- Determination of intracellular pH using sensitive, clickable fluorescent probes
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We synthesized and evaluated a series of acidic fluorescent pH probes exhibiting robust pH dependence, high sensitivity and photostability, and excellent cell membrane permeability. Titration analyses indicated that probe 3 could increase its fluorescence intensity 800-fold between pH 8.0 and 4.1. Additionally, its pKa value is optimal for intracellular probing of acidic organelles. Fluorescent imaging of HepG2 and Hela cells further revealed that probe 3 demonstrates outstanding capacity for monitoring of intracellular [H+] levels. The easily accessible terminal alkyne/azido function groups of these probes offer the possibility of rapidly constructing sensor molecule libraries using 'click' chemistry.
- Yapici, Nazmiye B.,Mandalapu, Srinivas Rao,Chew, Teng-Leong,Khuon, Satya,Bi, Lanrong
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- A luminogenic lanthanide-based probe for the highly selective detection of nanomolar sulfide levels in aqueous samples
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A bimetallic terbium(iii)/copper(ii) complex (Tb-1·Cu2+) for the time-gated luminescent detection of hydrogen sulfide in aqueous samples is reported. The probe shows excellent selectivity towards HS- over various anions and cations, including the ions common to natural waterways and waste water samples, displaying a 73-fold increase in luminescence in the presence of sulfide. The probe exhibits extremely fast reaction times and a low limit of detection (130 nM). The probe was used to quantify sulfide in an industrial "sour water" sample, with the result in excellent agreement with those from two independent assay methods (methylene blue and AzMC).
- Aulsebrook, Margaret L.,Biswas, Suvendu,Leaver, Franklin M.,Grace, Michael R.,Graham, Bim,Barrios, Amy M.,Tuck, Kellie L.
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- Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors
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Multidrug resistance (MDR) is one of the main obstacles of clinical chemotherapy. A great deal of research shows that the occurrence of drug resistance in various malignant tumors is closely related to the expression of P-glycoprotein (P-gp) on the surface of the cell membrane. In this paper, based on the structure-activity relationship of phenylethyl tetrahydroisoquinoline, we choose tariquidar as the lead compound for the design and synthesis of 17 novel tetrahydroisoquinoline P-gp inhibitors. Additionally, in vitro and in vivo cytotoxicity assays and reversed MDR activity assays were evaluated. Among them, compound 3 had a good reversal of MDR activity and the reversal mechanism study of it was carried out. All of these results demonstrated that compound 3 was considered to be a promising P-gp-mediated MDR reversal candidate.
- Gao, Yang,Shi, Wei,Cui, Jian,Liu, Chunxia,Bi, Xinzhou,Li, Zhuo,Huang, Wenlong,Wang, Guangji,Qian, Hai
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- Radiolabeling of RGD peptide and preliminary biological evaluation in mice bearing U87MG tumors
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2-[18F]Fluoroethyl azide ([18F]FEA) and terminal alkynyl modified propioloyl RGDfK were selected in this study. [ 18F]FEA was prepared by nucleophilic radiofluorination of 2-azidoethyl 4-toluenesulfonate with radiochemical yield of 71 ± 4% (n = 5, decay-corrected). We assessed the various conditions of the CuAAC reaction between [18F]FEA and propioloyl RGDfK, which included peptide concentration, reaction time, temperature and catalyst dosage. The 18F-labeled-RGD peptide ([18F]F-RGDfK) could be obtained in 60 min by a two-step radiochemical synthesis route, with total radiochemical yield of 60 ± 2% (n = 3, decay-corrected) through click chemistry. [ 18F]F-RGDfK showed high stability in phosphate buffered saline and new-born calf serum. Micro-PET imaging at 1 h post injection of [ 18F]F-RGDfK showed medium concentration of radioactivity in tumors while much decreased concentration in tumors in the blocking group. These results showed that [18F]F-RGDfK obtained by click chemistry maintained the affinity and specificity of the RGDfK peptide to integrin αvβ3. This study provided useful information for peptide radiofluorination by using click chemistry.
- Li, Jianbo,Shi, Lingli,Jia, Lina,Jiang, Dawei,Zhou, Wei,Hu, Weiqing,Qi, Yujin,Zhang, Lan
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- Targeting Mitochondria in Tumor-Associated Macrophages using a Dendrimer-Conjugated TSPO Ligand that Stimulates Antitumor Signaling in Glioblastoma
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Mitochondria mediate critical cellular processes, including proliferation, apoptosis, and immune responses; as such, their dysfunction is pathogenic in many neurodegenerative disorders and cancers. In glioblastoma, targeted delivery of mitochondria-focuse
- Kannan, Rangaramanujam M.,Kannan, Sujatha,Liaw, Kevin,Sharma, Anjali,Sharma, Rishi,Slusher, Barbara S.,Thomas, Ajit G.
