Self-reporting styrylthiazolium photopharmaceuticals: mitochondrial localisation as well as SAR drive biological activity

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Li Gao - (Author)
  • Yvonne Kraus - (Author)
  • Andrea Stegner - (Author)
  • Thomas Wein - (Author)
  • Constanze Heise - (Author)
  • Leonie von Brunn - (Author)
  • Elena Fajardo-Ruiz - (Author)
  • Julia Thorn-Seshold - (Author)
  • Oliver Thorn-Seshold - , Ludwig Maximilian University of Munich (Author)

Abstract

Novel photoswitches offering features complementary to the well-established azobenzenes are increasingly driving high-precision research in cellular photopharmacology. Styrylthiazolium (StyTz) and styrylbenzothiazolium (StyBtz) are cellularly untested E/Z-isomerisation photoswitches which are nearly isosteric to azobenzenes, but have distinct properties: including ca. 60 nm red-shifted π → π* absorption, self-reporting fluorescence, Z → E relaxation on typical biological timescales, and decent solubility (positive charge). We tested StyTz and StyBtz for their potential as photopharmaceutical scaffolds, by applying them to photocontrol microtubule dynamics. They light-specifically disrupt microtubule network architecture and block cell proliferation: yet, testing lead compound StyBtz2 for its molecular mechanism of action showed that it did not inhibit microtubule dynamics. Using its self-reporting fluorescence, we tracked its localisation in live cells and observed accumulation of E-StyBtz2 into mitochondria; during prolonged illumination, it was released into the cytosol, and blebbing and cell death were observed. We interpret this as light-dependent rupturing of mitochondria on acute timescales. We conclude that StyTz/StyBtz can be interesting photopharmaceutical scaffolds for addressing mitochondrial, rather than cytosolic, targets.

Details

Original languageEnglish
Pages (from-to)7787-7794
Number of pages8
JournalOrganic & biomolecular chemistry
Volume20
Issue number39
Publication statusPublished - 26 Sept 2022
Peer-reviewedYes
Externally publishedYes

External IDs

Scopus 85139739697

Keywords