Isoindol-1,3-dione and isoindol-1-one derivatives with high binding affinity to beta-amyloid fibrils.
Bioorganic & medicinal chemistry letters 2008 Jan 19; In press
Lee H HJ, Lim S SJ, Oh S SJ, Moon D DH, Kim D DJ, Tae J J, Yoo K KH
Life Sciences Research Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
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 (0.42-0.94nM). 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 0.46-0.49nM) than those of Indoprofen (K(i)=0.52nM) and PIB (K(i)=0.70nM). These results suggest that isoindolones could be served as a scaffold for potential AD diagnostic probes to monitor Abeta fibrils.
Keywords: amyloid alzheimer's