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- Synthesis and preliminary evaluation of 18F-icotinib for EGFR-targeted PET imaging of lung cancer
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Epidermal growth factor receptor (EGFR) has emerged as an attracting target in the field of imaging and treatment for non-small cell lung cancer (NSCLC). Radiolabeled EGFR-tyrosine kinase inhibitors (EGFR-TKIs) specifically targeting EGFR are deemed as pr
- Lu, Xinmiao,Wang, Cheng,Li, Xiao,Gu, Peilin,Jia, Lina,Zhang, Lan
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- Research on preparation and in vitro evaluation of the dendrimer–peptide nuclear acid conjugate for amplification pretargeting
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Amplification pretargeting has the potential to increase the tracer's accumulation in the tumor. This study aimed to develop a three-step amplification pretargeting strategy in nuclear medicine with a polymer conjugated with multiple copies of peptide nuclear acid (PNA). In this study, the tracer 18F-labeled complementary PNA (18F-cPNA) was prepared by click-chemistry with high radiochemical purity (>99%) and great stability in vitro. The PAMMA dendrimer generation 4 (G4) was conjugated with multiple copies of PNAs. The average number of PNA groups in the G4-PNA conjugate was determined by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and the accessibility to the 18F-cPNA was identified by size-exclusion high-performance liquid chromatography (SE-HPLC). There were approximately 11.7 of 64 carboxyl groups modified with PNAs, of which more than 99% were accessible to 18F-cPNA. 18F-cPNA was added to a mixture of CC49-cPNA and G4-PNA, and the complex exhibited a single peak on high-performance liquid chromatography (HPLC) as evidence of complete hybridization between 18F-cPNA and CC49-cPNA/G4-PNA. The LS174T tumor cells were incubated with CC49-cPNA followed by G4-PNA as an amplification platform before 18F-cPNA was added to hybridize with CC49-cPNA/G4-PNA. Compared with conventional pretargeting without G4-PNA, the radioactivity signal was amplified about four times, which demonstrated that the dendrimer–PNA conjugate plays a crucial role in signal amplification.
- Cai, Le,He, Shuhua,Zheng, Xiaobei,Li, Jie,Wang, Hong,Liu, Yuxia,Zhang, Lan
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- Designed P-glycoprotein inhibitors with triazol-tetrahydroisoquinoline-core increase doxorubicin-induced mortality in multidrug resistant K562/A02 cells
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Multidrug resistance (MDR) refers to the cross-resistance of cancer cells to one drug, accompanied by other drugs with different mechanisms and structures, which is one of the main obstacles of clinical chemotherapy. Overexpression of P-glycoprotein (P-gp) was an extensively studied cause of MDR. Therefore, inhibiting P-gp have become an important strategy to reverse MDR. In this study, two series of triazole-tetrahydroisoquinoline-core P-gp inhibitors were designed and synthesized. Among them, compound I-5 had a remarkable reversal activity of MDR activity and the preliminary mechanism study was also carried out. All the results proved that compound I-5 was considered as a promising P-gp-mediated MDR reversal candidate.
- Kairuki,Qiu, Qianqian,Pan, Miaobo,Li,Zhou,Ghaleb, Hesham,Huang, Wenlong,Qian, Hai,Jiang
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- Exploring carbonic anhydrase inhibition with multimeric coumarins displayed on a fullerene scaffold
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Carbonic anhydrases (CAs) are ubiquitous Zn metallo-enzymes that catalyze the reversible hydration/dehydration of CO2/HCO3-. CAs are involved in many key biological processes, therefore their inhibition has become an attractive research field. Distinct families of CA inhibitors (CAIs) have been reported, most of them interacting with the Zn(ii) at the active site. Some compounds such as the coumarins are hydrolyzed before binding the entrance of the active site cavity, and thus behave as "suicide" inhibitors. This study reports the first synthesis of multimeric suicide inhibitors, designed to address the selectivity and the potency of CA multivalent inhibition. Twelve coumarin units have been grafted to a central fullerene scaffold thanks to a CuAAC reaction and the final dodecamers were assayed against 4 relevant CAs. The multimers were always stronger inhibitors than the monomeric species but no strong "multivalent effect" was found. However, our study showed that the multimeric presentation of the coumarin around the C60, indeed affected the selectivity of the relative inhibition among the 4 CAs assayed.
- Abellán-Flos, Marta,Tan?, Muhammet,Supuran, Claudiu T.,Vincent, Stéphane P.
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- Radiosynthesis and biological evaluation of 18F-labeled 4-anilinoquinazoline derivative (18F-FEA-Erlotinib) as a potential EGFR PET agent
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Epidermal growth factor receptor (EGFR) has gained significant attention as a therapeutic target. Several EGFR targeting drugs (Gefitinib and Erlotinib) have been approved by US Food and Drug Administration (FDA) and have received high approval in clinica
- Huang, Shun,Han, Yanjiang,Chen, Min,Hu, Kongzhen,Qi, Yongshuai,Sun, Penghui,Wang, Men,Wu, Hubing,Li, Guiping,Wang, Quanshi,Du, Zhiyun,Zhang, Kun,Zhao, Suqing,Zheng, Xi
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- Caspase-3 Substrates for Noninvasive Pharmacodynamic Imaging of Apoptosis by PET/CT
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Quantitative imaging of apoptosis in vivo could enable real-time monitoring of acute cell death pathologies such as traumatic brain injury, as well as the efficacy and safety of cancer therapy. Here, we describe the development and validation of F-18-labeled caspase-3 substrates for PET/CT imaging of apoptosis. Preliminary studies identified the O-benzylthreonine-containing substrate 2MP-TbD-AFC as a highly caspase 3-selective and cell-permeable fluorescent reporter. This lead compound was converted into the radiotracer [18F]-TBD, which was obtained at 10% decay-corrected yields with molar activities up to 149 GBq/μmol on an automated radiosynthesis platform. [18F]-TBD accumulated in ovarian cancer cells in a caspase- and cisplatin-dependent fashion. PET imaging of a Jo2-induced hepatotoxicity model showed a significant increase in [18F]-TBD signal in the livers of Jo2-treated mice compared to controls, driven through a reduction in hepatobiliary clearance. A chemical control tracer that could not be cleaved by caspase 3 showed no change in liver accumulation after induction of hepatocyte apoptosis. Our data demonstrate that [18F]-TBD provides an immediate pharmacodynamic readout of liver apoptosis in mice by dynamic PET/CT and suggest that [18F]-TBD could be used to interrogate apoptosis in other disease states.
- Engel, Brian J.,Gammon, Seth T.,Chaudhari, Rajan,Lu, Zhen,Pisaneschi, Federica,Yang, Hailing,Ornelas, Argentina,Yan, Victoria,Kelderhouse, Lindsay,Najjar, Amer M.,Tong, William P.,Zhang, Shuxing,Piwnica-Worms, David,Bast, Robert C.,Millward, Steven W.
