, Philippe,Stadelmann, Thomas,Tremblay, Jacob,C?té, Jér?me,Fr?hlich, Ulrike,Leclair, Grégoire,Marsault, éric
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p. 5365 - 5383
(2021/05/04)
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- Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFRT790M mutant cell lines
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Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI–H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFRT790M resistance mutation harboring NCI–H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI–H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFRT790M harboring tumor cell lines (NCI–H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.
- Zhao, Lei,Fan, Tingting,Shi, Zhichao,Ding, Chao,Zhang, Cunlong,Yuan, Zigao,Sun, Qinsheng,Tan, Chunyan,Chu, Bizhu,Jiang, Yuyang
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- Discovery of triazolyl thalidomide derivatives as anti-fibrosis agents
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Fibrosis with excessive accumulation of extracellular matrix (ECM) often causes progressive organ dysfunction and results in many inflammatory and metabolic diseases, including systemic sclerosis, pulmonary fibrosis, advanced liver disease and advanced kidney disease. The store-operated calcium entry (SOCE) pathway and the related signaling pathway were both found to be the important routes for fibrogenesis. Our aim in this study was to discover novel compounds to inhibit fibrogenesis. A number of triazolyl thalidomide derivatives were synthesized and evaluated for their anti-fibrosis activities. Compounds 7b-e, 8c-d, 10a-b and 10e inhibited intracellular Ca2+ activation and showed no cytotoxicity. Among them, 6-{4-[(3-(1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}hexanoic acid (10e) with the most potent inhibitory effect was chosen for further examination. The results revealed that compound 10e, a SOCE inhibitor, reversed the migratory ability of TGF-β1-induced myofibroblasts, dedifferentiated myofibroblasts to fibroblasts due to cytoskeleton remodeling, and restrained myofibroblast activation by targeting Orai1 and TGF-β1/SMAD2/3 signaling pathways. The in silico study indicated that compound 10e, with the appropriate lipophilic carbon chain and carboxylic acid, showed a good drug-likeness model score. Conclusively, the SOCE inhibitor, compound 10e, is used as a promising lead compound for the development of a new treatment for fibrosis. This journal is
- Tang, Kai-Wei,Hsu, Wen-Li,Chen, Cheng-Ru,Tsai, Ming-Hsien,Yen, Chia-Jung,Tseng, Chih-Hua
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p. 3589 - 3599
(2021/03/03)
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- ENVIRONMENTALLY-FRIENDLY HYDROAZIDATION OF OLEFINS
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The present invention provides processes for the synthesis of organic azides, intermediates for the production thereof, and compositions related thereto.
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Page/Page column 62; 79-80
(2020/01/24)
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- Comparative binding and uptake of liposomes decorated with mannose oligosaccharides by cells expressing the mannose receptor or DC-SIGN
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Mannose Receptor (MR) and DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) are two mannose-specific targets for antigens carried by liposomes but DC-SIGN is more specific of DCs. Here, DC targeting is addressed by using DPPC/D
- Gao, Haifei,Gon?alves, Cristine,Gallego, Téo,Fran?ois-Heude, Marc,Malard, Virginie,Mateo, Véronique,Lemoine, Fran?ois,Cendret, Virginie,Djedaini-Pilard, Florence,Moreau, Vincent,Pichon, Chantal,Midoux, Patrick
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- Photosensitized Intermolecular Carboimination of Alkenes through the Persistent Radical Effect
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An intermolecular, two-component vicinal carboimination of alkenes has been accomplished by energy transfer catalysis. Oxime esters of alkyl carboxylic acids were used as bifunctional reagents to generate both alkyl and iminyl radicals. Subsequently, addition of the alkyl radical to an alkene generates a transient radical for selective radical–radical cross-coupling with the persistent iminyl radical. Furthermore, this process provides direct access to aliphatic primary amines and α-amino acids by simple hydrolysis.
- Bellotti, Peter,Glorius, Frank,Patra, Tuhin,Strieth-Kalthoff, Felix
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supporting information
p. 3172 - 3177
(2020/02/05)
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- Catechin-amantadine conjugate as well as preparation method and application thereof
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The invention discloses a catechin-amantadine conjugate as well as a preparation method and application thereof. The structure of the derivative is shown in the specification. The preparation method comprises the following steps: selectively protecting catechin; synthesizing a protected catechin terminal alkyne precursor under an alkaline condition; synthesizing an amantadine azide intermediate; carrying out click reaction on the terminal alkyne precursor and an azido adamantane precursor to synthesize a catechin adamantane conjugate; and in the presence of a hydrogenation catalyst, carrying out deprotection to synthesize the catechin-amantadine conjugate. The synthesized catechin-amantadine conjugate is novel in structure and simple in synthesis route, a noble metal catalyst is not used,and the synthesized catechin-amantadine has good anti-influenza activity.
