- Water-soluble copolymeric materials: Switchable NIR two-photon fluorescence imaging agents for living cancer cells
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A simple one-pot multi-component ROMP of hydrophilic, spiropyran (SP) and tert-butyloxycarbonyl-protected (Boc-protected) amino-functionalized norbornenes was developed, and a series of water-soluble copolymeric materials were provided. The photochromic SP moiety endows the copolymers the properties of switchable fluorescence imaging with alternating near-IR (NIR) two-photon and visible single-photon excitations; thereby the copolymers can serve as a promising NIR two-photon fluorescent probe for living cancer cells. The cationic ammonium group enhances the cell transporting capability of the copolymers as well. The present strategy of one-pot ROMP also makes polynorbornene a modular and flexible scaffold in designing and synthesizing specifically biocompatible polymers with applications in imaging, diagnosis and therapy. The Royal Society of Chemistry 2014.
- Xie, Nan,Feng, Ke,Chen, Bin,Zhao, Ming,Peng, Shiqi,Zhang, Li-Ping,Tung, Chen-Ho,Wu, Li-Zhu
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- Design and synthesis of threading intercalators to target DNA
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Threading intercalators are high affinity DNA binding agents that bind by inserting a chromophore into the duplex and locating one group in each groove. The first threading intercalators that can be conjugated to acids, sulfonic acids and peptides to target them to duplex DNA are described, based upon the well studied acridine-3- or 4-carboxamides. Cellular uptake of the parent acridine is rapid and it can be visualized in the nucleus of cells. Both the parent compounds and their conjugates maintain antitumor activity.
- Howell, Lesley A.,Gulam, Rosul,Mueller, Anja,O'Connell, Maria A.,Searcey, Mark
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- Nanoscale photosensitizer with tumor-selective turn-on fluorescence and activatable photodynamic therapy treatment for COX-2 overexpressed cancer cells
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Effective targeting andin situimaging-guided treatment are particularly important for accurate clinical photodynamic therapy (PDT) of malignant tumors. Herein, we propose a single molecule, namedIMC-DAH-SQ, which possesses dual-targeting components, including structure-inherent targeting (SIT) and cyclooxygenase-2 (COX-2) targeting units, and controllable turn-on near infrared (NIR) fluorescence. Due to its amphiphilicity,IMC-DAH-SQassembles into a nanoprobe with low background fluorescence. After incubation with tumor cells, the SIT and COX-2 recognition characteristics ofIMC-DAH-SQendow it with preferential tumor-targeting activity. The strong binding with overexpressed COX-2 can collapse the nanoprobe to monomers after accumulation in tumor cells, leading to turn-on NIR fluorescence that is completely different from normal cells. Additionally, benefiting from the single molecular model tactic, the nanoprobe has the advantages of simple synthesis without ever considering the loading rate and separation between the photosensitizer and targeting unit. Other favorite features, including superior biocompatibility, weak dark toxicity, and mitochondria enrichment capability, are implemented. All these traits not only afford nanoprobe precision tumor cell targeting capability but also provide promising imaging-guided antitumor therapy. We believe that the single molecular protocol will establish a novel strategy for simultaneous diagnosis and anticancer medicine treatment utilizing versatile but small compounds.
- Wang, Lan,Zhang, Yuhuan,Han, Ying,Zhang, Qi,Wen, Zhenfu,Li, Hongjuan,Sun, Shiguo,Chen, Xin,Xu, Yongqian
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- Fluorescent H2Receptor Squaramide-Type Antagonists: Synthesis, Characterization, and Applications
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Fluorescence labeled ligands have been gaining importance as molecular tools, enabling receptor-ligand-binding studies by various fluorescence-based techniques. Aiming at red-emitting fluorescent ligands for the hH2R, a series of squaramides labeled with pyridinium or cyanine fluorophores (19-27) was synthesized and characterized. The highest hH2R affinities in radioligand competition binding assays were obtained in the case of pyridinium labeled antagonists 19-21 (pKi: 7.71-7.76) and cyanine labeled antagonists 23 and 25 (pKi: 7.67, 7.11). These fluorescent ligands proved to be useful tools for binding studies (saturation and competition binding as well as kinetic experiments), using confocal microscopy, flow cytometry, and high content imaging. Saturation binding experiments revealed pKd values comparable to the pKi values. The fluorescent probes 21, 23, and 25 could be used to localize H2 receptors in HEK cells and to determine the binding affinities of unlabeled compounds.
- Alencastre, Inês,Bernhardt, Günther,Biselli, Sabrina,Buschauer, Armin,Chen, Mengya,Erdmann, Daniela,Gomez-Lazaro, Maria,Keller, Max,Lamghari, Meriem,Littmann, Timo,Maia, André F.,Ozawa, Takeaki,Tanaka, Miho,Tropmann, Katharina
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- Peptoid dendrimers-microwave-assisted solid-phase synthesis and transfection agent evaluation
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Three generations of peptoid-based dendrimers were synthesised by solid-phase methods, using N-Fmoc-N-(6-N′-Fmoc-aminohexyl)-glycine as both the initiator core and the monomer unit, which offer an unusual dendrimeric periphery composed of both secondary and primary amines. The third generation compound proved to be an efficient mediator of transfection while displaying minimal cytotoxicity.
- Diaz-Mochon, Juan J.,Fara, Mario A.,Sanchez-Martin, Rosario M.,Bradley, Mark
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- Design, synthesis and anticancer activity of 2-amidomethoxy-1,4-naphthoquinones and its conjugates with Biotin/polyamine
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In continuation with the previous work, a series of 5-hydroxy-2-amidomethoxy-1,4-naphthoquinones were prepared to establish the structure-activity relationship studies toward anticancer activity (IC50 in μM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among the synthesized compounds, naphthoquinone amines, 5 (0.8; 0.6; 0.8), 14 (0.8; 0.6; 0.5) and the amine precursor, 4 (1.3; 0.3; 1.0) displayed potent anticancer activities. A tumor targeting drug delivery system was achieved by synthesizing the conjugate 6 (1.4; 0.5; 1.1) of naphthoquinone-amine 5 and Biotin which also proved its potency. Finally, to introduce polyamine conjugate, spermidine was attached with 2-amidomethoxy-1,4-naphthoquinone. The naphthoquinone-spermidine conjugate 27 (1.2; 1.7; 1.7) also retained the activity. Thus, potent naphthoquinone amines were explored and Biotin/polyamine conjugate was developed as tumor targeting drug delivery system.
- Manickam, Manoj,Boggu, Pulla Reddy,Pillaiyar, Thanigaimalai,Nam, Yeo Jin,Abdullah, Md.,Lee, Seung Jin,Kang, Jong Seong,Jung, Sang-Hun
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- Photo-responsive supramolecular hyaluronic acid hydrogels for accelerated wound healing
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Supramolecular hydrogels confer control over structural properties in a reversible, dynamic, and biomimetic fashion. The design of supramolecular hydrogels with an improved structural and functional recapitulation of damaged organs is important for clinical applications. For wound healing management, in particular, an effective healing process, through the modulation of epidermal growth factor (EGF) delivery using supramolecular polysaccharide hydrogels, has yet to be developed. In this study, photo-responsive supramolecular polysaccharide hydrogels were formed through host-guest interactions between azobenzene and β-cyclodextrin groups conjugated to hyaluronic acid chains. By exploiting the photoisomerization properties of azobenzene under different wavelengths, a supramolecular hydrogel featuring a dynamic spatial network crosslink density through the application of a light stimulus was obtained. Under ultra violet (UV) light, the loosened hydrogel can rapidly release EGF, thereby enhancing EGF delivery at the wound site. Based on an in vivo assessment of the healing process through a full-thickness skin defect model, the controlled EGF release from a supramolecular hydrogel exhibited superior wound healing efficiency with respect to granulation tissue formation, growth factor levels, and angiogenesis. Therefore, the proposed supramolecular hydrogels are potentially valuable as controlled delivery systems for future clinical wound healing applications.