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- A complete series of 6-deoxy-monosubstituted tetraalkylammonium derivatives of α-, β-, and γ-cyclodextrin with 1, 2, and 3 permanent positive charges
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An efficient synthetic route toward the preparation of a complete series of monosubstituted tetraalkylammonium cyclodextrin (CD) derivatives is presented. Monotosylation of native CDs (α-, β-, γ-) at position 6 gave the starting material. Reaction of monotosylate (mono-Ts-CD) with 45% aqueous trimethylamine gave CDs substituted with one cationic functional group in a single step. Derivatives equipped with a substituent containing two cationic sites separated by an ethylene or a propylene linker were prepared by reacting mono-Ts-CD with neat N,N,N'-trimethylethane-1,2-diamine or N,N,N'- trimethylpropane-1,3-diamine and subsequent methylation by CH3I in good yields. Finally, analogues bearing a moiety with three tetraalkylammonium sites were synthesized by reacting mono-Ts-CD with bis(3-aminopropyl)amine and subsequent methylation. The majority of the presented reactions are very straightforward with a simple work-up, which avoids the need of chromatographic separation. Thus, these reactions are suitable for the multigram-scale production of monosubstituted cationic CDs. 2014 Popr et al;.
- Popr, Martin,Hybelbauerova, Simona,Jindrich, Jindrich
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- Synthesis and properties of octa-distyryl-BODIPY substituted zinc(II) phthalocyanines
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A novel type octa-distyryl-BODIPY substituted zinc(II) phthalocyanines 9 and 10 were prepared by the?copper-free Sonogashira coupling and “Click” reactions, respectively. The terminal ethynyl functionalized BODIPY (4,4’-difluoro-8-(4-propynyloxy)-phenyl-1
- Yan?k, Hülya,Ye?ilot, Serkan,Durmu?, Mahmut
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- High hole mobility and light-harvesting in discotic nematic dendrimers prepared: Via 'click' chemistry
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We report a new family of liquid crystalline porphyrin-core dendrimers with coumarin units at the periphery of the dendrimer. These compounds have been prepared by copper-catalyzed azide-alkyne "click" cycloaddition (CuAAC). The mesomorphic properties have been investigated via polarized optical microscopy (POM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The peripheral coumarin units play a key role in the liquid crystal behavior, contributing to the appearance of discotic nematic mesophases with hole mobility values among the highest values reported for discotic liquid crystals (of the order of 1 cm2 V-1 s-1). It has also been demonstrated that excitation of the coumarin moieties leads to energy transfer (antenna effect) to the luminescent porphyrin core. Therefore, this strategy, which involves 'click' chemistry, has been proven to be a powerful and elegant synthetic tool for the preparation of optoelectronic materials based on complex dendritic architectures.
- Concellón, Alberto,Termine, Roberto,Golemme, Attilio,Romero, Pilar,Marcos, Mercedes,Serrano, José Luis
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- Discovery of the First Environment-Sensitive Near-Infrared (NIR) Fluorogenic Ligand for α1-Adrenergic Receptors Imaging in Vivo
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Fluorescent ligands are gaining popularity as tools to aid GPCR research. Nonetheless, in vivo application of such tools is hampered due to their short excitation wavelengths in the visible range and lack of fluorogenic switch. Here we report the discovery of fluorescent ligands (3a-f) for α1-adrenergic receptors (α1-ARs) by conjugating the environment-sensitive fluorophore cyane 5 (Cy5) with the quinazoline pharmacophore. Among them, the conjugated compound 3a, with acylated piperazine and the shortest carbon chain spacer, exhibited potent binding and remarkable changes in fluorescence (10-fold) upon binding to α1-AR. Furthermore, it could be employed to selectively and specifically label α1-ARs with no washing procedures in single cells, prostate tissue slices, intact tumor xenografts and organs in living mice. Especially, the slice imaging results gave direct and visual evidence that there is a close relationship between α1-ARs and pathological prostate. It is anticipated that our fluorescent tools will find broad applications in the study of α1-AR pharmacology and physiology to aid development of novel therapeutics.
- Ma, Zhao,Lin, Yuxing,Cheng, Yanna,Wu, Wenxiao,Cai, Rong,Chen, Shouzhen,Shi, Benkang,Han, Bo,Shi, Xiaodong,Zhou, Yubin,Du, Lupei,Li, Minyong
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- Near-infrared fluorescent probe for sensitive detection of Pb(II) ions in living cells
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A new near-infrared fluorescent probe (NIR-PbP) for sensitive detection of Pb(II) ions in solution and living cells has been rationally designed and synthesized. The NIR-PbP is inherently non-fluorescent and gains fluorescence in the presence Pb(II) ions. The ion detection is based on Pb(II)-induced unmasking the fluorophore through the opening of the spyrocycle, with more than 500-fold fluorescence enhancement for sub-micromolar Pb(II) concentration. The NIR-PbP has high sensitivity, good photo-stability, low detection limit, and reversible response to Pb(II) ions.