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Paragraph 0028-0031; 0037-0038
(2020/09/12)
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- Chemical Targeting of Voltage Sensitive Dyes to Specific Cells and Molecules in the Brain
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Voltage sensitive fluorescent dyes (VSDs) are important tools for probing signal transduction in neurons and other excitable cells. The impact of these highly lipophilic sensors has, however, been limited due to the lack of cell-specific targeting methods in brain tissue or living animals. We address this key challenge by introducing a nongenetic molecular platform for cell- and molecule-specific targeting of synthetic VSDs in the brain. We employ a dextran polymer particle to overcome the inherent lipophilicity of VSDs by dynamic encapsulation and high-affinity ligands to target the construct to specific neuronal cells utilizing only native components of the neurotransmission machinery at physiological expression levels. Dichloropane, a monoamine transporter ligand, enables targeting of dense dopaminergic axons in the mouse striatum and sparse noradrenergic axons in the mouse cortex in acute brain slices. PFQX in conjunction with ligand-directed acyl imidazole chemistry enables covalent labeling of AMPA-type glutamate receptors in the same brain regions. Probe variants bearing either a classical electrochromic ANEP dye or state-of-the-art VoltageFluor-type dye respond to membrane potential changes in a similar manner to the parent dyes, as shown by whole-cell patch recording. We demonstrate the feasibility of optical voltage recording with our probes in brain tissue with one-photon and two-photon fluorescence microscopy and define the signal limits of optical voltage imaging with synthetic sensors under a low photon budget determined by the native expression levels of the target proteins. This work demonstrates the feasibility of a chemical targeting approach and expands the possibilities of cell-specific imaging and pharmacology.
- Fiala, Tomas,Wang, Jihang,Dunn, Matthew,?ebej, Peter,Choi, Se Joon,Nwadibia, Ekeoma C.,Fialova, Eva,Martinez, Diana M.,Cheetham, Claire E.,Fogle, Keri J.,Palladino, Michael J.,Freyberg, Zachary,Sulzer, David,Sames, Dalibor
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p. 9285 - 9301
(2020/06/04)
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- Direct Intermolecular Anti-Markovnikov Hydroazidation of Unactivated Olefins
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We herein report a direct intermolecular anti-Markovnikov hydroazidation method for unactivated olefins, which is promoted by a catalytic amount of bench-stable benziodoxole at ambient temperature. This method facilitates previously difficult, direct addition of hydrazoic acid across a wide variety of unactivated olefins in both complex molecules and unfunctionalized commodity chemicals. It conveniently fills a synthetic chemistry gap of existing olefin hydroazidation procedures, and thereby provides a valuable tool for azido-group labeling in organic synthesis and chemical biology studies.
- Li, Hongze,Shen, Shou-Jie,Zhu, Cheng-Liang,Xu, Hao
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supporting information
p. 9415 - 9421
(2019/06/21)
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- Design, synthesis, and anti-bacterial evaluation of triazolyl-pterostilbene derivatives
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Staphylococcus aureus resistance to current antibiotics has become the greatest global challenge facing public health. The development of new antimicrobial agents is urgent and important and is needed to provide additional therapeutic options. In our previous study, we found out that pterostilbene exhibited potent antibacterial activity, especially against methicillin-resistant Staphylococcus aureus (MRSA). According to previous studies, 1,2,3-triazole, with the characteristic of increasing the interaction with the target readily and enhancing water solubility, were widely used in the approved anti-bacterial drugs. Therefore, these results attract our interest to use the structure of pterostilbene as a scaffold for the hybrid 1,2,3-triazole moiety to develop a novel anti-MRSA infection agent. In this study, we demonstrated the design and synthesis of a series of triazolylpterostilbene derivatives. Among these compounds, compound 4d exhibited the most potent anti-MRSA activity with a minimum inhibitory concentration (MIC) value of 1.2-2.4 μg/mL and a minimum bactericidal concentration (MBC) value of 19.5-39 μg/mL. The structure-activity relationship and antibacterial mechanism were investigated in this study. Molecular docking studies were carried out to verify and rationalize the biological results. In this study, the results confirmed that our design could successfully increase the inhibitory activity and specificity against MRSA. Compound 4d could be used as a candidate for anti-bacterial agents and in depth vivo studies should be further investigated.
