- Tetrahydroisoquinoline derivative as well as preparation method and medical application thereof
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The invention relates to a tetrahydroisoquinoline derivative, a preparation method thereof and medical application of the tetrahydroisoquinoline derivative. Specifically, the invention relates to a tetrahydroisoquinoline derivative as shown in a general formula (I) and a medicinal salt thereof, a preparation method of the tetrahydroisoquinoline derivative and the medicinal salt thereof, and application of the tetrahydroisoquinoline derivative and the medicinal salt thereof as NHE3 inhibitors, particularly as a therapeutic agent for diseases related to body fluid retention or salt overload or gastrointestinal diseases. Wherein the definition of each substituent in the general formula (I) is the same as the definition in the specification.
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Paragraph 0209; 0215; 0389-0394
(2021/04/21)
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- BIODEGRADABLE COMPOUND, LIPID PARTICLE, COMPOSITION COMPRISING LIPID PARTICLE, AND KIT
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The present embodiment provides a compound represented by the formula (1): [in-line-formulae]Q-CHR2??(1)[/in-line-formulae] (Q is a nitrogen-containing aliphatic group containing two or more tertiary nitrogens but no oxygen, and R is an aliphatic group containing a biodegradable group). From the compound in combination with other lipids such as a lipid capable of reducing aggregation, lipid particles can be formed. Further, the compound can be used for a pharmaceutical composition to deliver an activator into cells.
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Paragraph 0096; 0139-0140
(2020/09/09)
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- DIMER COMPOUNDS, AND USE IN BINDING TOXIC REPEATS OF RNA
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Provided herein are compounds and methods for modulating abnormal repeat expansions of gene sequences. More particularly, provided are dimeric inhibitors of RNA and the uses of such inhibitors in regulating nucleotide repeat expansions, e.g., to treat Myotonic Dystrophy Type 1 (DM1), Myotonic Dystrophy Type 2 (DM2), Fuchs dystrophy, Huntington Disease, Amyotrophic Lateral Sclerosis, or Frontotemporal Dementia.
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Paragraph 0233; 0234
(2020/07/16)
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- Synthesis of peptide homo- and heterodimers as potential mimics of platelet-derived growth factor BB
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Pericyte loss is correlated with blood-brain barrier leakage in neurological disorders such as Alzheimer's disease. The platelet-derived growth factor receptor β (PDGFRβ)/platelet-derived growth factor BB (PDGF-BB) signalling pathway is key to the regulation of pericyte survival and proliferation. A series of peptide dimers mimicking the ligand PDGF-BB were prepared in the hope of stimulating PDGFRβ internalisation and activation of this pathway. Copper-catalysed azide-alkyne cycloaddition of peptide monomers with PEGylated linkers of varying length afforded the desired peptide dimers. Evaluation of the peptide dimers in human brain pericyte assays revealed no effect on PDGFRβ internalisation nor cell proliferation at concentrations 10 μM. The peptide dimers also did not act as antagonists at PDGFRβ at concentrations 10 μM.
- Stubbing, Louise A.,Kaur, Harveen,Feng, Sheryl X.,Aalderink, Miranda,Dragunow, Michael,Brimble, Margaret A.
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- Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands
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Herein, we report the development of bitopic ligands aimed at targeting the orthosteric binding site (OBS) and a metastable binding site (MBS) within the same receptor unit. Previous molecular dynamics studies on ligand binding to the β2-adrenergic receptor (β2AR) suggested that ligands pause at transient, less-conserved MBSs. We envisioned that MBSs can be regarded as allosteric binding sites and targeted by homobivalent bitopic ligands linking two identical pharmacophores. Such ligands were designed based on docking of the antagonist (S)-alprenolol into the OBS and an MBS and synthesized. Pharmacological characterization revealed ligands with similar potency and affinity, slightly increased β2/β1AR-selectivity, and/or substantially slower β2AR off-rates compared to (S)-alprenolol. Truncated bitopic ligands suggested the major contribution of the metastable pharmacophore to be a hydrophobic interaction with the β2AR, while the linkers alone decreased the potency of the orthosteric fragment. Altogether, the study underlines the potential of targeting MBSs for improving the pharmacological profiles of ligands.