- Bi, Jianheng,Fang, Mingxi,Wang, Jianbo,Xia, Shuai,Zhang, Yibin,Zhang, Jingtuo,Vegesna, Giri,Zhang, Shuwei,Tanasova, Marina,Luo, Fen-Tair,Liu, Haiying
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- Discovery to solve multidrug resistance: Design, synthesis, and biological evaluation of novel agents
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Chemotherapy remains a pillar in the treatment and management of various cancers. However, multidrug resistance (MDR) becomes a severe problem after long-term administration of chemotherapy drugs. Overexpression of P-glycoprotein (P-gp) is a significant cause for tumor MDR. Therefore, P-gp inhibition is considered as an effective strategy to reverse MDR. A third-generation P-gp inhibitor tariquidar was selected as a lead compound, and a new series of triazol-N-ethyl tetrahydroisoquinoline based compounds were designed as novel P-gp inhibitors and synthesized through click chemistry. These compounds presented higher reversal activities than the positive-control verapamil (VRP). Among 18 compounds, compound 11 without cytotoxicity reversed MDR in a dose-dependent manner, with a persistent longer chemosensitizing effect and reversibility compared to others. Mechanism studies discovered that compound 11 could escalate the intracellular accumulation of rhodamine-123 and doxorubicin in K562/A02 cells as well as inhibit their efflux from cells. The results obtained suggest that compound 11 is more potent than VRP administered under the same conditions; it may be a potent and safe candidate for P-gp modulation for further development.
- Qiu, Qianqian,Shi, Wei,Zhao, Shiyuan,Zhu, Yan,Ding, Zhengquan,Zhou, Shaoyang,Kairuki, Mutta,Huang, Wenlong,Qian, Hai
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- Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Dimers as HCV Entry Inhibitors
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A series of triterpene dimers bearing different scaffold were designed and synthesized via CuAAC reaction. Their anti-HCV entry activities were evaluated by HCVpp and VSVpp entry assays. It was found that echinocystic acid (EA) and its dimer were still necessary for maintaining anti-HCV entry activity, and replacement of EA by other triterpenes might significantly decrease its anti-viral activities. Using a linker bearing a piperazine group, compound 14 dramatically increased its potency with IC50 at 2.87 nmol/L. In addition, the undesired hemolytic effect of all these compounds was removed.
- Meng, Lingkuan,Wang, Qi,Tang, Tao,Xiao, Sulong,Zhang, Lihe,Zhou, Demin,Yu, Fei
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- Histidine analog amino acids providing metal-binding sites derived from bioinorganic model systems
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Metalloproteins are of utmost importance for nearly all biological processes. Valuable information about their functionalities came from mutagenesis studies and led to the de novo design of artificial proteins. Advances in peptide chemistry enable the tot
- Nadler, Andre,Hain, Christina,Diederichsen, Ulf
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- Synthesis, antimicrobial evaluation, and in silico studies of quinoline—1H-1,2,3-triazole molecular hybrids
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Abstract: Antimicrobial resistance has become a significant threat to global public health, thus precipitating an exigent need for new drugs with improved therapeutic efficacy. In this regard, molecular hybridization is deemed as a viable strategy to afford multi-target-based drug candidates. Herein, we report a library of quinoline—1H-1,2,3-triazole molecular hybrids synthesized via copper(I)-catalyzed azide-alkyne [3 + 2] dipolar cycloaddition reaction (CuAAC). Antimicrobial evaluation identified compound 16 as the most active hybrid in the library with a broad-spectrum antibacterial activity at an MIC80 value of 75.39?μM against methicillin-resistant S. aureus, E. coli, A. baumannii, and multidrug-resistant K. pneumoniae. The compound also showed interesting antifungal profile against C. albicans and C. neoformans at an MIC80 value of 37.69 and 2.36?μM, respectively, superior to fluconazole. In vitro toxicity profiling revealed non-hemolytic activity against human red blood cells (hRBC) but partial cytotoxicity to human embryonic kidney cells (HEK293). Additionally, in silico studies predicted excellent drug-like properties and the importance of triazole ring in stabilizing the complexation with target proteins. Overall, these results present compound 16 as a promising scaffold on which other molecules can be modeled to deliver new antimicrobial agents with improved potency. Graphic abstract: [Figure not available: see fulltext.].
- Awolade, Paul,Cele, Nosipho,Kerru, Nagaraju,Singh, Parvesh
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p. 2201 - 2218
(2020/06/17)
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- A novel18F-labeled clickable substrate for targeted imaging of SNAP-tag expressing cells by PETin vivo
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Bioorthogonal covalent labeling with self-labeling enzymes like SNAP-tag bears a high potential for specific targeting of cells for imagingin vitroand alsoin vivo. To this end, fluorescent SNAP substrates have been established and used in microscopy and fluorescence imaging while radioactive substrates for the highly sensitive and whole-body positron emission tomography (PET) have been lacking. Here, we show for the first time successful and high-contrast PET imaging of subcutaneous SNAP-tag expressing tumor xenografts by bioorthogonal covalent targeting with a novel18F-based radioligandin vivo.
- Depke, Dominic Alexej,Hermann, Sven,Konken, Christian Paul,Rentmeister, Andrea,R?sner, Lukas,Sch?fers, Michael
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supporting information
p. 9850 - 9853
(2021/10/08)
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- Production process of 4-methylbenzenesulfonic acid-2-azido ethyl ester
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The invention discloses a production process of 4-methylbenzenesulfonic acid-2-azido ethyl ester, which comprises the following steps: by using 2-bromoethane and sodium azide as initial raw materials,carrying out a substitution reaction on the 2-bromoethane and sodium azide to prepare an intermediate 3; and carrying out the substitution reaction on the intermediate 3 and p-toluenesulfonyl chloride to obtain a target product 2. By establishing strict internal control standards for initial raw materials and intermediates and strictly controlling key process step parameters, qualified products can be stably prepared in multiple batches.
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Paragraph 0021-0026
(2020/07/21)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 2075; 2076
(2019/07/10)
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- 18F-LABELED PEPTIDE LIGANDS USEFUL IN PET AND CERENKOV LUMINESCENE IMAGING
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The present technology is directed to compounds, intermediates thereof, compositions thereof, medicaments thereof, and methods related to the imaging of mammalian tissue via 18F- labeled peptide ligands disclosed herein.
