Design, Synthesis, and Evaluation of a Luminescent Cholesterol Mimic

Abstract

The development of new chemical tools with improved properties is essential to chemical and cell biology. Of particular interest is the development of mimics of small molecules with important cellular function that allow the direct observation of their trafficking in a cell. To this end, a novel 15-azasterol has been designed and synthesized as a luminescent cholesterol mimic for the monitoring of cholesterol trafficking. The brightness of this probe, which is ∼32times greater than the widely used dehydroergosterol probe, is combined with resistance to photobleaching in solution and in human fibroblasts and an exceptionally large Stokes-like shift of ∼150−200 nm. The photophysical properties of the probe have been studied experimentally and computationally, suggesting an intersystem crossing to the triplet excited state with subsequent phosphorescent decay. Molecular dynamics simulations show a similar binding mode of cholesterol and the azasterol probe to NPC proteins, demonstrating the structural similarity of the probe to cholesterol.

α-Cyanostilbene: a multifunctional spectral engineering motif

“…11 However, calculation of k nr using the FGR formalism is applicable only for structurally rigid molecular systems, in which the geometrical fluctuations are expected to be small upon photoexcitation, whereas it fails to cover p-frameworks enduring significant structural dislocations. Besides RIM characteristics, other mechanistic findings include E/Z isomerization, excited-state twisting, bond-stretching, ring puckering, and excited-state intramolecular proton transfer (ESIPT) [12][13][14][15][16] also significantly contribute to the aggregate emission. Thus, based on the abovementioned reasons, it is impossible to disentangle the emission of aggregates only from the RIM mechanism.…”