- Gaiser, Birgit I.,Danielsen, Mia,Marcher-R?rsted, Emil,R?pke J?rgensen, Kira,Wróbel, Tomasz M.,Frykman, Mikael,Johansson, Henrik,Br?uner-Osborne, Hans,Gloriam, David E.,Mathiesen, Jesper Mosolff,Sejer Pedersen, Daniel
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p. 7806 - 7839
(2019/09/07)
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- Freestanding flexible polymer films based on bridging of two EDOT units with functionalized chains for use in long-term-stable supercapacitors
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Freestanding flexible capacitive materials are ideal for use in bendable electronic devices. However, it is difficult to prepare pure PEDOT films in a freestanding state by chemical and electrochemical methods. Here, we used a simple strategy of introducing alkoxy, ether, ester, and amide chains for bridging two EDOT units to form precursors, which could then be electrodeposited readily to produce freestanding and flexible films. The precursor with the amide group was suitable for obtaining higher-quality films with improved thermal stability, mechanical properties, and capacitive performance. In addition, the asymmetric PBEDTA//PEDOT capacitors exhibited a capacitance retention rate of 98.5% after 5000 cycles, which is higher than those of PBEDTH//PEDOT (92.7%), PBEDTG//PEDOT (80.5%), and PBEDTE//PEDOT (86.8%) capacitors. This result indicates that the polymer films and, in particular, the PBEDTA films, are suitable for use in flexible supercapacitors.
- Ye, Guo,Zhou, Qianjie,Li, Danqin,Zuo, Yinxiu,Duan, Xuemin,Zhou, Weiqiang,Xu, Jingkun
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p. 4824 - 4834
(2018/04/02)
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- OPIOID RECEPTOR ANTAGONIST CONJUGATE AND USE THEREOF
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The present invention relates to an opioid receptor antagonist conjugate and a use thereof. In particular, the present invention relates to a covalent coupling conjugate of a hydrophilic polymer and an opioid receptor antagonist and the use thereof.
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Paragraph 0072
(2018/12/07)
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- LOW MOLECULAR WEIGHT POLYETHYLENE GLYCOL DRUG CONJUGATES HAVING IMPROVED DRUG BIOLOGICAL ACTIVITY
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Provided are polyethylene glycol drug conjugates of general formula (I), (II) or (III) and pharmaceutical compositions and a use thereof. The conjugates are formed by combining low molecular weight polyethylene glycol with 2-4 drug molecules. The conjugates can interact with receptor dimers or polymers, thereby improving the in vivo distribution of the drug, changing the oil and water distribution coefficient, enhancing the pharmacological activity, reducing the blood-brain barrier permeability of the drug, and improving the bioavailability of the drug.
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Paragraph 0048
(2016/04/19)
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- BIVALENT BROMODOMAIN LIGANDS, AND METHODS OF USING SAME
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Described herein are compounds capable of modulating one or more biomolecules substantially simultaneously, e.g., modulating two or more binding domains (e.g., bromodomains) on a protein or on different proteins. For example, in one aspect, a bivalent compound or a pharmaceutically acceptable salt, stereoisomer, metabolite, or hydrate thereof is provided. In another aspect, a method of treating a disease associated with a protein having tandem bromodomains in a patient in need thereof is provided. The method comprises administering to the patient the bivalent compound as described.