- Boyer, Cyrille,Hu, Yang,Li, Yang,Xu, Fu-Jian,Zhang, Rui,Zhang, Xiang,Zhao, Weiyi
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- Single-wall carbon nanotubes covalently linked with zinc (II) phthalocyanine bearing poly (aryl benzyl ether) dendritic substituents: Synthesis, characterization and photoinduced electron transfer
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A novel series of dendritic phthalocyanine-single-wall carbon nanotube nanoconjugates, zinc (II) phthalocyanine bearing poly (aryl benzyl ether) dendritic substituents covalently linked with single-wall carbon nanotubes through either ethylenediamine or hexamethylenediamine as the spacer linker, were prepared. The structures and morphologies of the dendritic phthalocyanine-single-wall carbon nanotube nanoconjugates were characterized by IR, Raman spectroscopy, transmission electron microscopy and thermal gravimetric analysis methods. The photophysical properties of the nanoconjugates were studied by steady-state and time-resolved fluorescence spectroscopy. The intramolecular electron transfer occurred from phthalocyanine (donor) to the carbon nanotubes (acceptor) by a photoinduced process. The electron transfer exchange rate constant and the electron transfer efficacy between the dendritic phthalocyanine and single-wall carbon nanotubes increased with decreasing length of spacer linker. These novel nanoconjugates were fundamentally important due to the synergy effects of carbon nanotubes and dendritic zinc phthalocyanine, which may find potential application as biological labels.
- He, Dandan,Peng, Yiru,Yang, Hongqin,Ma, Dongdong,Wang, Yuhua,Chen, Kuizhi,Chen, Pingping,Shi, Jiafang
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- Helix-coil transition in cylindrical brush polymers with poly-l-lysine side chains
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Cylindrical brush polymers with poly-l-lysine side chains were prepared by grafting lysine NCA from a macroinitiator via living ring-opening polymerization. The main chain degree of polymerization of the methacrylate main chain was Pw = 870, the side chains consisted of 25 and 55 lysine repeat units, respectively. Upon deprotection, the cylindrical brush polymers in 0.005 M NaBr exhibited an almost rodlike conformation with a Kuhn statistical segment length of several hundred nanometers. Cryo-TEM as well as AFM in aqueous solution clearly demonstrated pronounced undulations along the main chain at low ionic strength which could not be detected at higher salt concentrations. With increasing concentration of NaClO4 the PLL side chains underwent a coil-to-helix transition as revealed by CD measurements. The effect of the side chain coil-to-helix transition on the main chain stiffness could not be followed by light scattering due to intramolecular attraction ("folding") of the cylindrical brushes at high salt concentration, which is somewhat more pronounced for the helical as compared to the coiled PLL side chain conformation. Comparison with linear PLL revealed the coil-to-helix transition to be hardly affected by the high grafting density of the PLL side chains in the cylindrical brush structures.
- Sahl, Mike,Muth, Sandra,Branscheid, Robert,Fischer, Karl,Schmidt, Manfred
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- Preparation and Preliminary Biological Evaluation of Novel 99mTc-Labelled Thymidine Analogs as Tumor Imaging Agents
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Two kinds of novel thymidine derivatives, N-thymidine-yl-N′-methyl- N′-{N′′- [2-sulfanyl-(ethylamino)acetyl]-2-aminoethylsulfanyl- 1-hexanamide}-ethanediamine (TMHEA) and N-thymidine-yl-N′-methyl-N′- {N′′-[2-sulfanyl-(ethylamino)acetyl]-2- aminoethylsulfanyl-1- hexanamide}-hexanediamine (TMHHA) were prepared and successfully labeled with 99mTc in high labeling yields. The in vitro stability and in vivo biodistribution of 99mTc-TMHEA and 99mTc-TMHHA were investigated and compared. The biodistribution studies indicate that the radiotracer 99mTc-TMHEA displays selective tumor uptake, suggesting it is a potential tumor imaging agent.
- Lu, Chunxiong,Jiang, Quanfu,Tan, Cheng,Tang, Jie,Zhang, Jiankang
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- Synthesis, electrochemistry, DNA binding and in vitro cytotoxic activity of tripodal ferrocenyl bis-naphthalimide derivatives
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A series of tripodal ferrocenyl bis-naphthalimide derivatives were synthesized and characterized. All of the bis-naphthalimide derivatives exhibited good DNA binding ability which was confirmed by ethidium bromide (EB) displacement experiment and ultraviolet (UV)-visible absorption titration. And the binding mode of these compounds was proved to be a hybrid binding mode by experiments. The cytotoxicity of synthesized compounds against 4 different human cancer cell lines (EC109, BGC823, SGC7901 and HEPG2) was evaluated by thiazolyl blue tetrazolium bromide (MTT) assay. All of the bis-naphthalimide derivatives exhibited good anticancer activity than the positive control drug (amonafide), which was due to the promotion of reactive oxygen species (ROS) level in test cancer cells by the reversible one-electron redox process of ferrocenyl bis-naphthalimide derivatives. Although there was no obvious relationship between the binding constants and the chain length, the structure cytotoxicity relationship revealed that the linker of n = 3, m = 1 was the best choice for the tested tripodol bis-naphthalimide derivatives. Synopsis: A series of tripodal ferrocenyl bis-naphthalimide derivatives were synthesized to study the DNA binding ability and the cytotoxicity induced by reactive oxygen species. All of the compounds exhibited good DNA binding ability. And the structure cytotoxicity relationship revealed that the structure of 5h was the best choice.
- Fan, Yan-Ru,Wang, Bo-Jin,Jia, Deng-Guo,Yang, Xin-Bin,Huang, Yu
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- Selective Pseudo-irreversible Butyrylcholinesterase Inhibitors Transferring Antioxidant Moieties to the Enzyme Show Pronounced Neuroprotective Efficacy in Vitro and in Vivo in an Alzheimer's Disease Mouse Model
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A series of multitarget-directed ligands (MTDLs) was designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor. The obtained hybrids were investigated in vitro regarding their hBChE and hAChE inhibition, their enzyme kinetics, and their antioxidant physicochemical properties (DPPH, ORAC, metal chelating). In addition, in vitro assays were applied to investigate antioxidant effects using murine hippocampal HT22 cells and immunomodulatory effects on the murine microglial N9 cell line. The MTDLs retained their antioxidative properties compared to the parent antioxidant-moieties in vitro and the inhibition of hBChE was maintained in the submicromolar range. Representative compounds were tested in a pharmacological Alzheimer's disease (AD) mouse model and demonstrated very high efficacy at doses as low as 0.1 mg/kg. The most promising compound was also tested in BChE-/- mice and showed reduced efficacy. In vivo neuroprotection by BChE inhibition can be effectively enhanced by incorporation of structurally diverse antioxidant moieties.
