- Flexible multidentate benzyldiamine derivatives with high affinity for β-amyloid in cerebral amyloid angiopathy
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Abstract: Cerebral amyloid angiopathy (CAA) commonly found in the aged is pathologically characterized by β-amyloid (Aβ) deposition in the walls of arteries and capillaries of brain. In this study, four flexible multidentate benzyldiamine derivatives as potential probes for cerebrovascular Aβ deposition were designed and synthesized. In in vitro inhibition assays, the ligands 18–21 displayed high affinities for Aβ aggregates with Ki values of 1.45 ± 0.53?nM, 1.68 ± 0.35?nM, 1.16 ± 0.23?nM and 1.72 ± 0.19?nM, respectively. A significant improvement in the binding affinity over the monomer, compounds 9–12 or benzyldiamine derivatives, demonstrated the applicability of the multidentate approach. The underlying mechanism of these novel Aβ agents was explored by molecular docking technique, which theoretically verified the high affinities of the multidentate benzyldiamine derivatives for Aβ aggregates. Moreover, the molecular masses of the ligands 18–21 are more than 700 Dalton, which are believed to be hardly capable of penetrating blood brain barrier. In this regard, these ligands could be used to distinguish CAA from Alzheimer’s disease which is another Aβ-related disorder disease. To convert these ligands to positron emission tomography imaging agents, we attempted to radiosynthesize [18F]18. Though the radiolabeling was not very successful, the preliminary results suggested that these newly proposed multidentate benzyldiamine derivatives may be used as potential Aβ imaging agents in cerebral amyloid angiopathy. Graphic abstract: [Figure not available: see fulltext.].
- He, Yujia,Fu, Tingting,Li, Yuying,Xue, Weiwei,Cui, Mengchao,Wang, Liang,Niu, Mengda,Peng, Zhiping,Jia, Jianhua
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p. 525 - 533
(2020/05/25)
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- Sulfur-containing compound based on glutaryl imide skeleton and application of compound
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The present disclosure relates to compound shown in a formula (I) or salts, solvates, isotope-enriched analogs, tautomers, polymorphs, stereoisomers, or mixtures of stereoisomers of the compound, andthe application thereof in the treatment of tumours. The present disclosure also provides tumor treatment application of the compound showed in a formula (I') or pharmaceutically acceptable salts, solvates, isotope-enriched analogs, tautomers, polymorphic substances, stereoisomers, or mixtures of stereoisomers of the compound.
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Paragraph 0686-0687
(2020/09/12)
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- Polyfluorinated bis-styrylbenzene β-amyloid plaque binding ligands
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β-Amyloid (Aβ) binding affinities and specificities for six bis-styrylbenzenes with multiple magnetically equivalent fluorine atoms in the form of a tetrafluorophenyl core or symmetrical trifluoromethyl and trifluoromethoxy groups were determined by means of fluorescence titrations with amyloid peptide Aβ1-40 and a novel in vitro fluorescence-based assay using APP/PS1 transgenic mouse brain sections. Bisstyrylbenzenes with a tetrafluorophenyl core had increased Aβ binding affinities compared to their monofluorophenyl or phenyl counterparts. Bis-styrylbenzenes with carboxylic acid functional groups had lower Aβ binding affinities than their neutral counterparts. Selected bis-styrylbenzenes were demonstrated to have good blood - brain barrier penetration capabilities. These data extend the SAR of bis-styrylbenzene Aβ binding and provide direction for the development of a noninvasive probe for early detection of Alzheimer's disease using 19F MRI.
- Flaherty, Daniel P.,Walsh, Shannon M.,Kiyota, Tomomi,Dong, Yuxiang,Ikezu, Tsuneya,Vennerstrom, Jonathan L.
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p. 4986 - 4992
(2008/03/12)
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- Fluoro-substituted and 13C-labeled styrylbenzene derivatives for detecting brain amyloid plaques
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Two styrylbenzene derivatives, (E,E)-1-fluoro-2,5-bis-(3-hydroxycarbonyl-4- hydroxy)styrylbenzene (FSB) and (E,E)-1-bromo-2,5-bis(3-hydroxycarbonyl-4- hydroxy)styrylbenzene-α,α′-13C2 ([ 13C]BSB), were synthesized for use as a histochemical stain to detect amyloid plaques of Alzheimer's disease (AD) brain sections. An analysis of fluorescence spectra demonstrated that FSB shows approximately twofold fluorescence intensity relative to the conventional styrylbenzene derivative, (E,E)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB). Moreover, FSB was found to stain amyloid plaques and neurofibrillary tangles of AD brains with greater fluorescence intensity and a lower level of background signals compared to BSB. These finding indicate that FSB can be an excellent fluorescent compound to label human amyloid lesions with high sensitivity and specificity. Because of the possession of a nuclide with a quantized angular momentum, both FSB and [13C]BSB are also potential contrast agents for magnetic resonance imaging to locate AD pathologies in vivo.
- Sato, Kumi,Higuchi, Makoto,Iwata, Nobuhisa,Saido, Takaomi C.,Sasamoto, Kazumi
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p. 573 - 578
(2007/10/03)
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