Photoaffinity Probes for Alzheimer’s Disease

Key words

photoaffinity labels - photoaffinity probes - diazirines - nosyl stragety - Alzheimer’s disease

Significance

A convenient solid-phase synthesis of a variety of photoaffinity probes was achieved by utilizing the Ns (Ns = Nosyl) strategy. Thus, the synthesis of the photoaffinity probe 9 was achieved in 47% overall yield from diazirine 1 and alkyl bromide 2. The carbon-nitrogen bond formation at the side chain was accomplished by the Mitsunobu reaction of the Ns amines (e.g. 4; Ns strategy). By using a similar synthetic route, six photoaffinity probes were prepared. The synthetic probes were evaluated via the labeling ability with the preseniline 1 C-terminal fragments (PS 1 CTFs), and 9 exhibited inihibitory activity of Ab40 (IC₅₀ = 70 nM).

Comment

The authors have developed the Ns strategy for the convenient preparation of di- and trialkyl amines (see review below). PS 1 CTFs were identified as therapeutic targets for Alzheimer’s disease. To the authors’ knowledge, there have been no or only few systematic studies on the structure and labeling-ability relationship (SAR) of photoaffinity probes.

Review

T. Kan, T. Fukuyama Chem. Commun. 2004, 353.