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20201204_Propofol_Analogs_with_suppl.pdf (1.83 MB)

Efficient and Flexible Synthesis of New Photoactivatable Propofol Analogs

preprint
submitted on 04.12.2020, 20:15 and posted on 07.12.2020, 10:33 by Kenneth Skinner, Joseph Wzorek, Daniel Kahne, Rachelle Gaudet
Propofol is a widely used general anesthetic, which acts by binding to and modulating several neuronal ion channels. We describe the synthesis of photoactivatable propofol analogs functionalized with an alkyne handle for bioorthogonal chemistry. Such tools are useful for detecting and isolating photolabeled proteins. We designed expedient and flexible synthetic routes to three new diazirine-based crosslinkable propofol derivatives, two of which have alkyne handles. As a proof of principle, we show that these compounds activate heterologously expressed Transient Receptor Potential Ankyrin 1 (TRPA1), a key ion channel of the pain pathway, with a similar potency as propofol in fluorescence-based functional assays. This work demonstrates that installation of the crosslinkable and clickable group on a short nonpolar spacer at the para position of propofol does not affect TRPA1 activation, supporting the utility of these chemical tools in identifying and characterizing potentially druggable binding sites in propofolinteracting proteins.

Funding

Direct Identification of Druggable Sites in TRPA1

American Heart Association

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NSF Graduate Research Fellowship DGE-1144152

Ford Foundation Fellowship

History

Email Address of Submitting Author

gaudet@mcb.harvard.edu

Institution

Harvard University

Country

United States

ORCID For Submitting Author

0000-0002-9177-054X

Declaration of Conflict of Interest

We declare that we have no conflict of interest.

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