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Paragraph 00357-00361; 00366; 00367
(2015/06/11)
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- Grafting of polymeric platforms on gold by combining the diazonium salt chemistry and the photoiniferter method
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The grafting of stable and strongly attached polymeric platforms on gold is a key factor for successful applications in biology, catalysis and sensing. Here, we report on the use of a combination of the iniferter method and the diazonium salt chemistry for preparing smart polymeric platforms attached through covalent bonds on gold. For this, bifunctional molecules bearing aryl diazonium coupling agents for anchoring on gold and N,N-diethyldithiocarbamate groups for initiating the growth of polymer chains were used. These two moieties were separated by oligo(ethylene oxide) spacers of various lengths allowing a fine tuning of the hydrophilic properties of the grafted photoinitiator layers. Cross-linked copolymers of methacrylic acid (MAA) and N,N′-methylenebisacrylamide (MBAm) were then grown from the gold surfaces under UV light. The polymer films were characterized in terms of chemical composition and wettability by X-ray photoelectron spectroscopy and contact angle measurements, respectively. The grafting procedure was simple, rapid and effective in producing polymer-grafted Au surfaces at room temperature. The diethyldithiocarbamil groups remaining at the end of the growing tethered chains could then be easily exchanged by a UV-light induced radical-exchange experiment in order to obtain terminal amino moieties able to immobilize citrate-capped gold nanoparticles, through electrostatic interactions. The results obtained in the present work highlight the efficiency of the diazonium salt chemistry coupled to the photo-iniferter based surface grafting approach to spontaneously functionalize gold surfaces through covalent bonds. This strategy open new opportunities for the preparation of "smart" hybrid platforms made of pH-responsive polymers and nanoparticle assemblies.
- Ahmad, Randa,Mocaer, Adrien,Gam-Derouich, Sarra,Lamouri, Aazdine,Lecoq, Hélène,Decorse, Philippe,Brunet, Philippe,Mangeney, Claire
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- Esterification of carboxylic acids with alkyl halides using imidazolium based dicationic ionic liquids containing bis-trifluoromethane sulfonimide anions at room temperature
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Task-specific room temperature ionic liquids (RTILs) composed of symmetrical N-methylimidazolium rings linked with a short oligo (ethylene glycol) chain (cationic part) and bis-trifluoromethane sulfonimide (NTf2, anionic part) were successfully synthesized, and their physicochemical properties were determined by various modern analytical techniques. The catalytic activity of the synthesized RTILs was evaluated in the esterification reaction of acids with alkyl halides in solvent-free conditions at room temperature. From the screening test, all the synthesized RTILs showed a high yield with significant selectivity for respective esters in a very short reaction time. Especially, 0.1 equimolar of RTIL-1 ([tetraEG(mim)2][NTf2]2) was found to be, the most efficient and reusable catalyst for this reaction. As a result, 100% conversion and up to a 94% yield of the respective ester product was obtained in a 30 min reaction time. This might be due to their synergetic effect of Lewis acidity, wide liquid range, and high miscibility compared to the other homogeneous and heterogeneous catalysts. Beside this, RTIL was easily separated from the reaction mixture and reused several times without any significant loss of catalytic activity and structural property. The present dicationic ionic liquids (ILs) under a solvent-free catalytic system were found to be kinetically fast, naturally benign, and achieved good yields for esterification of carboxylic acids with alkyl halides.
- Jadhav, Arvind H.,Lee, Kyuyoung,Koo, Sangho,Seo, Jeong Gil
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p. 26197 - 26208
(2015/10/20)
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- Efficient selective dehydration of fructose and sucrose into 5-hydroxymethylfurfural (HMF) using dicationic room temperature ionic liquids as a catalyst
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Dicationic room temperature ionic liquids (RTILs), with short oligo ethylene glycol linkers have been found to be highly active catalyst for the selective dehydration of fructose and sucrose into 5-hydroxymethylfurfural (HMF). The bis (N-methylimidazolium) cations containing short oligo ethylene glycol linkers and mesylate (CH3SO3-) anions based ILs were employed in catalytic amount for sugar dehydration reactions. As a result, 92.3% of HMF yield was obtained from fructose in 40 min with one equivalent of [TetraEG(mim)2][OMs]2 at 120°C. While, 67.2% of HMF was achieved from dehydration of sucrose at 120°C in 150 min using two equivalents of [TetraEG(mim)2][OMs]2. Among those dicationic RTILs, [TetraEG(mim)2][OMs]2 RTIL was observed to be the most efficient catalyst, demonstrated by its ability to achieve 100% conversion and highest yield of HMF. In addition, effect of reaction time, molar ratio, temperature, and co-catalyst effect were discussed. The use of dicationic RTILs as a catalyst in sugar dehydration greatly reduces the equimolar ratio of catalyst and reaction time required for conversion of sugar into HMF.
