- In vivo targeted delivery of nucleic acids and CRISPR genome editors enabled by GSH-responsive silica nanoparticles
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The rapid development of gene therapy and genome editing techniques brings up an urgent need to develop safe and efficient nanoplatforms for nucleic acids and CRISPR genome editors. Herein we report a stimulus-responsive silica nanoparticle (SNP) capable of encapsulating biomacromolecules in their active forms with a high loading content and loading efficiency as well as a well-controlled nanoparticle size (~50 nm). A disulfide crosslinker was integrated into the silica network, endowing SNP with glutathione (GSH)-responsive cargo release capability when internalized by target cells. An imidazole-containing component was incorporated into the SNP to enhance the endosomal escape capability. The SNP can deliver various cargos, including nucleic acids (e.g., DNA and mRNA) and CRISPR genome editors (e.g., Cas9/sgRNA ribonucleoprotein (RNP), and RNP with donor DNA) with excellent efficiency and biocompatibility. The SNP surface can be PEGylated and functionalized with different targeting ligands. In vivo studies showed that subretinally injected SNP conjugated with all-trans-retinoic acid (ATRA) and intravenously injected SNP conjugated with GalNAc can effectively deliver mRNA and RNP to murine retinal pigment epithelium (RPE) cells and liver cells, respectively, leading to efficient genome editing. Overall, the SNP is a promising nanoplatform for various applications including gene therapy and genome editing.
- Wang, Yuyuan,Shahi, Pawan K.,Wang, Xiuxiu,Xie, Ruosen,Zhao, Yi,Wu, Min,Roge, Seth,Pattnaik, Bikash R.,Gong, Shaoqin
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- A pH-responsive silica–metal–organic framework hybrid nanoparticle for the delivery of hydrophilic drugs, nucleic acids, and CRISPR-Cas9 genome-editing machineries
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Efficient delivery of hydrophilic drugs, nucleic acids, proteins, and any combination thereof is essential for various biomedical applications. Herein, we report a straightforward, yet versatile approach to efficiently encapsulate and deliver various hydrophilic payloads using a pH-responsive silica–metal–organic framework hybrid nanoparticle (SMOF NP) consisting of both silica and zeolitic imidazole framework (ZIF). This unique SMOF NP offers a high loading content and efficiency, excellent stability, and robust intracellular delivery of a variety of payloads, including hydrophilic small molecule drugs (e.g., doxorubicin hydrochloride), nucleic acids (e.g., DNA and mRNA), and genome-editing machineries (e.g., Cas9-sgRNA ribonucleoprotein (RNP), and RNP together with donor DNA (e.g., RNP + ssODN)). The superior drug delivery/gene transfection/genome-editing efficiencies of the SMOF NP are attributed to its pH-controlled release and endosomal escape capabilities due to the proton sponge effect enabled by the imidazole moieties in the SMOF NPs. Moreover, the surface of the SMOF NP can be easily customized (e.g., PEGylation and ligand conjugation) via various functional groups incorporated into the silica component. RNP-loaded SMOF NPs induced efficient genome editing in vivo in murine retinal pigment epithelium (RPE) tissue via subretinal injection, providing a highly promising nanoplatform for the delivery of a wide range of hydrophilic payloads.