- Tang, Kai-Wei,Yang, Shih-Chun,Tseng, Chih-Hua
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- Schmidt Reaction of ω-Azido Valeryl Chlorides Followed by Intermolecular Trapping of the Rearrangement Ions: Synthesis of Assoanine and Related Pyrrolophenanthridine Alkaloids
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The Schmidt reaction of ω-azido valeryl chlorides in the presence of an additional nucleophile was explored. The arenes, alcohols, and amines were demonstrated as the intermolecular trapping reagents for isocyanate ion and N-acyliminium ion from the Schmidt rearrangement, affording the corresponding products with moderate to excellent yields. Two 2-oxoindoles from the reaction were successfully converted into four natural alkaloids, namely, assoanine, anhydrolycorine, oxoassoanine, and anhydrolycorinone.
- DIng, Shao-Lei,Ji, Yang,Su, Yan,Li, Rui,Gu, Peiming
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p. 2012 - 2021
(2019/02/14)
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- Salivary hydrogen sulfide measured with a new highly sensitive self-immolative coumarin-based fluorescent probe
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Ample evidence suggests that H2S is an important biological mediator, produced by endogenous enzymes and microbiota. So far, several techniques including colorimetric methods, electrochemical analysis and sulfide precipitation have been developed for H2S detection. These methods provide sensitive detection, however, they are destructive for tissues and require tedious sequences of preparation steps for the analyzed samples. Here, we report synthesis of a new fluorescent probe for H2S detection, 4-methyl-2-oxo-2H-chromen-7-yl 5-azidopentanoate (1). The design of 1 is based on combination of two strategies for H2S detection, i.e., reduction of an azido group to an amine in the presence of H2S and intramolecular lactamization. Finally, we measured salivary H2S concentration in healthy, 18–40-year-old volunteers immediately after obtaining specimens. The newly developed self-immolative coumarin-based fluorescence probe (C15H15N3O4) showed high sensitivity to H2S detection in both sodium phosphate buffer at physiological pH and in saliva. Salivary H2S concentration in healthy volunteers was within a range of 1.641–7.124 μM.
- Zaorska, Ewelina,Konop, Marek,Ostaszewski, Ryszard,Koszelewski, Dominik,Ufnal, Marcin
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- Host–Guest Complexes of Cyclodextrins and Nanodiamonds as a Strong Non-Covalent Binding Motif for Self-Assembled Nanomaterials
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We report the inclusion of carboxy- and amine-substituted molecular nanodiamonds (NDs) adamantane, diamantane, and triamantane by β-cyclodextrin and γ-cyclodextrin (β-CD and γ-CD), which have particularly well-suited hydrophobicity and symmetry for an optimal fit of the host and guest molecules. We studied the host–guest interactions in detail and generally observed 1:1 association of the NDs with the larger γ-CD cavity, but observed 1:2 association for the largest ND in the series (triamantane) with β-CD. We found higher binding affinities for carboxy-substituted NDs than for amine-substituted NDs. Additionally, cyclodextrin vesicles (CDVs) were decorated with d-mannose by using adamantane, diamantane, and triamantane as non-covalent anchors, and the resulting vesicles were compared with the lectin concanavalin A in agglutination experiments. Agglutination was directly correlated to the host–guest association: adamantane showed lower agglutination than di- or triamantane with β-CDV and almost no agglutination with γ-CDV, whereas high agglutination was observed for di- and triamantane with γ-CDV.
- Schibilla, Frauke,Voskuhl, Jens,Fokina, Natalie A.,Dahl, Jeremy E. P.,Schreiner, Peter R.,Ravoo, Bart Jan
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supporting information
p. 16059 - 16065
(2017/11/13)
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- Synthesis and biological evaluation of salinomycin triazole analogues as anticancer agents
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Salinomycin, a polyether antibiotic used for treatment of coccidial disease in animal husbandry, has demonstrated promising efficacy for treating different cancers. To enrich structure-activity relationship of salinomycin in tumours, we prepared a series of new triazole derivatives in specific site of salinomycin by click cycloaddition reactions, and assessed their antiproliferative activities on breast cancer cell lines. The screening results indicated that most derivatives modified at the C20 hydroxyl group have potent antitumour activity. Notably, salinomycin triazole dimers were 3.27–4.97 times more toxic than the natural substance in ERα-positive breast cancer cells (MCF-7), and had moderately improved toxicity in triple-negative breast cancer cells (MDA-MB-231).
- Huang, Minjian,Deng, Zixin,Tian, Jian,Liu, Tiangang
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p. 900 - 908
(2017/02/18)
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- AMPHIPHILIC POLYMER SYSTEMS
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The preparation of poly-2-oxazoline amphiphilic polymers and copolymers is described. Self-assembled particles comprising these amphiphilic polymers and which are useful for the targeted delivery of therapeutic and diagnostic agents are also described.
