Isoindol-1,3-dione and isoindol-1-one derivatives with high binding affinity to beta-amyloid fibrils.
Based on the structural features of Indoprofen and PIB, a series of isoindol-1,3-diones 1a-k and isoindol-1-ones 2a-l were designed and synthesized. These 23 compounds were evaluated by competitive binding assay against aggregated Abeta42 fibrils using [(125)I]TZDM. All the isoindolone derivatives showed very good binding affinities with K(i) values in the subnanomolar range (0.42-0.94 nM). Among them, isoindol-1,3-diones 1i and 1k and isoindol-1-ones 2c and 2i exhibited excellent binding affinities (K(i)=0.42-0.44 and 0.46-0.49 nM) than those of Indoprofen (K(i)=0.52 nM) and PIB (K(i)=0.70 nM). These results suggest that isoindolones could be served as a scaffold for potential AD diagnostic probes to monitor Abeta fibrils.
Lee
Hyu Ji
HJ
Life Sciences Research Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
Lim
Soo Jeong
SJ
Oh
Seung Jun
SJ
Moon
Dae Hyuk
DH
Kim
Dong Jin
DJ
Tae
Jinsung
J
Yoo
Kyung Ho
KH
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000814:Aniline Compounds; D052160:Benzothiazoles / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D007216:Indoprofen / Q000737:chemistry; D054833:Isoindoles / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013844:Thiazoles
C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; D006571:Heterocyclic Compounds; C110621:Isoindol-1-one; D054833:Isoindoles; D013844:Thiazoles; D007216:Indoprofen