- Abdeen, Amr A.,Gong, Shaoqin,Ma, Zhenqiang,Pattnaik, Bikash R.,Saha, Krishanu,Shahi, Pawan K.,Wang, Yuyuan,Xie, Ruosen,Yodsanit, Nisakorn,Zhang, Huilong
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- Thermotropic liquid crystals of 1H-imidazole amphiphiles showing hexagonal columnar and micellar cubic phases
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The linear and polycatenar type 1H-imidazole amphiphiles showing a strong self-assembly tendency to build various supramolecular structures in bulk were synthesized by the esterification reaction of 4′-alkyloxy phenols (for 1-4) and hydroxyphenyl trialkyl
- Seo, Sang Hyuk,Park, Jun Ha,Tew, Gregory N.,Chang, Ji Young
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- Imidazole derivative-functionalized carbon dots: Using as a fluorescent probe for detecting water and imaging of live cells
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A highly sensitive carbon dot-imidazole (CD-imidazole) nanoprobe is prepared through covalently conjugating imidazole group onto the surface of carbon dots for water fluorescence. In organic solvents, quenching of fluorescence occurs via photoinduced electron transfer (PET) process from the imidazole nitrogen to the CD acceptor. Addition of a trace amount of water into CD nanocomposites in various organic solvents leads to a fluorescence turn-on response, which can be attributed to the suppression of PET due to the formation of the free ion pair by proton transfer from the carboxyl groups that are on the CDs surface to the imidazole nitrogen through a water-bridge. This phenomenon can be used for the highly selective detection of trace amounts of water in organic solvents. Laser confocal microscope experiment shows the potential utilization of CD-imidazole for the probed proton-transfer reactions in living cells. This journal is
- Wang, Xudong,Wang, Dan,Guo, Yali,Yang, Chengduan,Iqbal, Anam,Liu, Weisheng,Qin, Wenwu,Yan, Dan,Guo, Huichen
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- LIPIDIC COMPOUNDS COMPRISING AT LEAST ONE TERMINAL RADICAL OF FORMULA -NH-CX-A OR -NH-CX-NH-A, COMPOSITIONS CONTAINING THEM AND USES THEREOF
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The disclosure concerns new lipid compounds, lipid nanoparticles (LNPs) containing them, and the use of lipid compounds or LNPs for nucleic acid administration. The lipid compounds according to the disclosure comprise at least one terminal radical of formula (I): *-NH-CX-(NH)n-A (I), wherein: -*- Represents a simple bond binding said radical of formula (I), directly or indirectly, to a lipophilic or hydrophobic tail group in C10 to C55; - n is 0 or 1; - X is an oxygen atom or a sulfur atom, and - A represents an unsaturated heterocyclic radical with 5 or 6 chains optionally substituted or a heteroaromatic cyclic radical with 5 or 6 links, both containing at least one nitrogen atom; or one of the pharmaceutically acceptable salts of said radical of formula (I); and said compound being in all possible racemic isomers, enantiomers and diastereoisomers.
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Page/Page column 77; 79; 83; 85
(2022/01/24)
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- N-indolyl imidazole formamide compound and preparation method and application thereof
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The invention belongs to the field of medicines, and relates to an N-indolyl imidazole formamide compound and a preparation method and application thereof. The structural general formula of the compound is shown in the specification. A pharmaceutical composition comprises the N-indolyl imidazole carboxamide compound, pharmaceutically acceptable salt, hydrate or solvate of the N-indolyl imidazole carboxamide compound and a pharmaceutically acceptable carrier of the N-indolyl imidazole carboxamide compound. The invention also discloses the application of the N-indolyl imidazole formamide compound or the pharmaceutically acceptable salt, hydrate or solvate thereof or the pharmaceutical composition in the preparation of anti-hyperuricemia and anti-gout drugs. Tests prove that the compound shows a good effect in an in-vitro xanthine oxidase inhibitory activity test. The preparation method is simple and feasible, relatively high in yield and easy for large-scale production.
