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

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 photoswitching of their bioactivity with near-UV/...

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Bibliographic Details
Published in:	Chemical science (Cambridge) Vol. 15; no. 31; pp. 12301 - 12309
Main Authors:	Reynders, Martin, Garścia, Małgorzata, Müller-Deku, Adrian, Wranik, Maximilian, Krauskopf, Kristina, de la Osa de la Rosa, Luis, Schaffer, Konstantin, Jötten, Anna, Rode, Alexander, Stierle, Valentin, Kraus, Yvonne, Baumgartner, Benedikt, Ali, Ahmed, Bubeneck, Andrei, Seal, Trina, Steinmetz, Michel O, Paulitschke, Philipp, Thorn-Seshold, Oliver
Format:	Journal Article
Language:	English
Published:	England Royal Society of Chemistry 07-08-2024 The Royal Society of Chemistry
Subjects:	Azo compounds Biological activity Chemical compounds Chemistry Isomerization Redesign
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Summary:	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 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Evotec GmbH, Neuried 82061, Germany. Current address: Ryvu Therapeutics, Leona Henryka Sternbacha 2, 30-394 Kraków, Poland.
ISSN:	2041-6520 2041-6539
DOI:	10.1039/d4sc03072a