- Scheiner, Matthias,Hoffmann, Matthias,He, Feng,Poeta, Eleonora,Chatonnet, Arnaud,Monti, Barbara,Maurice, Tangui,Decker, Michael
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p. 9302 - 9320
(2021/07/19)
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- Design, synthesis and biological evaluation of tyrosinase-targeting PROTACs
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The human tyrosinase is the most prominent therapeutic target for pigmentary skin disorders. However, the overwhelming majority efforts have been devoted to search mushroom tyrosinase inhibitors, which show poor inhibitory activity on human tyrosinase and certain side effects that cause skin damage in practical application. Herein, a series of degraders that directly targeted human tyrosinase was firstly designed and synthesized based on newly developed PROTAC technology. The best PROTAC TD9 induced human tyrosinase degradation obviously in dose and time-dependent manner, and its mechanism of inducing tyrosinase degradation has also been clearly demonstrated. Besides, encouraging results that low-toxicity PROTAC TD9 was applied to reduce zebrafish melanin synthesis have been obtained, highlighting the potential to treatment of tyrosinase-related disorders. Moreover, this work has innovatively expanded the application scope of PROTAC technology and laid a solid foundation for further development of novel drugs treating pigmentary skin disorders.
- Cui, Xin,Deng, Yun,Fu, Dingqiang,Li, Guangxun,Qin, Fengming,Tang, Zhuo,Xu, Yan,Yao, Shaohua,Yuan, Yi
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supporting information
(2021/10/12)
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- Polyamine-Conjugated Nitroxides Are Efficacious Inhibitors of Oxidative Reactions Catalyzed by Endothelial-Localized Myeloperoxidase
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The heme enzyme myeloperoxidase (MPO) is a key mediator of endothelial dysfunction and a therapeutic target in cardiovascular disease. During inflammation, MPO released by circulating leukocytes is internalized by endothelial cells and transcytosed into the subendothelial extracellular matrix of diseased vessels. At this site, MPO mediates endothelial dysfunction by catalytically consuming nitric oxide (NO) and producing reactive oxidants, hypochlorous acid (HOCl) and the nitrogen dioxide radical (?NO2). Accordingly, there is interest in developing MPO inhibitors that effectively target endothelial-localized MPO. Here we studied a series of piperidine nitroxides conjugated to polyamine moieties as novel endothelial-targeted MPO inhibitors. Electron paramagnetic resonance analysis of cell lysates showed that polyamine conjugated nitroxides were efficiently internalized into endothelial cells in a heparan sulfate dependent manner. Nitroxides effectively inhibited the consumption of MPO's substrate hydrogen peroxide (H2O2) and formation of HOCl catalyzed by endothelial-localized MPO, with their efficacy dependent on both nitroxide and conjugated-polyamine structure. Nitroxides also differentially inhibited protein nitration catalyzed by both purified and endothelial-localized MPO, which was dependent on ?NO2 scavenging rather than MPO inhibition. Finally, nitroxides uniformly inhibited the catalytic consumption of NO by MPO in human plasma. These studies show for the first time that nitroxides effectively inhibit local oxidative reactions catalyzed by endothelial-localized MPO. Novel polyamine-conjugated nitroxides, ethylenediamine-TEMPO and putrescine-TEMPO, emerged as efficacious nitroxides uniquely exhibiting high endothelial cell uptake and efficient inhibition of MPO-catalyzed HOCl production, protein nitration, and NO oxidation. Polyamine-conjugated nitroxides represent a versatile class of antioxidant drugs capable of targeting endothelial-localized MPO during vascular inflammation.
- Maiocchi, Sophie,Ku, Jacqueline,Hawtrey, Tom,De Silvestro, Irene,Malle, Ernst,Rees, Martin,Thomas, Shane R.,Morris, Jonathan C.
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p. 1681 - 1692
(2021/06/28)
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- Small molecule compound based on EZH2 protein degradation, and application thereof
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The invention discloses a series of small molecule compounds capable of selectively degrading EZH2 protein, and application thereof. The compounds can be prepared into proper pharmaceutical dosage forms for EZH2-mediated related tumor treatment.
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Paragraph 0109-0112
(2021/08/07)
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- Design, Synthesis, and Evaluation of VHL-Based EZH2 Degraders to Enhance Therapeutic Activity against Lymphoma
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Traditional EZH2 inhibitors are developed to suppress the enzymatic methylation activity, and they may have therapeutic limitations due to the nonenzymatic functions of EZH2 in cancer development. Here, we report proteolysis-target chimera (PROTAC)-based EZH2 degraders to target the whole EZH2 in lymphoma. Two series of EZH2 degraders were designed and synthesized to hijack E3 ligase systems containing either von Hippel-Lindau (VHL) or cereblon (CRBN), and some VHL-based compounds were able to mediate EZH2 degradation. Two best degraders, YM181 and YM281, induced robust cell viability inhibition in diffuse large B-cell lymphoma (DLBCL) and other subtypes of lymphomas, outperforming a clinically used EZH2 inhibitor EPZ6438 (tazemetostat) that was only effective against DLBCL. The EZH2 degraders displayed promising antitumor activities in lymphoma xenografts and patient-derived primary lymphoma cells. Our study demonstrates that EZH2 degraders have better therapeutic activity than EZH2 inhibitors, which may provide a potential anticancer strategy to treat lymphoma.
- Tu, Yalin,Sun, Yameng,Qiao, Shuang,Luo, Yao,Liu, Panpan,Jiang, Zhong-Xing,Hu, Yumin,Wang, Zifeng,Huang, Peng,Wen, Shijun
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p. 10167 - 10184
(2021/07/26)
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- PROTEIN-POLYMER HYBRID BIOMATERIALS
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For applications in drug delivery, “smart” materials have been designed to respond to conditions within microenvironments of tissues or cells. The present invention features stimuli-responsive cross-linked hydrogels that respond to specific metabolites of disease. For example, protein-polymer materials of the present invention are configured to release their drug cargo upon encountering the higher lactate concentrations within tumor microenvironments.
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Paragraph 0093
(2020/03/01)
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- Phidianidine A and Synthetic Analogues as Naturally Inspired Marine Antifoulants
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Stationary and slow-moving marine organisms regularly employ a natural product chemical defense to prevent being colonized by marine micro- and macroorganisms. While these natural antifoulants can be structurally diverse, they often display highly conserved chemistries and physicochemical properties, suggesting a natural marine antifouling pharmacophore. In our current report, we investigate the marine natural product phidianidine A, which displays several chemical properties found in highly potent marine antifoulants. Phidianidine A and synthetic analogues were screened against the settlement and metamorphosis of Amphibalanus improvisus cyprids, and several of the compounds displayed inhibitory activities at low micromolar concentrations with IC50 values down to 0.7 μg/mL observed. The settlement study highlights that phidianidine A is a potent natural antifoulant and that the scaffold can be tuned to generate simpler and improved synthetic analogues. The bioactivity is closely linked to the size of the compound and to its basicity. The study also illustrates that active analogues can be prepared in the absence of the natural constrained 1,2,4-oxadiazole ring. A synthetic lead analogue of phidianidine A was incorporated in a coating and included in antifouling field trials, where it was shown that the coating induced potent inhibition of marine bacteria and microalgae settlement.
- Labriere, Christophe,Elumalai, Vijayaragavan,Staffansson, Jannie,Cervin, Gunnar,Le Norcy, Tiffany,Denardou, Hugo,Réhel, Karine,Moodie, Lindon W. K.,Hellio, Claire,Pavia, Henrik,Hansen, J?rn H.,Svenson, Johan
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p. 3413 - 3423
(2020/11/23)
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- ANTIFUNGAL PEPTOIDS
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Described herein are antifungal peptoids, the development and characterization of the antifungal peptoids, methods of making the antifungal peptoids, and methods of using the antifungal peptoids. In some embodiments, the antifungal peptoids may be administered to a subject infected with or at risk of being infected with pathogenic fungi including, for example Cryptococcus spp. In some embodiments, the Cryptococcus spp. may include C. neoformans or C. gattii or both.
