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

Gao, Li; Kraus, Yvonne; Stegner, Andrea; Wein, Thomas; Heise, Constanze; Brunn, Leonie von; Fajardo-Ruiz, Elena; Thorn-Seshold, Julia und Thorn-Seshold, Oliver (2022): Self-reporting styrylthiazolium photopharmaceuticals: mitochondrial localisation as well as SAR drive biological activity. In: Organic & Biomolecular Chemistry, Bd. 20, Nr. 39: S. 7787-7794

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 pi -> pi* 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department für Pharmazie - Zentrum für Pharmaforschung
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 1477-0520
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 400324123
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 201269156
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 239283807
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 426018126