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Potent Hemithioindigo-Based Antimitotics Photocontrol the Microtubule Cytoskeleton in Cellulo

submitted on 30.07.2019, 20:31 and posted on 31.07.2019, 16:02 by Alexander Sailer, Franziska Ermer, Yvonne Kraus, Rebekkah Bingham, Ferdinand H. Lutter, Julia Ahlfeld, Oliver Thorn-Seshold

Hemithioindigo is a promising molecular photoswitch that has only recently been applied as a photoswitchable pharmacophore for control over bioactivity in cellulo. Uniquely, in contrast to other photoswitches that have been applied to biology, the pseudosymmetric hemithioindigo scaffold has allowed the creation of both dark-active and lit-active photopharmaceuticals for the same binding site by a priori design. However, the potency of previous hemithioindigo photopharmaceuticals has not been optimal for their translation to other biological models.

Inspired by the structure of tubulin-inhibiting indanones, we created hemithioindigo-based indanone-like tubulin-inhibitors (HITubs) and optimised their cellular potency as antimitotic photopharmaceuticals. These HITubs feature reliable and robust visible light photoswitching and high fatigue resistance. The use of the hemithioindigo scaffold also permitted us to employ a para-hydroxy hemistilbene motif – a structural feature which is denied to most azobenzenes due to the negligibly short lifetimes of their metastable Z isomers – which proved crucial to enhancing the potency and photoswitchability. The HITubs are ten times more potent than previously reported hemithioindigo photopharmaceutical antimitotics in a series of cell-free and cellular assays, and allowed robust photocontrol over tubulin polymerisation, microtubule network structure, cell cycle and cell survival.

We conclude that HITubs represent a powerful addition to the growing toolbox of photopharmaceutical reagents for microtubule cytoskeleton research. Additionally, as the hemithioindigo scaffold allows photoswitchable bioactivity for substituent patterns inaccessible to the majority of current photopharmaceuticals, wider adoption of the hemithioindigo scaffold may significantly expand the scope cellular and in vivo targets addressable by photopharmacology.


SFB TRR 152 project P24 number 239283807

DFG SFB1032 Nanoagents for Spatiotemporal Control project B09

DFG Emmy Noether


Email Address of Submitting Author


Ludwig-Maximilians University, Munich



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest.

Version Notes

version three point three