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Paragraph 0077
(2020/07/07)
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- Target protein degradation inducing compound, preparation method thereof and pharmaceutical composition for preventing or treating targeted protein related diseases containing the same as an active ingredient
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The present invention relates to a degraducer for inducing the decomposition of target protein, a producing method thereof, and a pharmaceutical composition for preventing or treating target protein-related diseases by containing the degraducer as an active ingredient. A novel compound represented by chemical formula 1, ULB-L-PTM, by the present invention, as a degraducer compound inducing the decomposition of target protein using cereblon E3 ubiquitin ligase, is able to significantly achieve a target protein degradation-inducing activity with an excellent binding activity of a cereblon E3 ubiquitin ligase binder thereby, being able to achieve an excellent protein degradation activity by targeting protein or polypeptide related to various diseases. The bromodomain-containing pharmaceutical composition for preventing or treating protein-related diseases or conditions contains the novel compound represented by chemical formula 1 as an active ingredient and has a useful effect of providing a health functional food composition for prevention or improvement.(AA) Example 22 (nM, 24h)COPYRIGHT KIPO 2020
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Paragraph 0826; 0828-0830
(2020/05/01)
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- Dynamic host-guest interaction enables autonomous single molecule blinking and super-resolution imaging
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Synthetic host-guest complexes are inherently dynamic as they employ weak and reversible noncovalent interactions for their recognition processes. We strategically exploited dynamic supramolecular recognition between fluorescently labeled guest molecules to complementary cucurbit[7]uril hosts to obtain stochastic switching between fluorescence ON- and OFF-states, enabling PAINT-based nanoscopic imaging in cells and tissues.
- Sasmal, Ranjan,Das Saha, Nilanjana,Schueder, Florian,Joshi, Divyesh,Sheeba, Vasu,Jungmann, Ralf,Agasti, Sarit S.
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supporting information
p. 14430 - 14433
(2019/12/09)
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- Strategy and validation of a structure-based method for the discovery of selective inhibitors of PAK isoforms and the evaluation of their anti-cancer activity
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p21 activated kinase 4 (PAK4), which belongs to the serine/threonine (Ser/Thr) protein kinase family, is a representative member of the PAK family and plays a significant role in multiple processes associated with cancer development. In this study, structure-based virtual screening was performed to discover novel and selective small molecule scaffolds, and a 6-hydroxy-2-mercapto-3-phenylpyrimidin-4(3H)-one-based compound (SPU-106, 14No.) was identified as an effective PAK4 inhibitor. By combining both a molecular docking study and molecular dynamics (MD) simulation strategies, the binding mode was determined in the PAK4 site. The SPU-106 compound could efficiently and selectively bind to the PAK4 kinase domain at an IC50 of 21.36 μM according to the kinase analysis. The designed molecular probe demonstrated that SPU-106 binds to the kinase domain in the C-terminus of PAK4. Further investigation revealed that the SPU-106 had a strong inhibitory effect on the invasion of SGC7901 cells but without any cytotoxicity. The western blot analysis indicated that the compound potently inhibited the PAK4/LIMK1/cofilin and PAK4/SCG10 signaling pathways. Thus, our work shows the successful application of computational strategies for the discovery of selective hits, and SPU-106 may be an effective PAK4 inhibitor for further development as an antitumor agent.
- Song, Pei-Lu,Wang, Gang,Su, Yuan,Wang, Han-Xun,Wang, Jian,Li, Feng,Cheng, Mao-Sheng
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- DYNAMIC HOST-GUEST INTERACTIVE SYSTEM
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The present invention relates to a dynamic host-guest interactive system that possesses unique characteristics and finds utility in multitude of areas, specifically, in imaging and site directed drug delivery. An aspect of the present disclosure provides a dynamic host-guest interactive system including a host molecule and a guest molecule interacting with each other through non-covalent forces, wherein the host molecule is associated with any or a combination of a targeting moiety and a therapeutic agent with proviso that when the host molecule is associated with the targeting moiety, the guest molecule is associated with an imager, and when the host molecule is associated with the therapeutic agent, the guest molecule is associated with the targeting moiety, and when the host molecule is associated with a combination of the therapeutic agent and the targeting moiety, the guest molecule is associated with the imager. Another aspect provides a dynamic host-guest interactive system for site specific drug delivery of relatively less cell membrane permeable drug(s).
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Paragraph 0065; 0074; 0078
(2019/03/05)
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- Structure-Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands?
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New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H1R, H2R, H3R, H4R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 (2). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig (gp) ileum (gpH1R) and right atrium (gpH2R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human (h) H3R, S-methylisothiourea analogue 143 obtained high affinity at the hH4R (pKi=8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies.
- Pockes, Steffen,Wifling, David,Buschauer, Armin,Elz, Sigurd
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p. 285 - 297
(2019/04/04)
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- Thiazole orange – Spermine conjugate: A potent human telomerase inhibitor comparable to BRACO-19
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In this report, we synthesized a series of TO conjugates containing different amino side chains and investigated their binding to telomeric G-quadruplex DNA (G4) using several biophysical methods including fluorometric titration and thermal denaturation monitored by fluorescence and circular dichroism. The composition of side chains strongly affects the binding of these molecules to G-quadruplex DNA. Incorporation of amino side chains increases the binding affinity of TO toward G4 but has a minimal effect on its selectivity for G4 over duplex DNA. The plausible binding modes are a synergistic effect of end-stacking and groove interactions as indicated by docking studies. Inhibition of human telomerase activity by TO derivatives was determined in vitro by the TRAP assay. Several derivatives can selectively inhibit the activity of telomerase over DNA polymerase at low concentrations. More significantly, TO-spermine conjugate (16) exhibits a remarkable effect on telomerase inhibition in the submicromolar range, which is comparable to the inhibition effect of a well-known G4 ligand, BRACO-19. Our results here provide guidance of utilizing TO derivatives as a viable scaffold to design novel G4 ligands, G4 probes, and potent telomerase inhibitors.
- Wang, Siwen,Yang, Dazhou,Singh, Mandeep,Joo, Hyun,Rangel, Vanessa M.,Tran, Aaron,Phan, Erich,Xue, Liang
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- ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS
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The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.
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Page/Page column 207; 208
(2019/12/04)
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- An acid/alkali double stimulus responsive nano container and its preparation method
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The invention discloses an acid/base double stimulation responsive nanometer container and a preparation method thereof. According to the nanometer container, mesoporous nanometer silicon dioxide is adopted as a framework; a host-guest compound is formed based on host pillar[5]arene and a guest molecular chain 1,6-(1-(1-methyl)imida zolehexyl)hexamethylene diamine; a supramolecular valve is formed on the surface of a microsphere through modification; a metal corrosion inhibitor is loaded in the microsphere; under the action of pH stimulation, macrocyclic pillar[5]arene in the nanometer container can move, thereby achieving controllable release of the metal corrosion inhibitor; and after the metal corrosion inhibitor enters a coating, metal corrosion can be effectively inhibited. The nanometer container disclosed by the invention has the advantages that the function of response to various external stimuluses can be achieved; double response to acid/base stimulation can be achieved; and the prospect of application to the fields of drug delivery, intelligent anti-corrosive coating and the like is broad.