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Paragraph 0050-0051
(2021/06/09)
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- Amide-based xanthine oxidase inhibitors bearing an N-(1-alkyl-3-cyano-1H-indol-5-yl) moiety: Design, synthesis and structure-activity relationship investigation
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Our previous work identified a promising isonicotinamide based xanthine oxidase (XO) inhibitor, N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (1), and concluded that amide is an effective linker in exploring the XO inhibitor chemical space that is completely different from the five-membered ring framework of febuxostat and topiroxostat. Indole, an endogenous bioactive substance and a popular drug construction fragment, was involved in the structural optimization campaign of the present effort. After the installation of some functional groups, N-(1-alkyl-3-cyano-1H-indol-5-yl) was generated and employed to mend the missing H-bond interaction between the 3′-cyano of 1 and Asn768 residue of XO by shortening their distance. In this context, eight kinds of heterocyclic aromatic amide chemotypes were rationally designed and synthesized to investigate the structure-activity relationship (SAR) of amide-based XO inhibitors. The optimized compound a6 (IC50 = 0.018 μM) exhibits 17.2-fold improved potency than the initial compound 1 (IC50 = 0.31 μM). Its potency is comparable to that of topiroxostat (IC50 = 0.013 μM). Molecular docking and molecular dynamics studies proved the existence of the stable H-bond between the cyano group and the Asn768 residue. Moreover, oral administration of a6 (11.8 mg/kg) could effectively reduce serum uric acid levels in an acute hyperuricemia rat model. Liver microsomal stability assay illustrated that compound a6 possesses well metabolic stability in rat liver microsomes. However, the in vivo potency of a6 was much lower than that of topiroxostat, which may be explained by the poor absorption found in the parallel artificial membrane permeability assay (PAMPA). In addition, 6a has non-cytotoxicity against normal cell lines MCF10A and 16HBE. Taken together, this work culminated in the identification of compound 6a as an excellent lead for further exploration of amide-based XO inhibitors.
- Zhang, Ting-jian,Tu, Shun,Zhang, Xu,Wang, Qiu-yin,Hu, Sen-sen,Zhang, Yi,Zhang, Zhen-hao,Wang, Zhao-ran,Meng, Fan-hao
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- UNIVERSAL MULTI-FUNCTIONAL GSH-RESPONSIVE SILICA NANOPARTICLES FOR DELIVERY OF BIOMOLECULES INTO CELLS
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The present technology provides a nanoparticle comprising: a silica network comprising crosslinked polysiloxanes, wherein the crosslinks between polysiloxanes comprise disulfide linkages, the polysiloxanes optionally bear weakly basic functional groups, the nanoparticle comprises an exterior surface comprising surface-modifying groups attached to and surrounding the silica network, wherein the surface-modifying groups comprising polyethylene glycol (PEG), polysarcosine, polyzwitterion or combinations of two or more of thereof; and the nanoparticle has an average diameter of 15 nm to 500 nm. The nanoparticles herein may include biomolecules such as polynucleic acids, proteins, and complexes thereof, e.g, Cas9 RNP.
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Paragraph 0102
(2021/11/26)
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- PH-RESPONSIVE SILICA METAL ORGANIC FRAMEWORK NANOPARTICLES FOR DELIVERY OF BIO ACTIVE MOLECULES
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Provided herein are silica metal organic framework (SMOF) nanoparticles that are pH- responsive for delivery of bioactive molecules. The nanoparticles include a organosilica network comprising a plurality of imidazolyl and/or carboxyl groups; a metal organic framework component comprising a transition metal coordinated to a coordinating ligand, wherein the transition metal is selected from the group consisting of zinc, iron, zirconium, copper, and cobalt, and the coordinating ligand is selected from an imidazolate ligand or a carboxylate ligand; a bioactive payload selected from the group consisting of a hydrophilic drug, a polynuclei c acid, a protein and a protein-polynucleic acid complex; and a surface-modifying polymer conjugated to the same or a different organosilica network and forming at least part of an exterior surface of the nanoparticle, wherein the surface-modifying polymer is selected from polyethylene glycol and/or a polyzwitterion; and wherein the zinc also coordinates the imidazolyl or carboxyl group of the organosilica network.
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Paragraph 0065
(2020/10/21)
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- Structure-activity relationship for the oxadiazole class of antibiotics
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The structure-activity relationship (SAR) for the newly discovered oxadiazole class of antibiotics is described with evaluation of 120 derivatives of the lead structure. This class of antibiotics was discovered by in silico docking and scoring against the crystal structure of a penicillin-binding protein. They impair cell-wall biosynthesis and exhibit activities against the Gram-positive bacterium Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant and linezolid-resistant S. aureus. 5-(1H-Indol-5-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazole (antibiotic 75b) was efficacious in a mouse model of MRSA infection, exhibiting a long half-life, a high volume of distribution, and low clearance. This antibiotic is bactericidal and is orally bioavailable in mice. This class of antibiotics holds great promise in recourse against infections by MRSA.