- Jadhav, Arvind H.,Kim, Hern,Hwang, In Taek
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supporting information; experimental part
p. 96 - 103
(2012/06/01)
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- Synthesis and evaluation of cardiac glycoside mimics as potential anticancer drugs
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The cardiac glycoside digitoxin, consisting of a steroid core linked to a labile trisaccharide, has been used for centuries for the treatment of congestive heart failure. The well known pharmacological effect is a result of the ability of cardiac glycosides to inhibit the Na+, K +-ATPase. Within recent years cardiac glycosides have furthermore been suggested to possess valuable anticancer activity. To mimic the labile trisaccharide of digitoxin with a stabile carbohydrate surrogate, we have used sulfur linked ethylene glycol moieties of varying length (mono-, di-, tri- or tetra-ethylene glycol), and furthermore used these linkers as handles for the synthesis of bivalent steroids. The prepared compounds were evaluated for their potencies to inhibit the Na+, K+-ATPase and for their cytotoxic effect on cancerous MCF-7 cells. A clear trend is observed in both inhibition and cytotoxic effect, where the bioactivity decreases as the size increases. The most potent Na+, K+-ATPase inhibitors are the compounds with the shortest ethylene glycol chain (Kapp 0.48 μM) and thiodigitoxigenin (Kapp 0.42 μM), which both are comparable with digitoxigenin (Kapp 0.52 μM). For the cancer cell viability assay the shortest mimics were found to have highest efficacy, with the best ligand having a monoethylene glycol unit (IC50 0.24 μM), which was slightly better than digitoxigenin (IC50 0.64 μM), while none of the novel cardiac glycoside mimics display an in vitro effect as high as digitoxin (IC50 0.02 μM).
- Jensen, Marie,Schmidt, Steffen,Fedosova, Natalya U.,Mollenhauer, Jan,Jensen, Henrik H.
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experimental part
p. 2407 - 2417
(2011/05/12)
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- Design, synthesis and biological evaluation of estradiol-PEG-linked platinum(II) hybrid molecules: Comparative molecular modeling study of three distinct families of hybrids
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The synthesis of a series of 17β-estradiol-platinum(II) hybrid molecules is reported. The hybrids are made of a PEG linking chain of various length and a 2-(2′-aminoethyl)pyridine ligand. They are prepared from estrone in only 5 chemical steps with an overall yield of 22%. The length of the PEG chain does not influence the solubility of the compounds as it remains relatively constant throughout the series. MTT assays showed that the derivative with the longest PEG chain showed the best activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231). The novel PEG-hybrids are also compared in terms of activities with two other families of 17β-estradiol- platinum(II) hybrids that we reported in previous studies. Molecular modeling study performed on a representative member of each family of hybrids reveals distinct molecular interactions with the estrogen receptor α which further corroborates their notably contrasting cytocidal activities on breast cancer cell lines. This study also shows that lipophilicity and the orientation of the tether chain between the estrogenic portion and the platinum(II) core contribute markedly to the biological activity of the various families of hybrids. The most active hybrids are those possessing an alkyl tether chain at position 16β of the steroid nucleus. For example, derivative 3 (p = 6) is about 16 times more potent on MCF-7 breast cancer cells than the corresponding 16α-PEG-hybrids (2b) made in this study.
- Provencher-Mandeville, Josée,Debnath, Chhanda,Mandal, Sanat K.,Leblanc, Valérie,Parent, Sophie,Asselin, éric,Bérubé, Gervais
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experimental part
p. 94 - 103
(2011/03/20)
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- POLYMERS PREPARED FROM MIXTURES OF MULTIFUNCTIONAL N-VINYLFORMAMIDE AND HYBRID REACTIVE N-VINYLFORMAMIDE CROSSLINKING MONOMER MOIETIES AND USES THEREOF
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The present invention provides polymers resulting from polymerization of at least one reactive vinyl monomer moiety and a multifunctional N-vinylformamide crosslinking moiety; polymers resulting from polymerization of at least one reactive vinyl monomer moiety and a hybrid N-vinylformamide crosslinking moiety having at least one N-vinylformamide functionality and at least one other reactive vinyl functionality; polymers resulting from polymerization of at least one hybrid reactive N-vinylformamide monomer moiety having one N-vinylformamide functionality and at least one other reactive non-vinyl functionality and a multifunctional N-vinylformamide crosslinking moiety; and polymers resulting from polymerization of at least one hybrid reactive N-vinylformamide monomer moiety having one N-vinylformamide functionality and at least one other reactive non-vinyl functionality and a hybrid N-vinylformamide crosslinking moiety having at least one N-vinylformamide functionality and at least one other reactive vinyl functionality. The invention further provides a wide variety of compositions comprising the novel crosslinked polymers.