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Paragraph 0131; 0133
(2019/07/13)
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- Exploring Rigid and Flexible Core Trivalent Sialosides for Influenza Virus Inhibition
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Herein, the chemical synthesis and binding analysis of functionalizable rigid and flexible core trivalent sialosides bearing oligoethylene glycol (OEG) spacers interacting with spike proteins of influenza A virus (IAV) X31 is described. Although the flexible Tris-based trivalent sialosides achieved micromolar binding constants, a trivalent binder based on a rigid adamantane core dominated flexible tripodal compounds with micromolar binding and hemagglutination inhibition constants. Simulation studies indicated increased conformational penalties for long OEG spacers. Using a systematic approach with molecular modeling and simulations as well as biophysical analysis, these findings emphasize on the importance of the scaffold rigidity and the challenges associated with the spacer length optimization.
- Kiran, Pallavi,Bhatia, Sumati,Lauster, Daniel,Aleksi?, Stevan,Fleck, Carsten,Peric, Natalija,Maison, Wolfgang,Liese, Susanne,Keller, Bettina G.,Herrmann, Andreas,Haag, Rainer
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supporting information
p. 19373 - 19385
(2018/11/27)
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- PYRIMIDINONE DERIVATIVES AND USES THEREOF TO NEUTRALIZE THE BIOLOGICAL ACTIVITY OF CHEMOKINES
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A subject of the present invention is a compound having the general formula (I) a pharmaceutically acceptable salt thereof or a tautomeric form thereof, wherein A, B3, B4, B5, Y, X, B1 and B2 are as defined in any one of claims 1 to 10. Another subject of the invention is the compound as defined above for use as a medicament, in particular for preventing and/or treating inflammation and inflammatory diseases, immune and auto-immune diseases, pain related diseases, genetic diseases and/or cancer.
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Page/Page column 46
(2018/02/28)
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- Selective Displacement of a Scorpionand Triazole Ligand from Metallocyclam Complexes Visualised with NMR Spectroscopy
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Target-activated metal complexes (TAMCs) – complexes that remain benign until reaching a specific biomolecular target, binding to which then effects structural change that turns on cytotoxicity or other activity – hold considerable allure. The successful
- Wong, Joseph K.-H.,Proschogo, Nicholas,Todd, Matthew H.,Rutledge, Peter J.
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supporting information
p. 1075 - 1086
(2017/03/08)
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- Unexpected Direct Synthesis of N-Vinyl Amides through Vinyl Azide–Enolate [3+2] Cycloaddition
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The unexpected synthesis of industrially important N-vinyl amides directly from aldehydes and α,β-unsaturated N-vinyl amides from esters is reported. This reaction probably proceeds through an initial [3+2] azide–enolate cycloaddition involving a vinyl azide generated in situ. A survey of the reaction scope and preliminary mechanistic findings supported by quantum computational analysis are reported, with implications for the future development of atom-efficient amide synthesis. Intriguingly, this study suggests that (cautious) reevaluation of azidoethene as a synthetic reagent may be warranted.
- Choi, Hans,Shirley, Harry J.,Hume, Paul A.,Brimble, Margaret A.,Furkert, Daniel P.
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supporting information
p. 7420 - 7424
(2017/06/13)
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- Discovery of 1,2,3-Triazole Derivatives for Multimodality PET/CT/Cryoimaging of Myelination in the Central Nervous System
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Myelin pathology is present in many neurological conditions such as multiple sclerosis (MS) and traumatic spinal cord injury (SCI). To facilitate development of novel therapies aimed at myelin repair, we set out to develop imaging agents that permit direct quantification of myelination in vivo. In this work, we designed and synthesized a series of fluorescent fluorinated myelin imaging agents that can be used for in vivo positron emission tomography (PET) imaging combined with subsequent post-mortem fluorescent cryoimaging. Structure-activity relationship (SAR) studies of the newly developed myelin imaging agents led us to identify a lead compound (TAFDAS, 21) that readily enters the brain and spinal cord and selectively binds to myelin. By conducting sequential PET and 3D cryoimaging in an SCI rat model, we demonstrated for the first time that PET and cryoimaging can be combined as a novel technique to image the spinal cord with high sensitivity and spatial resolution.
- Wu, Chunying,Eck, Brendan,Zhang, Sheng,Zhu, Junqing,Tiwari, Anand Dev,Zhang, Yifan,Zhu, Yunjie,Zhang, Jinming,Wang, Bin,Wang, Xizhen,Wang, Xu,You, Jingqiang,Wang, Jian,Guan, Yihui,Liu, Xingdang,Yu, Xin,Trapp, Bruce D.,Miller, Robert,Silver, Jerry,Wilson, David,Wang, Yanming
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p. 987 - 999
(2017/02/19)
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- Synthesis and biological evaluation of JL-A7 derivatives as potent ABCB1 inhibitors
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Cancer chemotherapy failure is often due to the overexpression of ATP-binding cassette (ABC) transporters (particularly ABCB1), resulting in a variety of structurally and pharmacologically unrelated drugs efflux. The multidrug resistance (MDR) phenomenon could be reversed by ABCB1 inhibitors. Now, JL-A7 as the lead compound based on a triazol-N-ethyl-tetrahydroisoquinoline scaffold, 18 compounds were designed and synthesized. Substitution in para positions yielded high activities toward ABCB1. Moreover, compound 5 could effectively block the drug efflux function of ABCB1 and increase the accumulation of anti-cancer drugs to achieve effective treatment concentration in MDR cells.
- Pan, Miaobo,Cui, Jian,Jiao, Lei,Ghaleb, Hesham,Liao, Chen,Zhou, Jiaqi,Kairuki, Mutta,Lin, Haiyan,Huang, Wenlong,Qian, Hai
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p. 4194 - 4202
(2017/07/05)
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- RADIOLIGANDS FOR MYELIN
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A radioligand for labeling myelin includes a fluorescent trans-stilbene derivative.