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Page/Page column 26
(2016/07/27)
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- Design and synthesis of novel dual-target agents for HDAC1 and CK2 inhibition
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Drug entities able to address multiple targets can be more effective than those directed to just one biological target. We disclose herein a series of novel dual inhibitors to target histone deacetylase 1 (HDAC 1) and protein kinase CK2. Our bifunctional compounds combine two complementary chemo-active prototypical scaffolds: a hydroxamate essential for the chelation of the zinc ion present in the active site of HDAC (Zinc Binding Group), and a 4,5,6,7-tetrabromobenzotriazole (TBB) moiety introduced to interact with the ATP binding site in CK2 and to act simultaneously as the cap group in the interaction with HDAC1. The synthesized dual-acting agents exhibited promising inhibitory activities towards HDAC1 and CK2. The best result was obtained for 5c with an IC50 of 5 μM for both enzymes. However, its N-2 substituted isomer 5e presented the best profile in cell-based assays, with cytotoxic activity in the low micromolar LC50 in two mammalian cancer cell lines and 4-fold less activity towards a pseudonormal mammalian cell line. Furthermore, this hybrid molecule induced apoptosis in leukemia cells in a concentration-dependent manner. All together this makes 5e a promising lead compound for future in vivo assays in animal tumor models.
- Purwin,Hernández-Toribio,Coderch,Panchuk,Skorokhyd,Filipiak,De Pascual-Teresa,Ramos
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p. 66595 - 66608
(2016/07/30)
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- Routes of Synthesis of Carbapenems for Optimizing Both the Inactivation of l, d -Transpeptidase LdtMt1 of Mycobacterium tuberculosis and the Stability toward Hydrolysis by β-Lactamase BlaC
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Combinations of β-lactams of the carbapenem class, such as meropenem, with clavulanate, a β-lactamase inhibitor, are being evaluated for the treatment of drug-resistant tuberculosis. However, carbapenems approved for human use have never been optimized for inactivation of the unusual β-lactam targets of Mycobacterium tuberculosis or for escaping to hydrolysis by broad-spectrum β-lactamase BlaC. Here, we report three routes of synthesis for modification of the two side chains carried by the β-lactam and the five-membered rings of the carbapenem core. In particular, we show that the azide-alkyne Huisgen cycloaddition reaction catalyzed by copper(I) is fully compatible with the highly unstable β-lactam ring of carbapenems and that the triazole ring generated by this reaction is well tolerated for inactivation of the l,d-transpeptidase LdtMt1 target. Several of our new carbapenems are superior to meropenem both with respect to the efficiency of in vitro inactivation of LdtMt1 and reduced hydrolysis by BlaC.
- Iannazzo, Laura,Soroka, Daria,Triboulet, Sébastien,Fonvielle, Matthieu,Compain, Fabrice,Dubée, Vincent,Mainardi, Jean-Luc,Hugonnet, Jean-Emmanuel,Braud, Emmanuelle,Arthur, Michel,Etheve-Quelquejeu, Mélanie
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p. 3427 - 3438
(2016/05/19)
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- NOVEL REAGENTS FOR UNIVERSAL SITE-SPECIFIC LABELING AND MODIFICATIONS OF NUCLEIC ACIDS
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The present invention discloses a method of harnessing versatile phosphoramidation reactions to regioselectively incorporate alkynyl/azido groups into post-synthetic nucleic acids primed with phosphate at the 5′ termini. With and without the presence of copper, the modified nucleic acids were subjected to azide-alkyne cycloaddition to obtain various nucleic acid conjugates including a peptide-oligonucleotide conjugate (POC) with a high yield.
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Paragraph 0047-0048
(2016/10/11)
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- Synthesis and Evaluation of a Library of Trifunctional Scaffold-Derived Compounds as Modulators of the Insulin Receptor
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We designed a combinatorial library of trifunctional scaffold-derived compounds, which were derivatized with 30 different in-house-made azides. The compounds were proposed to mimic insulin receptor (IR)-binding epitopes in the insulin molecule and bind to and activate this receptor. This work has enabled us to test our synthetic and biological methodology and to prove its robustness and reliability for the solid-phase synthesis and testing of combinatorial libraries of the trifunctional scaffold-derived compounds. Our effort resulted in the discovery of two compounds, which were able to weakly induce the autophosphorylation of IR and weakly bind to this receptor at a 0.1 mM concentration. Despite these modest biological results, which well document the well-known difficulty in modulating protein-protein interactions, this study represents a unique example of targeting the IR with a set of nonpeptide compounds that were specifically designed and synthesized for this purpose. We believe that this work can open new perspectives for the development of next-generation insulin mimetics based on the scaffold structure.