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Paragraph 0039-0040; 0043; 0059; 0075
(2018/11/22)
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- Iridium bipyridine complex and synthetic method thereof, and application of iridium bipyridine complex in DNA nanometer drug-carrier system
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The invention discloses an iridium bipyridine complex and a synthetic method thereof, and an application of the iridium bipyridine complex in a DNA nanometer drug-carrier system. The iridium bipyridine complex has a structural formula as shown in a formula I which is described in the specification. The complex has good water solubility, strong fluorescent properties and good in-vivo stability andtraceability. According to the invention, through manners of hexanediamine unilateral protection and deprotection, the yield of the complex can reach 80% or above. In order to further reinforce the killing effect of the iridium bipyridine complex on tumor cells, the invention constructs a DNA nanometer carrier with vasculogenic mimicry targeting to load the iridium bipyridine complex, so the targeting of the iridium bipyridine complex to vasculogenic mimicry is effectively improved; meanwhile, the efficiency of a drug entering tumor cell nucleus is enhanced; and the anti-tumor effect of the drug is finally improved.
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Paragraph 0085; 0104
(2018/03/26)
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- Dual-Responsive Doxorubicin-Conjugated Polymeric Micelles with Aggregation-Induced Emission Active Bioimaging and Charge Conversion for Cancer Therapy
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In recent years, intelligent polymeric micelles with multifunctions are in urgent demand for cancer diagnosis and therapy. Herein, pH and redox dual-responsive prodrug micelles with aggregation-induced emission (AIE) active cellular imaging and charge conversion have been prepared for combined chemotherapy and bioimaging based on a novel doxorubicin-conjugated amphiphilic PMPC-PAEMA-P (TPE-co-HD)-ss-P (TPE-co-HD)-PAEMA-PMPC copolymer. The doxorubicin is conjugated via a pH cleavable imine linkage and can be packed in the hydrophobic core along with the glutathione (GSH)-sensitive disulfide bond. The DOX-conjugated inner core is sealed with a pH-responsive PAEMA as the "gate", which would rapidly open in the acidic condition, following the drug release and charge conversion-mediated acceleration of endocytosis. After an efficient internalization, the disulfide bond can be cleaved by the high concentration of GSH causing the further accelerated drug release. Meanwhile, intracellular drug delivery can be traced due to the AIE behavior of micelles. Moreover, great tumor inhibition in vitro and in vivo has been demonstrated for these DOX-conjugated micelles. This smart prodrug micelle system would be a desirable drug carrier for cancer therapy and bioimaging.
- Su, Xin,Ma, Boxuan,Hu, Jun,Yu, Tao,Zhuang, Weihua,Yang, Li,Li, Gaocan,Wang, Yunbing
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p. 4050 - 4061
(2018/12/14)
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- Improved potency and reduced toxicity of the antifungal peptoid AEC5 through submonomer modification
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As proteolytically stable peptidomimetics, peptoids could serve as antifungal agents to supplement a therapeutic field wrought with toxicity issues. We report the improvement of an antifungal peptoid, AEC5, through an iterative structure-activity relationship study. A sarcosine scan was used to first identify the most pharmacophorically important peptoid building blocks of AEC5, followed by sequential optimization of each building block. The optimized antifungal peptoid from this study, β-5, has improved potency towards Cryptococcus neoformans and decreased toxicity towards mammalian cells. For example, the selectivity ratio for C. neoformans over mammalian fibroblasts was improved from 8 for AEC5 to 37 for β-5.
- Middleton, Madyson P.,Armstrong, Scott A.,Bicker, Kevin L.
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supporting information
p. 3514 - 3519
(2018/10/15)
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- Synthesis of novel Chlorin e6-curcumin conjugates as photosensitizers for photodynamic therapy against pancreatic carcinoma
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Curcumin (cur) has been comprehensively studied for its various biological properties, more precisely for its antitumor potential and it has shown the promising results as well. On the other hand, Chlorin e6 (Ce6) has mostly been used as a photosensitizer in photodynamic therapy (PDT) against a variety of carcinomas. In the present study, we have synthesized a series of Chlorin e6-curcumin (Ce6-cur) conjugates and investigated their photosensitizing potential against pancreatic cancer cell lines. All the synthesized compounds were characterized by UV, 1H NMR, 13C NMR and LC-MS. These Ce6-cur conjugates showed better physicochemical properties and higher singlet oxygen generation capability. The cellular uptake was studied in AsPC-1 cells using fluorescence-activated cell sorting (FACS). Compound 17 was rapidly internalized within 30 min and sustained for 24 h. Compound 17 showed excellent PDT efficacy with IC50 of 40, 35 and 41 nM against AsPC-1, MIA PaCa-2 and PANC-1 respectively with exceptional dark/phototoxicity ratio in the range of 2371–7500. Moreover, the treatment of compound 17 upregulated the expression of BAX, Cytochrome-C and cleaved caspase 9 while downregulating the Bcl-2 expression an anti-apoptotic protein marker. These results demonstrate outstanding capability of compound 17 as a potent photosensitizer which could improve the PDT efficacy in pancreatic cancer patients.
- Jalde, Shivakumar S.,Chauhan, Anil Kumar,Lee, Ji Hoon,Chaturvedi, Pankaj Kumar,Park, Joon-Suk,Kim, Yong-Wan
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- NOVEL CHLORIN E6-CURCUMIN DERIVATIVES, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME FOR TREATMENT OF CANCER
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The present invention relates to novel chlorine e6-curcumin derivatives, a preparation method thereof for the treatment of cancer, and in particularly, novel compounds were prepared by using different linkers such as hydrophobic and hydrophilic linkers to conjugate chlorine e6 to curcumin, the compounds under investigation showed excellent photophysical properties, stability, and anticancer activity.
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Paragraph 147; 148; 149; 150
(2019/01/10)
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- A Combined Photochemical and Multicomponent Reaction Approach to Precision Oligomers
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We introduce the convergent synthesis of linear monodisperse sequence-defined oligomers through a unique approach, combining the Passerini three-component reaction (P-3CR) and a Diels–Alder (DA) reaction based on photocaged dienes. A set of oligomers is prepared resting on a Passerini linker unit carrying an isocyano group for chain extension by P-3CR and a maleimide moiety for photoenol conjugation enabling a modular approach for chain growth. Monodisperse oligomers are accessible in a stepwise fashion by switching between both reaction types. Employing sebacic acid as a core unit allows the synthesis of a library of symmetric sequence-defined oligomers. The oligomers consist of alternating P-3CR and photoblocks with molecular weights up to 3532.16 g mol?1, demonstrating the successful switching from P-3CR to photoenol conjugation. In-depth characterization was carried out including size-exclusion chromatography (SEC), high-resolution electrospray ionization mass spectrometry (ESI-MS) and NMR spectroscopy, evidencing the monodisperse nature of the precision oligomers.
- Konrad, Waldemar,Bloesser, Fabian R.,Wetzel, Katharina S.,Boukis, Andreas C.,Meier, Michael A. R.,Barner-Kowollik, Christopher
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supporting information
p. 3413 - 3419
(2018/02/09)
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- Organic triplet photosensitive agent with host-guest recognition group and preparation method of organic triplet photosensitive agent
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The invention discloses an organic triplet photosensitive agent with a host-guest recognition group and a preparation method of the organic triplet photosensitive agent, which belong to the technicalfield of the synthesis of photosensitive agents. Hexanediamine is introduced on a meso-position benzene ring position of Bodipy in a C60-Bodipy binary compound organic triplet photosensitive agent tobe used as a supermolecule combination site, the triplet photosensitive agent with a hyperon combination site and a supermolecule main body with a triplet receptor are self-assembled in a solution, and a space distance between the triplet photosensitive agent and the triplet receptor is shortened to a molecular dimensional range, so that the triplet photosensitive agent can transfer the energy without being dispersed in an effective service life range, the non-radiation deactivation probability of a triplet exciton can be reduced, the energy transfer efficiency between the photosensitive agentand the receptor can be increased, and the upconversion efficiency can be increased.
