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Titolo:
Isomerization of (Z,Z) to (E,E) 1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene in strong base: Probes for amyloid plaques in the brain
Autore:
Lee, CW; Zhuang, ZP; Kung, MP; Plossl, K; Skovronsky, D; Gur, T; Hou, C; Trojanowski, JQ; Lee, WMY; Kung, HF;
Indirizzi:
Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA Univ Penn PhiladelphiaPA USA 19104 pt Radiol, Philadelphia, PA 19104 USA Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 & Lab Med, Philadelphia, PA 19104 USA Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 Pharmacol, Philadelphia, PA 19104 USA
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 14, volume: 44, anno: 2001,
pagine: 2270 - 2275
SICI:
0022-2623(20010705)44:14<2270:IO(T(1>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
ALZHEIMERS GAMMA-SECRETASE; CONGO-RED; BETA-PEPTIDE; DISEASE; BINDING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
21
Recensione:
Indirizzi per estratti:
Indirizzo: Kung, HF Univ Penn, Dept Radiol & Pharmacol, 3700 Market St,Room 305, Philadelphia,PA 19104 USA Univ Penn 3700 Market St,Room 305 Philadelphia PA USA19104 4 USA
Citazione:
C.W. Lee et al., "Isomerization of (Z,Z) to (E,E) 1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene in strong base: Probes for amyloid plaques in the brain", J MED CHEM, 44(14), 2001, pp. 2270-2275

Abstract

In developing probes for detecting beta -amyloid (A beta) plaques in the brain of Alzheimer's disease (AD), we have synthesized 1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (5, BSB). Due to the presence of two double bonds, formation of four different isomers is possible. Four isomers, E,E-5, E,Z-5, Z,E-5, and Z,Z-5, were prepared. Surprisingly, all showed strong fluorescent labeling of A beta plaques in the brain of postmortem brain sections of patients with confirmed AD. In vitro binding assay also showed that all four isomers of BSB (E,E-5, E,Z-5, Z,E-5, and Z,Z-5) displayed a similar high binding affinity inhibiting the binding of [I-125]E,E, 6, 1-iodo-2,5-bis-(3-hydroxycarbonyl-4-methoxy)styrylbenzene (IMSB) to A beta (1-40) aggregates. The inhibition constants (K-i) of E,E-5, E,Z-5, E,Z-5, andZ,Z-5 were 0.11 +/- 0.01, 0.19 +/- 0.03, 0.27 +/- 0.06, and 0.13 +/- 0.02 nM, respectively. Due to the fact that geometric stability of these styrylbenzenes is unknown, and the conversion of Z,Z-5 to E,E-5 may occur automatically in the binding or labeling assaying conditions, we have investigated the kinetics of conversion of Z,Z-5 to E,E-5 by NMR in D2O/NaOD at elevatedtemperatures (70, 95, and 115 degreesC). The activation energy was determined to be 14.15 kcal/mol. The results strongly suggest that the isomeric conversion at room temperature in aqueous buffer solution is unlikely. All ofthe styrylbenzene isomers clearly showed potential as useful tools for studying A beta aggregates in the brain. The data suggest that, despite the rigidity of this series of styrylbenzenes, the binding sites on A beta aggregates may have certain flexibility and the binding pockets could be adaptable for binding to other smaller ligands. Such information could be exploitedto develop new ligands for detecting amyloid plaques in AD.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/01/20 alle ore 13:21:01