- Spink, Edward,Ding, Derong,Peng, Zhihong,Boudreau, Marc A.,Leemans, Erika,Lastochkin, Elena,Song, Wei,Lichtenwalter, Katerina,O'Daniel, Peter I.,Testero, Sebastian A.,Pi, Hualiang,Schroeder, Valerie A.,Wolter, William R.,Antunes, Nuno T.,Suckow, Mark A.,Vakulenko, Sergei,Chang, Mayland,Mobashery, Shahriar
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p. 1380 - 1389
(2015/03/04)
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- Synthesis, self-assembly, and catalytic activity of 1H-imidazole amphiphiles
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We prepared polycatenar 1H-imidazole amphiphiles having a structure in which a 1H-imidazole head was connected through a benzene ring to a pheny group having two or three oligo(ethylene glycol) chains and studied their supramolecular assembly by fluorescence spectroscopy, transmission electron microscopy (TEM) and atomic force microscopy (AFM). When the aqueous solutions of the amphiphiles (5 × 10-5 M ~ 10-3 M) were deposited onto a carbon-coated copper grid and dried, twisted structures with diameters of ~200-300 nm were imaged by TEM and AFM. We presume that the structures comprised a chain of the amphiphile dimers formed via successive hydrogen bonding between the 1H of the imidazole group and 3N of the neighboring one. In a solution of pH 4, entangled fibers with diameters of several nanometers were observed by TEM. In a pH 10 solution, film-like aggregates formed exclusively. The 1H-imidazole amphiphiles hydrolyzed tetraethoxysilane to induce gelation to form fibrous and spherical silica structures at neutral pH in aqueous solutions. No silica was formed when imidazole was used instead of the amphiphiles, suggesting that the selfassembled aggregates of the amphiphiles were responsible for the gelation.
- Park, Jun Ha,Kim, Min Soo,Seo, Sang Hyuk,Chang, Ji Young
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experimental part
p. 2193 - 2198
(2012/06/04)
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- Smectic layered polymer networks based on side chain liquid crystalline polymers having thermally reversible urea bonds
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The preparation of nanospaced polymer networks from side chain liquid crystalline polymers having thermally reversible urea bonds between the polymers and the pendent mesogenic groups was described. It was observed that the polymers had smectic layered st
- Seo, Sang Hyuk,Kim, Young-Woon,Chang, Ji Young
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p. 1525 - 1527
(2007/10/03)
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- PTEN INHIBITORS
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The therapeutic use of inhibitors of PTEN activity in the treatment of PTEN-mediated diseases, conditions, and injuries is disclosed.
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Page/Page column 71
(2008/06/13)
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- Synthesis of imidazo[1,5-a]quinoxalin-4(5H)-one template via a novel intramolecular cyclization process
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A novel, efficient, and regiospecific method for the construction of the imidazo[1,5-a]quinoxalin-4(5H)-one template is described. The key reaction involves an intramolecular cyclization process and provides the desired products in excellent yield.
- Norris, Derek,Chen, Ping,Barrish, Joel C.,Das, Jagabandhu,Moquin, Robert,Chen, Bang-Chi,Guo, Peng
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p. 4297 - 4299
(2007/10/03)
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- SUBSTITUTED IMIDAZOLES HAVING ANGIOTENSIN II RECEPTOR BLOCKING ACTIVITY
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Angiotensin II receptor antagonists having the formula: STR1 which are useful in regulating hypertension and in the treatment of congestive heart failure, renal failure, and glaucoma, pharmaceutical compositions including these antagonists, and methods of
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