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Paragraph 0069; 0088; 0090-0092; 0102; 0116-0118; 0125
(2018/08/03)
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- Synthesis and biological evaluation of bifendate derivatives bearing 6,7-dihydro-dibenzo[c,e]azepine scaffold as potential P-glycoprotein and tumor metastasis inhibitors
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As a continuation of previous research, fifteen bifendate derivatives bearing 6,7-dihydro-dibenzo [c,e]azepine scaffold were synthesized and evaluated as P-gp-medicated multidrug resistance (MDR) reversal agents. Biological evaluation indicated that compounds 6k and 9c more potently reversed P-gp-mediated MDR than bifendate and verapamil (VRP) by blocking P-gp mediated drug efflux function and not by decreasing P-gp expression in K562/A02 MDR cells. Interestingly, wound-healing and chamber migration assay showed that 6k and 9c could significantly attenuate the migration of MDA-MB-231 cells. Notably, 6k and 9c could markedly suppress the invasive activity of MDA-MB-231 cells, thus displayed potential anti-metastasis activity. Preliminary mechanism studies indicated that the anti-metastasis activity of 6k and 9c was associated with their inhibitory effect on the activity and expression of MMP-2 and MMP-9. These results, together with the MDR reversal results indicated that compounds 6k and 9c might be promising leads for developing novel anti-cancer agents with P-gp and tumor metastasis inhibitory activities.
- Gu, Xiaoke,Jiang, Yanfei,Qu, Yingying,Chen, Jing,Feng, Dingding,Li, Chenglin,Yin, Xiaoxing
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p. 379 - 388
(2018/01/17)
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- Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors
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A series of novel pyrimidylaminoquinoline derivatives 8(a-i) and 9(a-i) containing amino side chain, and the bisaminoquinoline analogs 3(b-e) have been designed and synthesized by structural modifications on a lead DOT1L inhibitor, 3a. All the compounds have been evaluated for their DOT1L inhibitory activities. The results showed that most of the compounds have strong anti DOT1L activities. Compounds 3e, 8h and 9e are the most potential ones from each category with the IC50 values of 1.06 ± 0.35 μM, 5.72 ± 1.56 μM and 3.55 ± 1.28 μM, respectively. Such inhibitors expressed significant binding interactions with DOT1L by surface plasmon resonance (SPR)-based binding assay. The results of molecular docking experiments suggested that they could occupy the SAM binding pocket of DOT1L. Compounds 8h and 9e exhibited better inhibitory activities but poor selectivities against the both MLL-rearranged MV4-11 cells and the non MLL-rearranged Kasumi-1 cells than those of 3a and 3e, which suggested that the introduction of the amino side chain would be beneficial for their anti leukemia cells proliferation activities, possibly due to the improvement of the fat solubility. Additionally, the direct cellular inhibition activities were found that compound 9e could effectively down-regulate both the level of H3k79 methylation and MLL-rearranged leukemia gene expression of Hoxa9 and Meis1 in MV4-11 in the qRT-PCR and western blot studies. These observations suggested DOT1L was one of the potential targets but perhaps not the most pivotal one for these compounds, which made their poor selectivities against leukemia cells proliferation.
- Zhang, Li,Chen, Yantao,Liu, Na,Li, Linjuan,Xiao, Senhao,Li, Xiaoliu,Chen, Kaixian,Luo, Cheng,Chen, Shijie,Chen, Hua
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supporting information
p. 649 - 654
(2018/07/31)
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- Corroboration of Zn(ii)-Mg(ii)-tertiary structure interplays essential for the optimal catalysis of a phosphorothiolate thiolesterase ribozyme
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The TW17 ribozyme, a catalytic RNA selected from a pool of artificial RNA, is specific for the Zn2+-dependent hydrolysis of a phosphorothiolate thiolester bond. Here, we describe the organic synthesis of both guanosine α-thio-monophosphate and the substrates required for selecting and characterizing the TW17 ribozyme, and for deciphering the catalytic mechanism of the ribozyme. By successively substituting the substrate originally conjugated to the RNA pool with structurally modified substrates, we demonstrated that the TW17 ribozyme specifically catalyzes phosphorothiolate thiolester hydrolysis. Metal titration studies of TW17 ribozyme catalysis in the presence of Zn2+ alone, Zn2+ and Mg2+, and Zn2+ and [Co(NH3)6]3+ supported our findings that Zn2+ is absolutely required for ribozyme catalysis, and indicated that optimal ribozyme catalysis involves the presence of outer-sphere and one inner-sphere Mg2+. A survey of the TW17 ribozyme activity at various pHs revealed that the activity of the ribozyme critically depends on the alkaline conditions. Moreover, a GNRA tetraloop-containing ribozyme constructed with active catalysis in trans provided catalysis and multiple substrate turnover efficiencies significantly higher than ribozymes lacking a GNRA tetraloop. This research supports the essential roles of Zn2+, Mg2+, and a GNRA tetraloop in modulating the TW17 ribozyme structure for optimal ribozyme catalysis, leading also to the formulation of a proposed reaction mechanism for TW17 ribozyme catalysis.
- Wang, Tzu-Pin,Su, Yu-Chih,Chen, Yi,Severance, Scott,Hwang, Chi-Ching,Liou, Yi-Ming,Lu, Chia-Hui,Lin, Kun-Liang,Zhu, Rui Jing,Wang, Eng-Chi
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p. 32775 - 32793
(2018/10/15)
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- Chemoselective Installation of Amine Bonds on Proteins through Aza-Michael Ligation
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Chemical modification of proteins is essential for a variety of important diagnostic and therapeutic applications. Many strategies developed to date lack chemo- and regioselectivity as well as result in non-native linkages that may suffer from instability in vivo and adversely affect the protein's structure and function. We describe here the reaction of N-nucleophiles with the amino acid dehydroalanine (Dha) in a protein context. When Dha is chemically installed in proteins, the addition of a wide-range N-nucleophiles enables the rapid formation of amine linkages (secondary and tertiary) in a chemoselective manner under mild, biocompatible conditions. These new linkages are stable at a wide range of pH values (pH 2.8 to 12.8), under reducing conditions (biological thiols such as glutathione) and in human plasma. This method is demonstrated for three proteins and is shown to be fully compatible with disulfide bridges, as evidenced by the selective modification of recombinant albumin that displays 17 structurally relevant disulfides. The practicability and utility of our approach is further demonstrated by the construction of a chemically modified C2A domain of Synaptotagmin-I protein that retains its ability to preferentially bind to apoptotic cells at a level comparable to the native protein. Importantly, the method was useful for building a homogeneous antibody-drug conjugate with a precise drug-to-antibody ratio of 2. The kinase inhibitor crizotinib was directly conjugated to Dha through its piperidine motif, and its antibody-mediated intracellular delivery results in 10-fold improvement of its cancer cell-killing efficacy. The simplicity and exquisite site-selectivity of the aza-Michael ligation described herein allows the construction of stable secondary and tertiary amine-linked protein conjugates without affecting the structure and function of biologically relevant proteins.
- Freedy, Allyson M.,Matos, Maria J.,Boutureira, Omar,Corzana, Francisco,Guerreiro, Ana,Akkapeddi, Padma,Somovilla, Víctor J.,Rodrigues, Tiago,Nicholls, Karl,Xie, Bangwen,Jiménez-Osés, Gonzalo,Brindle, Kevin M.,Neves, André A.,Bernardes, Gon?alo J. L.
