Azide-alkyne fragment library

FIGURE 10.7 Azide-alkyne fragment library hits... 

The fragment library consisted of tacrine and ethidium derivatives with tethers of variable lengths to both azides and alkynes (Figure 10.6). In total, the library included 36 different tacrine-ethidium combinations. Each combination could form two regioisomeric triazoles, so a grand total of 72 different products was possible. 

The use of click chemistry has also been applied to the synthesis of benzophe-none-modified y-secretase probes. The group of Yao reported the preparation of a compound library built up from Bpa-containing alkyne 77 and azide 78 (Fig. 7) [81]. The azide part contains a racemic hydroxyethylene moiety, and variations were made in its aryl sulfonamide domain. The compound library was screened for its potency against y-secretase inhibition and the most potent compounds were used to label active PS1 in a cell lysate. In addition, Fuwa and coworkers reported a divergent synthesis of y-secretase A/BPs by means of click chemistry with alkyne 79 and azide 80 [82]. Variations were made in the aryl part of the alkyne (dibenzoazepine or benzodiazepine) and in the type of spacer between the benzo-phenone moiety and biotin in the azide. PAL using these probes provided the authors with evidence that the molecular target of this type of probe is the N-terminal fragment of PS1. 

Oxidation of 50 (Scheme 10.8) with 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and bis[acetoxy(iodo)]benzene (BAIB) in a 1 1 mixture of acetonitrile and water [66], afforded acid 47 in good yields. The two amines 45 and 46 were synthesized from 49 and 50, respectively, via the corresponding azides (Scheme 10.8). Functionalization of44-47 with the m-alkyne linkers (Scheme 10.10) yielded the 11 linker-armed Gal fragments 54-64 used in the library. 

---