A photo-SAR study of photoswitchable azobenzene tubulin-inhibiting antimitotics identifying a general method for near-quantitative photocontrol

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Martin Reynders - (Author)
  • Małgorzata Garścia - (Author)
  • Adrian Müller-Deku - (Author)
  • Maximilian Wranik - (Author)
  • Kristina Krauskopf - (Author)
  • Luis de la Osa de la Rosa - (Author)
  • Konstantin Schaffer - (Author)
  • Anna Jötten - (Author)
  • Alexander Rode - (Author)
  • Valentin Stierle - (Author)
  • Yvonne Kraus - (Author)
  • Benedikt Baumgartner - (Author)
  • Ahmed Ali - (Author)
  • Andrei Bubeneck - (Author)
  • Trina Seal - (Author)
  • Michel O. Steinmetz - (Author)
  • Philipp Paulitschke - (Author)
  • Oliver Thorn-Seshold - , Ludwig Maximilian University of Munich (Author)

Abstract

Azobenzene analogues of the tubulin polymerisation inhibitor combretastatin A4 (PSTs) were previously developed to optically control microtubule dynamics in living systems, with subsecond response time and single-cell spatial precision, by reversible in situ photoswitching of their bioactivity with near-UV/visible light. First-generation PSTs were sufficiently potent and photoswitchable for use in live cells and embryos. However, the link between their seconds-scale and hours-scale bioactivity remained untested. Furthermore, the scope for modifications to tune their photo-structure-activity-relationship or expand their function was unknown. Here, we used large-field-of-view, long-term tandem photoswitching/microscopy to reveal the temporal onset of cytostatic effects. We then synthesised a panel of novel PSTs exploring structural variations that tune photoresponse wavelengths and lipophilicity, identifying promising blue-shifted analogues that are better-compatible with GFP/YFP imaging. Taken together, these results can guide new design and applications for photoswitchable microtubule inhibitors. We also identified tolerated sites for linkers to attach functional cargos; and we tested fluorophores, aiming at RET isomerisation or reporter probes. Instead we found that these antennas greatly enhance long-wavelength single-photon photoisomerisation, by an as-yet un-explored mechanism, that can now drive general progress towards near-quantitative long-wavelength photoswitching of photopharmaceuticals in living systems, with minimal molecular redesign and broad scope.

Details

Original languageEnglish
Pages (from-to)12301-12309
Number of pages9
JournalChemical science
Volume15
Issue number31
Publication statusPublished - 2 Jul 2024
Peer-reviewedYes
Externally publishedYes

External IDs

Scopus 85198643130

Keywords