Design, Synthesis, and Evaluation of a Luminescent Cholesterol Mimic

Emily M. Work, Guillermo Ferraudi, Luke Kiefer, Gang Liu, Michael Grigalunas, Atul Bhardwaj, Rasmin Kaur, Janel M. Dempsey, Daniel Wüstner, Paul Helquist, Olaf Wiest*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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 ∼32-times 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.

Original languageEnglish
JournalJournal of Organic Chemistry
Volume86
Issue number2
Pages (from-to)1612–1621
ISSN0022-3263
DOIs
Publication statusPublished - 15. Jan 2021

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