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supporting information
p. 18365 - 18375
(2017/12/27)
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- Fullerene bisadduct regioisomers containing an asymmetric diamide tether
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Four macrocyclic bis(pyrrolidino)fullerene regioisomers with e-edge, e-face, trans-4 and cis-2 addition patterns were synthesized from the corresponding monoadduct by Prato's cycloaddition in a yield of 50%, and fully characterized by spectroscopic techniques. Bisadduct regioisomers were isolated easily in a pure form using dry-flash column chromatography. The relative ratio of the isolated regioisomers e-edge/e-face/trans-4/cis-2 was 1.0:1.9:1.5:4.9. Morphology of self-assembled structures of the four bisadduct regioisomers in solution was characterized using scanning electron microscopy.
- Kop, Tatjana J.,?or?evi?, Jelena,Bjelakovi?, Mira S.,Mili?, Dragana R.
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supporting information
p. 7073 - 7078
(2017/11/10)
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- Peptidomimetics That Inhibit and Partially Reverse the Aggregation of Aβ1-42
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The peptide sequence KLVFF resembles the hydrophobic core of the Aβ peptide known to form amyloid plaques in Alzheimer's disease. Starting from its retro-inverso peptide, we have synthesized three generations of peptidomimetics. Step by step natural amino acids have been replaced by aromatic building blocks accessible from the Pd-catalyzed Catellani reaction. The final compound 18 is stable against proteolytic decay and largely prevents the aggregation of Aβ1-42 over extended periods of time. The activity of the new inhibitors was tested first by fluorescence correlation spectroscopy. For closer examination of compound 18, additional techniques were also applied: laser-induced liquid bead ion desorption mass spectrometry, confocal laser scanning microscopy, thioflavin T fluorescence, and gel electrophoresis. Compound 18 not only retards the aggregation of chemically synthesized Aβ but also can partially dissolve the oligomeric structures. Thioflavin binding mature fibrils, however, seem to resist the inhibitor.
- Stark, Tina,Lieblein, Tobias,Pohland, Maximilian,Kalden, Elisabeth,Freund, Petra,Zangl, René,Grewal, Rekha,Heilemann, Mike,Eckert, Gunter P.,Morgner, Nina,G?bel, Michael W.
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p. 4840 - 4849
(2017/09/19)
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- Highly Ordered Nanoporous Films from Supramolecular Diblock Copolymers with Hydrogen-Bonding Junctions
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We designed efficient precursors that combine complementary associative groups with exceptional binding affinities and thiocarbonylthio moieties enabling precise RAFT polymerization. Well defined PS and PMMA supramolecular polymers with molecular weights up to 30 kg mol?1are synthesized and shown to form highly stable supramolecular diblock copolymers (BCPs) when mixed, in non-polar solvents or in the bulk. Hierarchical self-assembly of such supramolecular BCPs by thermal annealing affords morphologies with excellent lateral order, comparable to features expected from covalent diblock copolymer analogues. Simple washing of the resulting materials with protic solvents disrupts the supramolecular association and selectively dissolves one polymer, affording a straightforward process for preparing well-ordered nanoporous materials without resorting to crosslinking or invasive chemical degradations.
- Montarnal, Damien,Delbosc, Nicolas,Chamignon, Cécile,Virolleaud, Marie-Alice,Luo, Yingdong,Hawker, Craig J.,Drockenmuller, Eric,Bernard, Julien
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p. 11117 - 11121
(2016/07/06)
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- Flow-mediated synthesis of Boc, Fmoc, and Dd iv monoprotected diamines
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A series of monoprotected aliphatic diamines (21 examples) were synthesized via continuous flow methods. The carbamates and enamines were obtained in 45-91% yields using a 0.5 mm diameter PTFE tubular flow reactor. Using readily accessible protecting group precursors, the procedure serves as an attractive alternative to existing batch-mode synthetic routes by providing direct, multigram access to N-Boc-, N-Fmoc-, and N-Ddiv-protected compounds with productivity indexes of 1.2-3.6 g/h.
- Jong, Thingsoon,Bradley, Mark
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supporting information
p. 422 - 425
(2015/03/03)
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- Functionalized triazolopeptoids-a novel class for mitochondrial targeted delivery
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Here we introduce linear 1,4-triazolopeptoids as a novel class of cell penetrating peptidomimetics suitable as organ targeting molecular transporters of bioactive cargo. Repetitive triazole moieties with up to three residues were assembled on solid supports using copper-catalyzed alkyne-azide cycloadditions (CuAAC) in a submonomer approach. Depending on the lipophilicity of their side chain appendages the 1,4-triazolopeptoids showed either endosomal localization or a strong colocalization with the mitochondria of HeLa cells with moderate toxicity. While the basic triazolopeptoids mainly target the neuromast cells in zebrafish embryos, the lipophilic ones colocalize with either cartilage in the jaws and the blood vessel system. This journal is
- Althuon, Daniela,R?nicke, Franziska,Fürniss, Daniel,Quan, Jasmin,Wellh?fer, Isabelle,Jung, Nicole,Schepers, Ute,Br?se, Stefan
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supporting information
p. 4226 - 4230
(2015/04/14)
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- A supramolecular dissociation strategy for protein sensing
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We report a simple, robust, and general strategy for protein detection based on supramolecular dissociation. The simplicity of the design is exemplified by the fact that the host assemblies can be widely varied and that these assemblies can be achieved from commercially available surfactants. An operating mechanism that is consistent with all the data has been proposed.
- Wang, Hui,Zhuang, Jiaming,Raghupathi, Krishna R.,Thayumanavan
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supporting information
p. 17265 - 17268
(2015/12/05)
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- A ratiometric fluorescent molecular probe for visualization of mitochondrial temperature in living cells
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Mitochondrial thermodynamics is the key to understand cellular activities related to homeostasis and energy balance. Here, we report the first ratiometric fluorescent molecular probe (Mito-RTP) that is selectively localized in the mitochondria and visualize the temperature. We confirmed that Mito-RTP could work as a ratiometric thermometer in a cuvette and living cells.
- Homma, Mitsumasa,Takei, Yoshiaki,Murata, Atsushi,Inoue, Takafumi,Takeoka, Shinji
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supporting information
p. 6194 - 6197
(2015/04/14)
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- Hybrid molecule from Farnesylthiosalicylic acid-diamine and phenylpropenoic acid as Ras-related signaling inhibitor with potent antitumor activities
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Novel series of Farnesylthiosalicylic acid-diamine/phenylpropenoic acid hybrids were designed and synthesized. Their in vitro growth inhibitory assays showed that most compounds displayed strong antiproliferation activity against seven cancer cells. Especially, the new hybrid 12f, by the conjugation of 10a with ferulic acid, could selectively suppress the proliferation of tumor cells and display significantly lower toxicities to normal cells than its intermediate 10a. Furthermore, 12f dose-dependently induced SMMC-7721 cell apoptosis. Additionally, our observations demonstrated that 12f inhibited both Ras-related signaling and phosphorylated NF-κB synergistically, which may be advantageous to the strong antitumor activities of 12f. Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.
- Ling, Yong,Wang, Zhiqiang,Wang, Xuemin,Li, Xianghua,Wang, Xinyang,Zhang, Wei,Dai, Hong,Chen, Li,Zhang, Yihua
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p. 145 - 152
(2015/01/30)
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- Design, synthesis and in vitro evaluation of novel uni- and bivalent ligands for the cannabinoid receptor type 1 with variation of spacer length and structure
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Using rimonabant, a potent inverse agonist for cannabinoid receptor type 1 (CB1R), as parent ligand, a series of novel univalent and bivalent ligands were designed by variation of spacer length and its chemical structure. The ligands synthesized were evaluated for affinity and selectivity by radioligand displacement and a functional steady-state GTPase assay. The results showed the nature of the spacer influences the biological readout. Albeit all compounds show significantly lower affinities than rimonabant, this fact could be used to demonstrate that affinities and selectivity are influenced by the chemical structure and length of the spacer and might be helpful for designing bivalent probes for other GPCR receptors.
