Discovery of (S)-3'-hydroxyblebbistatin and (S)-3'-aminoblebbistatin: polar myosin II inhibitors with superior research tool properties

  • Org Biomol Chem. 2017 Mar 1;15(9):2104-2118. doi: 10.1039/c7ob00006e.
Sigrid Verhasselt  1 ,  Bart I Roman  1 ,  Olivier De Wever  2 ,  Kristof Van Hecke  3 ,  Rik Van Deun  3 ,  Marc E Bracke  2 ,  Christian V Stevens  1
Affiliations
  • 1. SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. [email protected] [email protected].
  • 2. Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
  • 3. Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281 S3, 9000 Ghent, Belgium.
PMID: 28220174 DOI: 10.1039/c7ob00006e
Abstract

In search of Myosin II inhibitors with superior research tool properties, a chemical optimization campaign of the blebbistatin scaffold was conducted in this paper. (S)-Blebbistatin is the best known small-molecule inhibitor of Myosin II ATPase activity. Unfortunately, as a research tool this compound has several deficiencies: it is photolabile and (photo)toxic, has low water solubility, and its (fluorescent) precipitates interfere in (fluorescence) readouts. In view of obtaining tool compounds with improved properties, both enantiomers of a series of D-ring modified polar analogs were prepared. We identified (S)-3'-hydroxyblebbistatin (S)-2 and (S)-3'-aminoblebbistatin (S)-3 as two Myosin II inhibitors with a 30-fold higher water solubility than (S)-blebbistatin. These molecules furthermore do not cause interference in (fluorescence) readouts. (S)-2 and (S)-3 thus are superior alternatives to (S)-blebbistatin as research tools to study Myosin II.

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