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Paragraph 00177
(2017/10/06)
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- Near-Infrared-Emitting BODIPY-trisDOTA111In as a Monomolecular Multifunctional Imaging Probe: From Synthesis to In Vivo Investigations
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A new generation of monomolecular imaging probes (MOMIP) based on a distyryl-BODIPY (BODIPY=boron-dipyrromethene) coupled with three DOTA macrocycles has been prepared (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The MOMIP presents good fluorescence properties and is very stable in serum. The bimodal probe was conjugated to trastuzumab, and an optical in vivo study showed high accumulation of the imaging agent at the tumor site.111In radiometallation of the bioconjugate was performed in high radiochemical yield, highlighting the potential of this new BODIPY-chelators derivative as a bimodal imaging probe.
- Maindron, Nicolas,Ipuy, Martin,Bernhard, Claire,Lhenry, Damien,Moreau, Mathieu,Carme, Sabin,Oudot, Alexandra,Collin, Bertrand,Vrigneaud, Jean-Marc,Provent, Peggy,Brunotte, Fran?ois,Denat, Franck,Goze, Christine
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supporting information
p. 12670 - 12674
(2016/08/30)
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- Design, synthesis and biological evaluation of LBM-A5 derivatives as potent P-glycoprotein-mediated multidrug resistance inhibitors
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A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors with triazol-N-phenethyl-tetrahydroisoquinoline or triazol-N-ethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 4 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity toward K562 cells (IC50 >100 μM). Compared with VRP, compound 4 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 4 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 4 could remarkably increase the intracellular accumulation of Adriamycin (ADM) in K562/A02 cells as well as inhibit rhodamine-123 (Rh123) efflux from the cells. These results suggested that compound 4 may represent a promising candidate for developing P-gp-mediated MDR inhibitors.
- Wu, Yuxiang,Pan, Miaobo,Dai, Yuxuan,Liu, Baomin,Cui, Jian,Shi, Wei,Qiu, Qianqian,Huang, Wenlong,Qian, Hai
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p. 2287 - 2297
(2016/04/26)
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- RAFAMYCIN ANALOGS AND METHODS FOR MAKING SAME
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A semi-synthetic rapamycin analog with a triazole moiety or a pharmaceutically acceptable salt or prodrug thereof, is a broad-spectrum cytostatic agent and a mTOR inhibitor, and is useful in the treatment of various cancers, or tumors in organs such as kidney, liver, breast, head and neck, lung, prostate, and restenosis in coronary arteries, peripheral arteries, and arteries in the brain, immune and autoimmune diseases. Also disclosed are fungal growth-, restenosis-, post-transplant tissue rejection- and immune- and autoimmune disease-inhibiting compositions and a method of inhibiting cancer, fungal growth, restenosois, post-transplant tissue rejection, and immune and autoimmune disease in a mammal. One particular preferred application of such triazole-moiety containing rapamycin analog is in treating renal carcinoma, lung cancer, colon cancer, and breast cancers wherein potency of the drug, its half-life, tissue distribution properties, and its pharmacokinetic properties including bioavailability through oral and intravenous routes are essential to the clinical outcomes.
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Paragraph 0067
(2015/02/25)
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- Design, synthesis and evaluation of novel triazole core based P-glycoprotein-mediated multidrug resistance reversal agents
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A novel series of triazol-N-ethyl-tetrahydroisoquinoline based compounds were designed and synthesized via click chemistry. Most of the synthesized compounds showed P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) reversal activities. Among them, compound 7 with little cytotoxicity towards GES-1 cells (IC50 >80 μM) and K562/A02 cells (IC50 >80 μM) exhibited more potency than verapamil (VRP) on increasing anticancer drug accumulation in K562/A02 cells. Moreover, compound 7 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 7 in reversing MDR revealed that it could remarkably increase the intracellular accumulation of both rhodamine-123 (Rh123) and adriamycin (ADM) in K562/A02 cells as well as inhibit their efflux from the cells. These results suggested that compound 7 showed more potency than the classical P-gp inhibitor VRP under the same conditions, which may be a promising P-gp-mediated MDR modulator for further development.
- Jiao, Lei,Qiu, Qianqian,Liu, Baomin,Zhao, Tianxiao,Huang, Wenlong,Qian, Hai
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p. 6857 - 6866
(2015/02/02)
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- RAFAMYCIN ANALOGS AND METHODS FOR MAKING SAME
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A semi-synthetic rapamycin analog with a triazole moiety or a pharmaceutically acceptable salt or prodrug thereof, is a broad-spectrum cytostatic agent and a m TOR inhibitor, and is useful in the treatment of various cancers, or tumors in organs such as kidney, liver, breast, head and neck, lung, prostate, and restenosis in coronary arteries, peripheral arteries, and arteries in the brain, immune and autoimmune diseases. Also disclosed are fungal growth-, restenosis-, post- transplant tissue rejection- and immune- and autoimmune disease- inhibiting compositions and a method of inhibiting cancer, fungal growth, restenosois, post-transplant tissue rejection, and immune and autoimmune disease in a mammal. One particular preferred application of such triazole-moiety containing rapamycin analog is in treating renal carcinoma, lung cancer, colon cancer, and breast cancers wherein potency of the drug, its half-life, tissue distribution properties, and its pharmacokinetic properties including bioavailability through oral and intravenous routes are essential to the clinical outcomes.
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Paragraph 35
(2014/06/23)
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- IMAGING NEURAL ACTIVITY
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The present invention provides a novel radiofluorinated compound for imaging voltage-gated sodium channels (VGSCs) that is more straightforward to synthesise than the known radiofluorinated phenoxyphenyl pyrazole carboxylic acid compounds. The compound of the present invention demonstrates specific uptake and retention in key tissues as well as good in vivo stability. Also provided by the present invention is a radiopharmaceutical composition comprising the radiofluorinated compound of the invention, precursor compounds and methods for the synthesis of said radiofluorinated compound, and methods for using said radiofluorinated compound.
