A Photocleavable Masked Nuclear‐Receptor Ligand Enables Temporal Control of C. elegans Development

Abstract

C. elegans development and lifespan are controlled by the nuclear hormone receptor DAF-12, an important model for vertebrate vitamin D and liver-X receptors. Similar to its mammalian homologs, DAF-12 function is regulated by bile acid-like steroidal ligands, the dafachronic acids; however, tools for investigating their biosynthesis and function in vivo are lacking. We report a flexible synthesis for DAF-12 ligands and masked ligand derivatives that enable precise temporal control of DAF-12 function. For ligand masking, we introduce photocleavable amides of 5-methoxy-N-methyl-2-nitroaniline (MMNA). MMNA-masked ligands are bioavailable and after incorporation into the worm can be used to trigger expression of DAF-12 target genes and initiate development from dauer larvae to adults by brief, innocuous UV-irradiation. In-vivo release of DAF-12 ligands and other small-molecule signals using MMNA-based probes will enable functional studies with precise spatial and temporal resolution.

Stereochemical editing logic powered by the epimerization of unactivated tertiary stereocenters

“…The same logic can be applied in the synthesis of allocholate derivative (+)-45b, which shares a common scaffold with various bioactive compounds and has found application in supramolecular systems (35,36). Starting from (+)-cholic acid (44), a one-pot esterificationoxidation sequence afforded trione (+)-45a in 81% yield.…”

Straightforward Synthesis of Chiral Terpenoid Building Blocks by Ru-Catalyzed Enantioselective Hydrogenation

“…Finally, determination of relative and absolute configuration was accomplished by the transformation of fragment 1a into diol 11a , whose enantiomer 11d is already described (Scheme ). , Configuration of C6 stereocenters of isomers 1b–1d was set by the substrate, that is, ( R ) or ( S )-citronellol, while the absolute configuration of the C2 stereocenter was predicted by the catalyst absolute configuration according to literature examples . Relative configuration of 11a was confirmed by comparison of 13 C NMR spectroscopy with its previously described enantiomer 11d .…”

“…The experimental protocol was inspired by previous results provided by scientific literature. Most examples of enantioselective hydrogenation of 2-methyl-3-alkyl substrates were performed on tiglic acid or other achiral substrates, but examples of Ru-catalyzed enantioselective hydrogenation of more complex, chiral substrates have also been reported. , …”

Small-molecule pheromones and hormones controlling nematode development

“…A photocleavable, masked derivative of Δ 7 -dafachronic acid has been synthesized that enables light-mediated release of the hormone into the worm. 83 This derivative could potentially be employed to study tissue-specific functions or biosynthetic steps of the dafachronic acids.…”