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Page/Page column 17-18
(2011/08/03)
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- Synthesis of 17β-estradiol-platinum(II) hybrid molecules showing cytotoxic activity on breast cancer cell lines
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The synthesis of a series of 17β-estradiol-platinum(II) hybrid molecules is reported. The hybrids are made of a PEG linking chain of various length and a 2-(2′-aminoethyl)pyridine ligand. They are prepared from estrone in five chemical steps with an overall yield of 22%. The length of the PEG chain does not influence the solubility of the compounds as it remains relatively constant throughout the series. MTT assays showed that the derivative with the longest PEG chain showed the best activity against breast cancer cell lines (MCF-7 and MDA-MB-231). Molecular modeling study rationalized the results.
- Provencher-Mandeville, Josée,Desc?teaux, Caroline,Mandal, Sanat K.,Leblanc, Valérie,Asselin, éric,Bérubé, Gervais
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p. 2282 - 2287
(2008/09/20)
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- Synthesis of unique 17β-estradiol homo-dimers, estrogen receptors binding affinity evaluation and cytocidal activity on breast, intestinal and skin cancer cell lines
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A rapid and efficient synthesis of a series of C2-symmetric 17β-estradiol homo-dimers is described. The new molecules are linked at position 17α of the steroid nucleus with either an alkyl chain or a polyethylene glycol chain. They are made from estrone in only five chemical steps with an overall yield exceeding 30%. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER+ and ER-) human breast tumor cell lines: MCF-7 and MDA-MB-231. Some of the dimers present selective cytotoxic activity against the ER+ cell line. However, they are not very cytotoxic when compared to the antiestrogen tamoxifen. Unfortunately, they show only weak affinity for the estrogen receptor alpha (ERα) and no affinity for the estrogen receptor beta (ERβ). The new compounds were also tested on human intestinal (HT-29) cancer and on murine skin cancer (B16-F10) cell lines for further biological assessment. Interestingly, the dimers were found to be cytotoxic to the murine skin cancer cell line but were inactive towards the intestinal cancer cell line.
- Bérubé, Gervais,Rabouin, Daniel,Perron, Valérie,N'Zemba, Blaise,Gaudreault, René-C.,Parent, Sophie,Asselin, éric
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p. 911 - 921
(2007/10/03)
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- Multi-channel receptors and their relation to guest chemosensing and reconfigurable molecular logic gates
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The synthesis and characterisation of a family of multi-channel receptors containing crown-cation binding sites anchored to a 1-aminophenyl-1,2,2- tricyanoethylene group is reported. The ligands L1-L6bear a 1-aminophenyl-1,2,2-tricyanoethylene scaffolding which is simultaneously a redox-active group (showing reduction processes at moderately modest potentials) and an acceptor moiety in the 1-aminophenyl-1,2,2-tricyanoethylene chromophore. Additionally, dyes L1-L6 also show fluorescence emission. The colour variation of L1-L6 in acetonitrile in the presence of the metal cations Ag+, Cd2+, Cu2+, Fe2+, Hg2+, Pb2+ and Zn2+ has been studied. Selective hypsochromic shifts were found for the systems L 4-Pb2+, L5-Hg2+ and L 6-Hg2+ For Hg2+ with L5 and L 6 and Pb2+ with L4, emission fluorescence enhancements most likely associated with metal coordination to the anilinium nitrogen were observed. The electrochemical behaviour of receptors L 1-L6 was studied in acetonitrile with platinum as working electrode and [Bu4N][BF4] as supporting electrolyte. This family of receptors shows a one-electron reversible reduction process at around -0.70 V vs. SCE, attributed to the reduction of the tricyanovinyl group. Additionally, all the receptors also show the oxidation of the anilinium moiety at about 1.2-1.4 V vs. SCE. Significant anodic shifts of both reduction and oxidation waves were found in the presence of certain metal cations. The relationship of these multiple-channel signalling receptors with guest chemosensing and reconfigurable molecular-based logic gates is discussed. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.