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Page/Page column 22; 23
(2013/09/26)
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- RADIOLABELED ANALOG(S) OF COMPOUND 0118 AND USE THEREOF IN CONNECTION WITH PET AND/OR SPECT IMAGING TO DETERMINE WHETHER A PHARMACEUTICAL CONTAINING COMPOUND 0118 IS A CANDIDATE CANCER TREATMENT FOR A PATIENT
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A method for determining whether compound 0118 is a candidate treatment for a patient includes processing, via a processor, image data of tissue of interest of a patient including a cancer to determine whether a radiolabeled analog of compound 0118 is present in the tissue of interest represented in the image data and generating a signal indicating that compound 0118 is a candidate treatment for the patient in response to the determining that the radiolabeled analog of compound 0118 is present in a predetermined amount in the tissue of interest represented in the image data, wherein the presence of the radiolabeled analog of compound 0118 in the tissue of interest indicates presence of a sub-type of cancer having a galectin-1 molecular target, which is a sub-type of treatable by compound 0118.
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Page/Page column 18
(2014/01/08)
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- Fully automated radiosynthesis of [1-(2-[18F]fluoroethyl),1H[1, 2,3]triazole 4-ethylene] triphenylphosphonium bromide as a potential positron emission tomography tracer for imaging apoptosis
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A novel phosphonium salt bearing a fluorine-18 labelled triazole has been designed as a potential imaging agent for apoptosis. The radiosynthesis of [1-(2-[18F]fluoroethyl),1H[1,2,3]triazole 4-ethylene] triphenylphosphonium bromide ([18F]MitoPhos-01) has been carried out on a fully automated system in a two-step reaction. Radiolabelling an ethyl azide and then carrying out a copper-mediated 1,3-cycloaddition reaction has allowed for total synthesis time to be slightly more than 1 h from aqueous [18F]fluoride. After purification by HPLC, the average radiochemical yield was determined to be 9% (not decay corrected); the specific activity was on average 70 GBq/μmol at the end of synthesis, and the radiochemical purity was >99%. A novel phosphonium salt bearing a fluorine-18 labelled triazole has been designed as a potential imaging agent for apoptosis. The radiosynthesis of [1-(2-[18F]fluoroethyl),1H[1,2,3]triazole 4-ethylene] triphenylphosphonium bromide ([18F]MitoPhos-01) has been carried out on a fully automated system in a two-step reaction, with the average radiochemical yield determined to be 9% (not decay corrected); the specific activity being around 70 GBq/μmol at the end of synthesis and the radiochemical purity above 99%. Copyright
- Haslop, Anna,Gee, Antony,Plisson, Christophe,Long, Nicholas
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p. 313 - 316
(2013/07/26)
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- A fluorous and click approach for screening potential PET probes: Evaluation of potential hypoxia biomarkers
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Radiopharmaceuticals for nuclear imaging are essentially targeting molecules, labeled with short-lived radionuclides (e.g., F-18 for PET). A significant drawback of radiopharmaceuticals development is the difficulty to access radiolabeled molecule libraries for initial in vitro evaluation, as radiolabeling has to be optimized for each individual molecule. The present paper discloses a method for preparing libraries of 18F-labeled radiopharmaceuticals using both the fluorous-based 18F-radiochemistry and the Huisgen 1,3-dipolar (click) conjugation reaction. As a proof of concept, this approach allowed us to obtain a series of readily accessible 18F-radiolabeled nitroaromatic molecules, for exploring their structure-activity relationship and further in vitro evaluation of their hypoxic selectivity.
- Bejot, Romain,Carroll, Laurence,Bhakoo, Kishore,Declerck, Jér?me,Gouverneur, Veronique
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supporting information; experimental part
p. 324 - 329
(2012/03/10)
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- New rhodamine nitroxide based fluorescent probes for intracellular hydroxyl radical identification in living cells
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The synthesis, characteristics, and biological applications of a series of new rhodamine nitroxide fluorescent probes that enable imaging of hydroxyl radicals (?OH) in living cells are described. These probes are highly selective for ?OH in aqueous solution, avoiding interference from other reactive oxygen species (ROS), and they facilitate ?OH imaging in biologically active samples. The robust nature of these probes (high specificity and selectivity, and facile synthesis) offer distinct advantages over previous methods for ?OH detection.
- Yapici, Nazmiye B.,Jockusch, Steffen,Moscatelli, Alberto,Mandalapu, Srinivas Rao,Itagaki, Yasuhiro,Bates, Dallas K.,Wiseman, Sherri,Gibson, K. Michael,Turro, Nicholas J.,Bi, Lanrong
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supporting information; experimental part
p. 50 - 53
(2012/03/11)
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- Aromatic aldehyde functionalized polycaprolactone and polystyrene macromonomers: Synthesis, characterization and aldehyde-aminooxy click reaction
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New bis-aldehyde functionalized initiators, viz, 4,4′-(4,4′-(5- hydroxypentane-2,2-diyl)bis(4,1-phenylene))bis(oxy)dibenzaldehyde (1) and 4,4′-bis(4-(4-(formylphenoxy) phenyl) pentyl 2-bromopropanoate (2) were synthesized starting from commercially available 4,4′-bis(4-hydroxyphenyl) pentanoic acid. These initiators were utilized, respectively, for ring opening polymerization of -caprolactone and atom transfer radical polymerization of styrene. Well-defined polycaprolactone macromonomers (MnGPC: 2600-19400, PDI: 1.37-1.47) and polystyrene macromonomers (MnGPC: 2800-28200, PDI: 1.11-1.16) with bis-aldehyde functionality were synthesized. The kinetic study of styrene polymerization showed controlled polymerization behaviour. The presence of aldehyde functionality in macromonomers was confirmed by 1H NMR spectroscopy. The reactivity of aldehyde functionality was demonstrated by carrying out aldehyde-aminooxy click reaction of polycaprolactone macromonomer with O-(2-azidoethyl) hydroxylamine which proceeded in a quantitative manner without backbone degradation.
