Short synthesis of a broadly Reactive, cell permeable serine hydrolase Fluorophosphonate-Alkyne probe

Srihari Konduri; Joshua Schweer; Dionicio Siegel

doi:10.1016/j.bmcl.2023.129434

Short synthesis of a broadly Reactive, cell permeable serine hydrolase Fluorophosphonate-Alkyne probe

Bioorg Med Chem Lett. 2023 Oct 15:95:129434. doi: 10.1016/j.bmcl.2023.129434. Epub 2023 Aug 7.

Authors

Srihari Konduri¹, Joshua Schweer¹, Dionicio Siegel²

Affiliations

¹ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0934, United States.
² Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0934, United States. Electronic address: drsiegel@ucsd.edu.

PMID: 37557924
DOI: 10.1016/j.bmcl.2023.129434

Abstract

An abbreviated synthesis of the cell permeable fluorophosphonate-alkyne probe (FP-alkyne) for the broad assessment of serine hydrolase activity has been developed. While FP-alkyne has proven pivotal in numerous chemical biology studies access has relied on a lengthy preparation over nine steps. We have developed a four-step synthesis, starting from commercially available compounds, with three purification steps to provide a new expedited route allowing easy access to a useful tool compound for exploring serine hydrolases chemistry and biology. This route was used in our own studies to generate FP-alkyne which in turn was used to identify the enzyme responsible for Fatty Acid Esters of Hydroxy Fatty Acids (FAHFA) biosynthesis. The use of this route can enable the syntheses of new tool compounds in addition to improving accessibility to FP-alkyne.

Keywords: Alkyne; Covalent; FP-Alkyne; Fluorophosphonate; Pan reactive; Probe; Route development; Serine hydrolase; Synthesis; Tool compound.