S. Sinn, E. Spuling, S. Bräse, F. Biedermann, Chem. Sci., 2019.
In this study, we report the first supramolecular indicator displacement assay (IDA) based on cucurbit[n]uril (CBn) hosts that is operational in blood serum. Rational design principles for host-guest chemosensing in competitively bindig media were derived through detailed mathematical simulations. It was shown that currently known CBn-based chemosensing ensembles are not suited for use in highly competitive matrices such as blood serum. Conversely, the simulations indicated that a combination of cucurbituril (CB8) and a ultra-high affinity dye would be a promising IDA reporter pair for the detection of Alzheimer’s drug memantine in blood serum. Therefore, a novel class of [2.2]paracyclophane-derived indicator dyes for the host CB8 was developed that possesses one of the highest host-guest affinities (Ka > 1012 M?1 in water) known in supramolecular host-guest chemistry, and which provides a a large Stokes shift (up to 200 nm). The novel IDA assay was then tested for the detection of memantine in blood serum at a physiologically relevant sub- to low micromolar concentration range.