Figure 2. Synthesis and bioactivity of the γ-secretase modulator photo-probe AR243.
(A) The γ-secretase modulator (GSM) photo-probe AR243 was synthesized by a copper(I)-catalyzed three-component coupling between piperidine-derivative 1, diazirinyl-benzaldehyde 2, and biotin-alkyne 3. The intermediate was then de-protected to yield the free acidic photo-probe. i: CuBr, molecular sieves, Tol. 60°C, 2 d. ii: TBAF, THF, r.t., 2 h. (B) CHO cells with stable co-expression of wild type APP and wild type PSEN1 were treated with increasing concentrations of the photo-probe AR243 or DMSO vehicle, and Aβ levels in conditioned media were quantified by sandwich immunoassay. AR243 caused a dose-dependent decrease in Aβ42 levels with a concomitant increase in Aβ38 levels, confirming its bioactivity as a potent GSM with an IC50 for Aβ42 reduction of 290 nM.