- Fabre, Benjamin,Pícha, Jan,Vaněk, Václav,Selicharová, Irena,Chrudinová, Martina,Collinsová, Michaela,?áková, Lenka,Budě?ínsky, Milo?,Jirá?ek, Ji?í
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supporting information
p. 710 - 722
(2016/12/22)
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- Living copolymer-protein/peptide hybrids for biomedical applications
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Water soluble polymers having formula I: Y-(L1)n1-(C(O))n2—(R1)n3—R2 are claimed. The polymers may contain multiple water soluble, immunogenicity reducing moieties and multiple active moieties. The polymers may be linked to a protein, or a peptide having up to twelve amino acids.
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- Facile synthesis and18F-radiolabeling of α4β1-specific LLP2A-aryltrifluoroborate peptidomimetic conjugates
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The peptidomimetic, LLP2A, is a specific, high-affinity ligand for α4β1integrin receptors. Previously, several PEGylated LLP2A conjugates were evaluated in vivo as imaging agents for the detection of lymphoma, leukemia, multiple myel
- Walker, Daniel,Li, Ying,Roxin, áron,Schaffer, Paul,Adam, Michael J.,Perrin, David M.
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supporting information
p. 5126 - 5131
(2016/10/04)
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- MASSIVE PARALLEL METHOD FOR DECODING DNA AND RNA
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This invention provides methods for attaching a nucleic acid to a solid surface and for sequencing nucleic acid by detecting the identity of each nucleotide analogue after the nucleotide analogue is incorporated into a growing strand of DNA in a polymerase reaction. The invention also provides nucleotide analogues which comprise unique labels attached to the nucleotide analogue through a cleavable linker, and a cleavable chemical group to cap the —OH group at the 3′-position of the deoxyribose.
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- Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer's disease
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In an effort to combat the multifaceted nature of Alzheimer's disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC50 of 111.7 ± 9.0 nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Aβ, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD.
- Chojnacki, Jeremy E.,Liu, Kai,Saathoff, John M.,Zhang, Shijun
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supporting information
p. 7324 - 7331
(2015/11/16)
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- Preparation of thermocleavable conjugates based on ansamitocin and superparamagnetic nanostructured particles by a chemobiosynthetic approach
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A combination of mutasynthesis, precursor-directed biosynthesis and semisynthesis provides access to new ansamitocin derivatives including new nanostructured particle-drug conjugates. These conjugates are based on the toxin ansamitocin and superparamagnetic iron oxide-silica core shell particles. New ansamitocin derivatives that are functionalized either with alkynylor azido groups in the ester side chain at C-3 are attached to nanostructured iron oxide core-silica shell particles. Upon exposure to an oscillating electromagnetic field these conjugates heat up and the ansamitocin derivatives are released by a retro-Diels-Alder reaction. For example, one ansamitocin derivative exerts strong antiproliferative activity against various cancer cell lines in the lower nanomolar range while the corresponding nanostructured particle-drug conjugate is not toxic. Therefore, these new conjugates can serve as dormant toxins that can be employed simultaneously in hyperthermia and chemotherapy when external inductive heating is applied.
- Mancuso, Lena,Knobloch, Tobias,Buchholz, Jessica,Hartwig, Jan,M?ller, Lena,Seidel, Katja,Collisi, Wera,Sasse, Florenz,Kirschning, Andreas
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p. 17541 - 17551
(2015/02/19)
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- Synthesis of 7-triazole-substituted camptothecin via click chemistry and evaluation of in vitro antitumor activity
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Camptothecin (CPT) is a natural topoisomerase I inhibitor with powerful antineoplastic activity against colorectal, breast, lung and ovarian cancers. To discover more potent antitumor agents, a series of new CPT derivatives were synthesized utilizing click chemistry. All compounds were assessed for cytotoxicity against A549, HCT-116, HT-29, LoVo, MDA-MB-231 cell lines, and some compounds exhibited good in vitro potency. Furthermore, all compounds kept or enhanced Topo I inhibition. A series of novel 7-triazole substituted camptothecin via click chemistry was designed, synthesized, and evaluated for their in vitro antitumor activity. Copyright
- Wang, Lei,Yuan, Wei,Zhang, Jie,Tong, Linjiang,Luo, Yu,Chen, Yi,Lu, Wei,Huang, Qingqing
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p. 157 - 162
(2014/03/21)
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- Azide-alkyne cycloaddition for universal post-synthetic modifications of nucleic acids and effective synthesis of bioactive nucleic acid conjugates
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The regioselective post-synthetic modifications of nucleic acids are essential to studies of these molecules for science and applications. Here we report a facile universal approach by harnessing versatile phosphoramidation reactions to regioselectively incorporate alkynyl/azido groups into post-synthetic nucleic acids primed with phosphate at the 5′ termini. With and without the presence of copper, the modified nucleic acids were subjected to azide-alkyne cycloaddition to afford various nucleic acid conjugates including a peptide-oligonucleotide conjugate (POC) with high yield. The POC was inoculated with human A549 cells and demonstrated excellent cell-penetrating ability despite cell deformation caused by a small amount of residual copper chelated to the POC. The combination of phosphoramidation and azide-alkyne cycloaddition reactions thus provides a universal regioselective strategy to post-synthetically modify nucleic acids. This study also explicated the toxicity of residual copper in synthesized bioconjugates destined for biological systems. This journal is the Partner Organisations 2014.