- Jimenez, Diego,Martinez-Manez, Ramon,Sancenon, Felix,Ros-Lis, Jose V.,Soto, Juan,Benito, Angel,Garcia-Breijo, Eduardo
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p. 2393 - 2403
(2007/10/03)
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- A facile synthesis of C2-symmetric 17β-estradiol dimers
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A rapid and efficient synthesis of a series of C2-symmetric 17β-estradiol dimers is described. The new molecules are linked at position 17α of the steroid nucleus with either an alkyl chain or a polyethylene glycol chain. They are made from estrone in five chemical steps with an overall yield exceeding 30%. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER+ and ER-) human breast tumor cell lines: MCF-7 and MDA-MB-231. Some of the dimers present selective cytotoxic activity against the ER+ cell line.
- Rabouin, Daniel,Perron, Valerie,N'Zemba, Blaise,C.-Gaudreault, Rene,Berube, Gervais
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p. 557 - 560
(2007/10/03)
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- Synthesis and analysis of polyethylene glycol linked P-glycoprotein-specific homodimers based on (-)-stipiamide
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A series of five homodimeric polyethylene glycol (PEG) linked homodimers based on the multidrug resistance reversal agent (-)-stipiamide were made and tested for their ability to interact with P-glycoprotein, the protein responsible for multidrug resistance, using ATPase and photoaffinity displacement assays. Key reactions include a new alkoxide-mesylate displacement for the assembly of the PEG linkers and a double Sonogashira coupling reaction.
- Andrus, Merritt B.,Turner, Timothy M.,Updegraff, Emily P.,Sauna, Zuben E.,Ambudkar, Suresh V.
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p. 3819 - 3822
(2007/10/03)
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- Design and synthesis of a more highly selective ammonium ionophore than nonactin and its application as an ion-sensing component for an ion-selective electrode
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A novel ammonium ionophore, which exhibits superior NH4+ selectivity compared with that of the natural antibiotic nonactin, was successfully designed and synthesized based on a 19-membered crown compound (TD19C6) having three decalin
- Suzuki, Koji,Siswanta, Dwi,Otsuka, Takeshi,Amano, Tsuyoshi,Ikeda, Takafumi,Hisamoto, Hideaki,Yoshihara, Ryoko,Ohba, Shigeru
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p. 2200 - 2205
(2007/10/03)
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- Syntheses and Reactions of Crown Ether-Bridged Stilbenes
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A high yield synthesis of o,o' crown ether-bridged stilbenes 3b-e by reductive McMurry condensation of (2-formylphenyl)oligoethylene glycols 2b-e with facile (E/Z) diastereomer separation by selective cation complexation is described.Derivatization of the stilbene double bonds of (E)- or (Z)-3b-e affords dihydroxy crown ethers 4c, d and 5c, d diastereo- and enantioselectively.Likewise, trans- and cis-epoxides 11b-d and 12b-d are stereospecifically obtained.A crown ether-bridged diphenylacetaldehyde 13 is formed by rearrangement of 11c or 12c.Photocyclization of 3e yields large-ring 1,8-phenanthrene crown ether 18.The crystal structures of racemic 5c and of 12d are presented.A high caesium selectivity compared to the other alkali metal and alkaline earth cations is found for ion exchange membranes with incorporated crown ether (Z)-3c. - Key Words: McMurry reaction / Crown ethers / Hydroxylation, enantioselective / Ion exchange membranes
- Merz, Andreas,Karl, Andreas,Futterer, Thomas,Stacherdinger, Natascha,Schneider, Oliver,et al.
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p. 1199 - 1210
(2007/10/02)
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