Potent hemithioindigo-based antimitotics photocontrol the microtubule cytoskeleton in cellulo

• DOI: 10.3762/bjoc.16.14
• Publication Date: 2020-01-27T09:44:00Z
• Authors: Alexander Sailer; Franziska Ermer; Yvonne Kraus; Rebekkah Bingham; Ferdinand H Lutter; Julia Ahlfeld; Oliver Thorn-Seshold
• Keywords: 0301 basic medicine; 03 medical and health sciences; QD241-441; photoswitch; antimitotics; hemithioindigo; Science; Q; Organic chemistry; cytoskeleton; photopharmacology; Full Research Paper

Background: Hemithioindigo is a promising molecular photoswitch that has only recently been applied as photoswitchable pharmacophore for control over bioactivity in cellulo. Uniquely, contrast to other photoswitches have biology, the pseudosymmetric hemithioindigo scaffold allowed creation of both dark-active and lit-active photopharmaceuticals same binding site by priori design. However, potency previous not optimal their translation biological models. Results: Inspired structure tubulin-inhibiting indanones, we created hemithioindigo-based indanone-like tubulin inhibitors (HITubs) optimised cellular antimitotic photopharmaceuticals. These HITubs feature reliable robust visible-light photoswitching high fatigue resistance. The use also permitted us employ para-hydroxyhemistilbene motif, structural which denied most azobenzenes due negligibly short lifetimes metastable Z-isomers, proved crucial enhancing photoswitchability. were ten times more potent than previously reported photopharmaceutical antimitotics series cell-free assays, photocontrol polymerisation, microtubule (MT) network structure, cell cycle, survival. Conclusions: represent powerful addition growing toolbox reagents MT cytoskeleton research. Additionally, allows substituent patterns inaccessible majority current photopharmaceuticals, wider adoption may significantly expand scope vivo targets addressable photopharmacology.