- Sane, Prakash S.,Tawade, Bhausaheb V.,Palaskar, Dnyaneshwar V.,Menon, Shamal K.,Wadgaonkar, Prakash P.
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p. 713 - 721,9
(2012/12/11)
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- Effective click construction of bridged-and spiro-multicyclic polymer topologies with tailored cyclic prepolymers (kyklo-telechelics)
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An alkyne-azide addition, i.e., click, reaction in conjunction with an electrostatic self-assembly and covalent fixation (ESA-CF) process has been demonstrated to effectively construct a variety of unprecedented multicyclic polymer topologies. A series of single cyclic poly(telrahydrofuran), poly (THF), precursors having an alkyne group (Ia), an azide group (Ib), two alkyne groups at the opposite positions (Ic), and an alkyne group and an azide group at the opposite positions (Id) have been prepared by the ESA-CF process. Moreover, a bicyclic 8-shaped precursor having two alkyne groups at the opposite positions (Ie) was synthesized. The subsequent click reaction of Ia with linear (IIa) and three-armed star (IIb) telechelic precursors having azide groups has been performed to construct bridged-type two-way (IIIa) and three-way (IIIb) paddle-shaped polymer topologies, respectively. Likewise, spiro-type tandem tricyclic (IVa) and tetracyclic (IVb) topologies resulted from Ib/Ic and Ib/Ie, respectively. Furthermore, three types of multicyclic topologies that are composed of repeating ring (Va), alternating ring/linear (Vb), and alternating ring/star (Vc) units have been synthesized from Id, Ic/IIa, and Ic/IIb, respectively.
- Sugai, Naoto,Heguri, Hiroyuki,Ohta, Kengo,Meng, Qingyuan,Yamamoto, Takuya,Tezuka, Yasuyuki
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supporting information; experimental part
p. 14790 - 14802
(2011/01/05)
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- The 2-(2-Azidoethyl)cycloalkanone strategy for bridged amides and medium-sized cyclic amine derivatives in the Aubé-Schmidt reaction
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2-(2-Azidoethyl)cycloalkanones afford bridged lactams in the Aubé-Schmidt reaction, sometimes in excellent yield, and solvolysis yields derivatives of medium-ring amines. Attempts to divert the Schmidt reaction with an arene-mediated fragmentation of the normal Schmidt intermediate have led to an initial example. Georg Thieme Verlag Stuttgart.
- Macleod, Fraser,Lang, Stuart,Murphy, John A.
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supporting information; experimental part
p. 529 - 534
(2010/10/02)
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- Novel cyclodextrin dimers and derivatives thereof, methods for preparing them and their use, in particular, for the solubilizing pharmacologically active substances
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The invention relates to a compound according to the following general formula (I), in which: m represents an integer equal to 5, 6 or 7; n and n1 represent an integer from 1 to 5; the A groups represent, in particular, a hydrogenated atom; X r
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- An intramolecular [2 + 3] cycloaddition route to fused 5-heterosubstituted tetrazoles
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(matrix presented) Fused 5-heterotetrazole ring systems are synthesized in high yield via intramolecular [2 + 3] cycloadditions of organic azides and heteroatom-substituted nitriles. Cyanates, thiocyanates, and cyanamides are all competent dipolarophiles for this reaction. A variety of scaffolds are tolerated when the new enclosed ring is five- or six-membered.
- Demko, Zachary P.,Sharpless, K. Barry
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p. 4091 - 4094
(2007/10/03)
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- Synthesis of novel dansyl appended cyclodextrins. Self-inclusion and sensor properties
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The synthesis of three dansyl appended cyclodextrin derivatives, differing in the spacer length between cyclodextrin and the dansyl moiety, is described. In compound 4 the fluorophore is directly attached to the cyclodextrin. Compound 5 contains an ethyl spacer and compound 6 a triethylene glycol spacer. These compounds are designed to detect neutral organic guest molecules like cyclohexanol and adamantanecarboxylic acid in water by fluorescence spectroscopy. At neutral pH none of the compounds is sensitive towards guest molecules. For compound 4 this is due to the fact that the dansyl group is located outside the cyclodextrin cavity. For compunds 5 and 6 the low sensitivity is the result of a strong self-inclusion of the dansyl group. Lowering the pH results in protonation of the dimethylamino group of the dansyl moiety, which makes the self-inclusion less favourable leading to a strongly increased response towards guests. This phenomenon allows the sensors to be switched on and off by lowering or increasing the pH of the solution. Compound 6 is able to detect adamantanecarboxylic acid at 5 × 10-7 mol-1 dm3 concentration at pH 1.
- Nelissen, Hubertus F. M.,Venema, Fokke,Uittenbogaard, Rene M.,Feiters, Martinus C.,Nolte, Roeland J. M.
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p. 2045 - 2053
(2007/10/03)
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- ETUDE DE LA CHIMIOSELECTIVITE DE LA REACTION DES DICHLOROBORANES AVEC LES AZIDES FONCTIONNELS: UNE SYNTHESE EFFICACE D'AMINES SECONDAIRES FONCTIONNALISEES.
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The reaction of cyclohexyldichloroborane, used as a model, with a wide variety of functionalized azides has been studied.It has been shown to be an efficient synthesis of secondary amines in terms of chemioselectivity, yields and wide applicability.
- Carboni, B.,Vaultier, M.,Carrie, R.
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p. 1799 - 1810
(2007/10/02)
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