- Su, Yu-Chih,Lo, Yu-Lun,Hwang, Chi-Ching,Wang, Li-Fang,Wu, Min Hui,Wang, Eng-Chi,Wang, Yun-Ming,Wang, Tzu-Pin
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p. 6624 - 6633
(2014/08/18)
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- β-Sultams exhibit discrete binding preferences for diverse bacterial enzymes with nucleophilic residues
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β-Sultams are potent electrophiles that modify nucleophilic residues in selected enzyme active sites. We here identify and characterize some of the specific bacterial targets and show a unique inhibition of the azoreductase family.
- Kolb, Roman,Bach, Nina C.,Sieber, Stephan A.
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p. 427 - 429
(2014/01/06)
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- Dual-acting histone deacetylase-topoisomerase i inhibitors
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Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands th
- Guerrant, William,Patil, Vishal,Canzoneri, Joshua C.,Yao, Li-Pan,Hood, Rebecca,Oyelere, Adegboyega K.
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supporting information
p. 3283 - 3287
(2013/06/27)
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- Cancer phototherapy in living cells by multiphoton release of doxorubicin from gold nanospheres
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Doxorubicin is a widely used but toxic cancer chemotherapeutic agent. In order to localize its therapeutic action and minimize side effects, it was covalently conjugated to peptide-encapsulated gold nanospheres by click-chemistry and then photo-released in a controlled fashion by a multiphoton process. Selective treatment of a chosen region in a 2D layer of U2Os cancer cells is shown by driving photorelease with 561 nm irradiation at μW power. These results show promising directions for the development of practical applications based on nanocarriers that can ensure drug delivery with high spatial and temporal control. The Royal Society of Chemistry 2013.
- Voliani, Valerio,Signore, Giovanni,Vittorio, Orazio,Faraci, Paolo,Luin, Stefano,Perez-Prieto, Julia,Beltram, Fabio
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p. 4225 - 4230
(2013/09/02)
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- An enantioselective strategy for the synthesis of (S)-tylophorine via one-pot intramolecular schmidt/bischler-napieralski/imine-reduction cascade sequence
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A novel enantioselective strategy for the total synthesis of (S)-tylophorine was developed in an overall yield of 48% with more than 99% ee from readily avaliable azido acid and phenanthryl alcohol. This route features an Evans stereoselective alkylation and an unprecedented one-pot intramolecular Schmidt/Bischler-Napieralski/imine-reduction cascade sequence, in which three new bonds and two rings formed in 84% yield. The intramolecular Schmidt rearrangement of the azido aldehyde was proved to be racemization-free.
- Su, Bo,Chen, Fazhong,Wang, Qingmin
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p. 2775 - 2779
(2013/04/24)
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- Efficient construction of proline-containing β-turn mimetic cyclic tetrapeptides via CuAAC macrocyclization
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A range of macrocyclic β-turn mimetic tetrapeptides was prepared by efficient copper-tris(triazole) ligand complex catalyzed azide-alkyne "click" macrocyclizations in good to high yields. Preliminary conformational studies using X-ray crystallography and NMR spectroscopy demonstrated the presence of intramolecular H-bonds characteristic of β-turns in these cyclic tetrapeptides.