- Huang, Guozheng,Pemp, Daniela,Stadtmueller, Patricia,Nimczick, Martin,Heilmann, Joerg,Decker, Michael
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supporting information
p. 4209 - 4214
(2014/09/29)
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- Synthesis of azobenzenealkylmaleimide probes to photocontrol the enzyme activity of a bacterial histone deacetylase-like amidohydrolase
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A series of azobenzenealkylmaleimides (AMDs) with different spacer length was synthesized and coupled via Michael-Addition to a specific mutant of a bacterial histone deacetylase-like amidohydrolase (HDAH). Michaelis-Menten parameters (Vmax and Km) were employed to characterize the effect of both, the spacer length and the configuration (cis vs. trans) of the attached azobenzene moiety, on the HDAH enzyme activity. The photoswitch behavior of the AMD/enzyme conjugate activity was clearly influenced by the AMD spacer length. This study highlights the importance of steric rearrangement of the photoswitch with respect to the active site and describes a strategy to optimize the photocontrol of HDAH.
- Horstmann, Benjamin,Korbus, Michael,Friedmann, Tatjana,Wolff, Christiane,Thiele, Christina Marie,Meyer-Almes, Franz-Josef
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supporting information
p. 155 - 161
(2015/02/18)
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- Mitochondria-targeting phosphorescent iridium(iii) complexes for living cell imaging
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Two phosphorescent iridium(iii) complexes conjugated to a lipophilic triphenylphosphonium cation moiety, IrMitoOlivine and IrMitoNIR, were synthesized. The complexes show high mitochondria-specificity and relatively lower cytotoxicity. Time-lapse confocal imaging indicates that both complexes exhibit an excellent anti-photobleaching capability under continuous laser irradiation.
- Zhang, Qingqing,Cao, Rui,Fei, Hao,Zhou, Ming
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p. 16872 - 16879
(2015/02/02)
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- A nanomolar multivalent ligand as entry inhibitor of the hemagglutinin of avian influenza
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Influenza virus attaches itself to sialic acids on the surface of epithelial cells of the upper respiratory tract of the host using its own protein hemagglutinin. Species specificity of influenza virus is determined by the linkages of the sialic acids. Birds and humans have α2-3 and α2-6 linked sialic acids, respectively. Viral hemagglutinin is a homotrimeric receptor, and thus, tri- or oligovalent ligands should have a high binding affinity. We describe the in silico design, chemical synthesis and binding analysis of a trivalent glycopeptide mimetic. This compound binds to hemagglutinin H5 of avian influenza with a dissociation constant of K D = 446 nM and an inhibitory constant of KI = 15 μM. In silico modeling shows that the ligand should also bind to hemagglutinin H7 of the virus that causes the current influenza outbreak in China. The trivalent glycopeptide mimetic and analogues have the potential to block many different influenza viruses.
- Waldmann, Moritz,Jirmann, Raffael,Hoelscher, Ken,Wienke, Martin,Niemeyer, Felix C.,Rehders, Dirk,Meyer, Bernd
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supporting information
p. 783 - 788
(2014/02/14)
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- Synthesis and characterisation of folic acid based lanthanide ion probes
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As a first step in the process of developing folate based visual probes and contrast agents, we have designed and synthesised a series of first generation lanthanide(III) molecular probes. The molecular probe structure included a lanthanide(III) (Eu(III), Tb(III), Gd(III)) chelate which was linked (2 or 3) to either a folic acid or pteroic acid targeting motif. We have defined the emission properties of the molecular probes at different pHs, the emission lifetimes, and the number of metal bound water molecules. The cellular uptake of the molecular probes was investigated in HeLa cells and the amount of Eu(III) internalisation quantified by inductively coupled plasma mass spectrometry. Our results highlighted several key features of probe design: a shorter linker was more optimal for both Eu(III) ion emission intensity and cellular uptake; the folic acid targeting motif exhibited higher cellular uptake when compared to pteroic acid; the emission intensity of the folic acid based probes was pH insensitive, whereas the pteroic acid based probes were pH sensitive. These first generation folate molecular probes displayed promising chemical and physical properties, suggesting that optical and MRI probes can potentially be developed, to enable the imaging of folate receptors in cancer cells and tissues.
- Du, Zhangli,Borlace, Glenn N.,Brooks, Robert D.,Butler, Ross N.,Brooks, Doug A.,Plush, Sally E.
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- Concise syntheses and antitumor activities of a-hydroxy(mercapto)amide derivatives
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A novel process for preparing a-hydroxy(mercapto)-N-[6-(3-phenylureido) hexyl]amide derivatives was described and three new compounds 8-10 were synthesized. The antitumor activities on Hut102, MCF7 and HepG2 of the compounds 7-10 were assayed. The results showed that the target compounds 7-10 exhibited some antitumor activities against tumor cell lines.
- Li,Qiu
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p. 3219 - 3223
(2014/07/22)
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- Synthesis and biological evaluation of novel farnesylthiosalicylic acid/salicylic acid hybrids as potential anti-tumor agents
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A series of FTS/salicylic acid hybrids was designed and synthesized and their in vitro antitumor activities were evaluated. It was found that the anti-proliferation activities of hybrids were better than that of FTS. Compound 10a displayed the strongest antitumor activities with IC50 values of 5.72-9.76 μmol/L and selectively inhibited tumor cell proliferation. In addition, 10a induced tumor cell apoptosis in a dose-dependent manner by up-regulating the expression of Bax and caspase-3 and down-regulating Bcl-2. Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.
- Wang, Zhi-Qiang,Chang, Ren-An,Huang, Hai-Ying,Wang, Xue-Min,Wang, Xin-Yang,Chen, Li,Ling, Yong
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p. 1545 - 1549
(2015/01/09)
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- CATIONIC BIS-UREA COMPOUNDS AS EFFECTIVE ANTIMICROBIAL AGENTS
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A cationic bis-urea compound is disclosed of formula (1): wherein: each m is independently an integer of 0 to 4,each k is independently 0 or 1,each Z′ is a monovalent radical independently selected from the group consisting of hydroxyl (*—OH), carboxyl (*—COOH), cyano (*—CN), nitro (*—NO2), sulfonate (*—SO3?), trifluoromethyl (*—CF3), halides, amine groups, ketone groups, alkyl groups comprising 1 to 6 carbons, alkoxy groups comprising 1 to 6 carbons, thioether groups comprising 1 to 6 carbons, and combinations thereof,each L′ is independently a divalent alkylene group comprising 1 to 6 carbons, wherein a *-[-L′-]k- is a single bond when k is 0,each Y′ is independently a monovalent non-polymeric radical comprising a positive charged amine, andeach X′ is independently a negative charged counterion.
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Paragraph 0180; 0181
(2013/11/05)
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- Stimuli-responsive supramolecular gelation in ferrocene-peptide conjugates
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Teaching an old dog new tricks: Ferrocene-dipeptide conjugates capable of forming gels in response to various external signals including sound, thermal, redox, and mechanical stress are reported (see figure). Interesting examples of how ferrocene-peptide conjugates can be exploited for the construction of organometallic gelators are demonstrated.
- Afrasiabi, Rouzbeh,Kraatz, Heinz-Bernhard
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supporting information
p. 17296 - 17300
(2014/01/06)
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