- Chouhan, Gagan,James, Keith
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p. 1206 - 1209
(2013/05/21)
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- Ligand-directed selective protein modification based on local single-electron-transfer catalysis
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A photocatalyst ([Ru(bpy)3]2+) bound to a protein ligand was essential for the title method. Local single-electron transfer from the catalyst resulted in the formation of tyrosyl radicals. N′-Acetyl-N,N- dimethyl-1,4-phenylenediamine was used as the tyrosyl radical trapping agent and used in a radical addition to afford selective modification of the target protein. Copyright
- Sato, Shinichi,Nakamura, Hiroyuki
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p. 8681 - 8684
(2013/09/12)
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- Altering peptide fibrillization by polymer conjugation
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A strategy is presented that exploits the ability of synthetic polymers of different nature to disturb the strong self-assembly capabilities of amyloid based β-sheet forming peptides. Following a convergent approach, the peptides of interest were synthesized via solid-phase peptide synthesis (SPPS) and the polymers via reversible addition-fragmentation chain transfer (RAFT) polymerization, followed by a copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) to generate the desired peptide-polymer conjugates. This study focuses on a modified version of the core sequence of the β-amyloid peptide (Aβ), Aβ(16-20) (KLVFF). The influence of attaching short poly(N-isopropylacrylamide) and poly(hydroxyethylacrylate) to the peptide sequences on the self-assembly properties of the hybrid materials were studied via infrared spectroscopy, TEM, circular dichroism and SAXS. The findings indicate that attaching these polymers disturbs the strong self-assembly properties of the biomolecules to a certain degree and permits to influence the aggregation of the peptides based on their β-sheets forming abilities. This study presents an innovative route toward targeted and controlled assembly of amyloid-like fibers to drive the formation of polymeric nanomaterials.
- Dehn, Sabrina,Castelletto, Valeria,Hamley, Ian W.,Perrier, Sebastien
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p. 2739 - 2747
(2012/11/13)
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- HISTONE DEACETYLASE (HDAC) INHIBITORS TARGETING PROSTATE TUMORS AND METHODS OF MAKING AND USING THEREOF
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Compounds of Formula (I), and methods of making and using thereof, are described herein; wherein AR is an aryl group, ZBG is a Zinc Binding Group, and other substituents are as defined herein. The compounds can be administered as a pharmaceutically acceptable salt, prodrug, or solvate. The compounds may be useful to treat and/or prevent hyperproliferative disorders which may include hormone sensitive and hormone refractory prostate cancers. The compounds can be formulated with a pharmaceutically acceptable carrier and, optionally one or more pharmaceutically acceptable excipients, for enteral or parenteral administration.
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Page/Page column 29
(2012/05/04)
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- Inhibition of lymphoid tyrosine phosphatase by benzofuran salicylic acids
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The lymphoid tyrosine phosphatase (Lyp, PTPN22) is a critical negative regulator of T cell antigen receptor (TCR) signaling. A single-nucleotide polymorphism (SNP) in the ptpn22 gene correlates with the incidence of various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Since the disease-associated allele is a more potent inhibitor of TCR signaling, specific Lyp inhibitors may become valuable in treating autoimmunity. Using a structure-based approach, we synthesized a library of 34 compounds that inhibited Lyp with IC50 values between 0.27 and 6.2 μM. A reporter assay was employed to screen for compounds that enhanced TCR signaling in cells, and several inhibitors displayed a dose-dependent, activating effect. Subsequent probing for Lyps direct physiological targets by immunoblot analysis confirmed the ability of the compounds to inhibit Lyp in T cells. Selectivity profiling against closely related tyrosine phosphatases and in silico docking studies with the crystal structure of Lyp yielded valuable information for the design of Lyp-specific compounds.
- Vang, Torkel,Xie, Yuli,Liu, Wallace H.,Vidovi?, Du?ica,Liu, Yidong,Wu, Shuangding,Smith, Deborah H.,Rinderspacher, Alison,Chung, Caty,Gong, Gangli,Mustelin, Tomas,Landry, Donald W.,Rickert, Robert C.,Schürer, Stephan C.,Deng, Shi-Xian,Tautz, Lutz
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p. 562 - 571
(2011/03/20)
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- CuAAC macrocyclization: High intramolecular selectivity through the use of copper-tris(triazole) ligand complexes
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A range of multivalent heteroaryl ligands, copper sources, and solvent systems have been investigated for use in CuAAC-mediated macrocyclization reactions. These studies have revealed the key factors governing selectivity for macrocyclization versus dimerization and identified a simple but specific set of reaction conditions capable of efficiently generating a diverse series of drug-like macrocycles at modest dilution in up to 95% yield.
- Chouhan, Gagan,James, Keith
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p. 2754 - 2757
(2011/06/26)
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- Labeling approaches for the GE11 peptide, an epidermal growth factor receptor biomarker
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The epidermal growth factor receptor (EGFR) is involved in the proliferation and differentiation of normal and malignant cells and is a major therapeutic target for a variety of human cancers. The peptide GE11 was reported to bind efficiently to the EGFR.
- Dissoki, Samar,Hagooly, Aviv,Elmachily, Smadar,Mishani, Eyal
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p. 693 - 701
(2012/07/27)
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- High-throughput synthesis of azide libraries suitable for direct "click" chemistry and in situ screening
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A key challenge in current drug discovery is the development of high-throughput (HT) amenable chemical reactions that allow rapid synthesis of diverse chemical libraries of enzyme inhibitors. The Cu(I)-catalyzed, 1,3-dipolar cycloaddition between an azide and an alkyne, better known as "click chemistry", is one such method that has received the most attention in recent years. Despite its popularity, there is still a lack of robust and efficient chemical strategies that give access to diverse libraries of azide-containing building blocks (key components in click chemistry). We report herein a highly robust and efficient strategy for high-throughput synthesis of a 325-member azide library. The method is highlighted by its simplicity and product purity. The utility of the library is demonstrated with the subsequent "click" synthesis of the corresponding bidentate inhibitors against PTP1B.
- Srinivasan, Rajavel,Tan, Lay Pheng,Wu, Hao,Yang, Peng-Yu,Kalesh, Karunakaran A.,Yao, Shao Q.
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supporting information; experimental part
p. 1821 - 1828
(2009/06/28)
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- BIPARTITE INHIBITORS OF BACTERIAL RNA POLYMERASE
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The invention provides a compound having a structural formula (I): X-α-Y, wherein X is an moiety that binds to the Rif pocket of a bacterial RNA polymerase, Y is a moiety that binds to the secondary channel of a bacterial RNA polymerase, and α is a linker. The compound can act as an inhibitor of bacterial RNA polymerase. The invention has applications in control of bacterial gene expression, control of bacterial growth, antibacterial chemistry, and antibacterial therapy.
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Page/Page column 28
(2008/06/13)
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- Synthesis of Cα methylated carboxylic acids: Isosteres of arginine and lysine for use as N-terminal capping residues in polypeptides
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Replacement of the N-terminal α-amine with the isosteric methyl functionality in bioactive peptides can influence various pharmacokinetic parameters, including hydrophobicity and stability. Cα methylated amino acid analogues are thus of great interest to expand the repertoire of nonnatural synthons available as N-terminal 'capping' residues for peptide-based drug design. Several novel arginine and lysine analogues stereoselectively modified in the Cα position with a methyl group in place of the α-amine were prepared.
- Orwig, Kevin S.,Dix, Thomas A.
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p. 7007 - 7009
(2007/10/03)
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- Facile and chemoselective reduction of carboxylic acids to alcohols using BOP reagent and sodium borohydride
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Hydroxybenzotriazolyl esters, formed in situ from carboxylic acids and BOP reagent, react with sodium borohydride in THF to give alcohols in high yields. This method is convenient, rapid and chemoselective, with such functional groups as nitro, halide, nitrile, azido and ester being unaffected.
- McGeary, Ross P.
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p. 3319 - 3322
(2007/10/03)
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- Long-acting Dihydropyridine Calcium Antagonists. Part 8. A Comparison of the Pharmacological and Pharmocokinetic Properties of Amlodipine with its Carba and Thio-bioisoesters
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In order to evaluate the contribution to the overall pharmacokinetic and pharmacological profile of amlodipine made by the side-chain ether oxygen atom and the intramolecular hydrogen bond to the DHP ring NH proton, the profile of amlodipine was compared
- Alker, David,Burges, Roger A.,Campbell, Simon F.,Carter, Anthony J.,Cross, Peter E.,et al.
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p. 1137 - 1140
(2007/10/02)
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- SYNTHESIS AND REACTIVITY OF METHYL γ-AZIDO BUTYRATES AND ETHYL δ-AZIDO VALERATES AND OF THE CORRESPONDING ACID CHLORIDES AS USEFUL REAGENTS FOR THE AMINOALKYLATION
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The azidoesters 13 and 14 and the corresponding acid chlorides 22 and 23 are shown to be interesting reagents for the nucleophilic and electrophilic aminoalkylation. α-substituted methyl γ-azidobutyrates 13 and ethyl δ-azido valerates 14 are easily accessible by alkylation of the lithium enolates of the parent compounds 13a and 14a respectively.Their chemoselective reduction leads to 3-substituted lactams 18 and 19.The acid chlorides 22 and 23 issued from 13 and 14 react with nucleophilic reagents, i.e. the carbanion of Meldrum acid, trimethylphosphite and n-butylmanganous iodide giving the the ω-azido,β-ketoesters 25 and 26, the ω-azido,α-acylphosphonates 29 and 30 and the ω-azido ketones 38 and 39 respectively in good yields.The treatment of 25 and 26 by Ph3P in anhydrous ether leads to the cyclic β-enaminoesters 27 and 28 whereas the α-acylphosphonates give the cyclic iminophosphonates 33 and 34a in good yields.These cyclizations occur via an intramolecular aza-Wittig reaction.
- Khoukhi, N.,Vaultier, M.,Carrie, R.
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p. 1811 - 1822
(2007/10/02)
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