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

Sigrid Verhasselt (UGent) , Bart Roman (UGent) , Olivier De Wever (UGent) , Kristof Van Hecke (UGent) , Rik Van Deun (UGent) , Marc Bracke (UGent) and Christian Stevens (UGent)
(2017) ORGANIC & BIOMOLECULAR CHEMISTRY. 15(9). p.2104-2118
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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.
Keywords
CANCER-CELLS, BLUE-LIGHT, BLEBBISTATIN, MECHANISM, MIGRATION, INVASION, HEARTS, MUSCLE

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Chicago
Verhasselt, Sigrid, Bart Roman, Olivier De Wever, Kristof Van Hecke, Rik Van Deun, Marc Bracke, and Christian Stevens. 2017. “Discovery of (S)-3′-hydroxyblebbistatin and (S)-3′-aminoblebbistatin : Polar Myosin II Inhibitors with Superior Research Tool Properties.” Organic & Biomolecular Chemistry 15 (9): 2104–2118.
APA
Verhasselt, S., Roman, B., De Wever, O., Van Hecke, K., Van Deun, R., Bracke, M., & Stevens, C. (2017). Discovery of (S)-3′-hydroxyblebbistatin and (S)-3′-aminoblebbistatin : polar myosin II inhibitors with superior research tool properties. ORGANIC & BIOMOLECULAR CHEMISTRY, 15(9), 2104–2118.
Vancouver
1.
Verhasselt S, Roman B, De Wever O, Van Hecke K, Van Deun R, Bracke M, et al. Discovery of (S)-3′-hydroxyblebbistatin and (S)-3′-aminoblebbistatin : polar myosin II inhibitors with superior research tool properties. ORGANIC & BIOMOLECULAR CHEMISTRY. 2017;15(9):2104–18.
MLA
Verhasselt, Sigrid, Bart Roman, Olivier De Wever, et al. “Discovery of (S)-3′-hydroxyblebbistatin and (S)-3′-aminoblebbistatin : Polar Myosin II Inhibitors with Superior Research Tool Properties.” ORGANIC & BIOMOLECULAR CHEMISTRY 15.9 (2017): 2104–2118. Print.
@article{8514040,
  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.},
  author       = {Verhasselt, Sigrid and Roman, Bart and De Wever, Olivier and Van Hecke, Kristof and Van Deun, Rik and Bracke, Marc and Stevens, Christian},
  issn         = {1477-0520},
  journal      = {ORGANIC \& BIOMOLECULAR CHEMISTRY},
  keyword      = {CANCER-CELLS,BLUE-LIGHT,BLEBBISTATIN,MECHANISM,MIGRATION,INVASION,HEARTS,MUSCLE},
  language     = {eng},
  number       = {9},
  pages        = {2104--2118},
  title        = {Discovery of (S)-3{\textquotesingle}-hydroxyblebbistatin and (S)-3{\textquotesingle}-aminoblebbistatin : polar myosin II inhibitors with superior research tool properties},
  url          = {http://dx.doi.org/10.1039/c7ob00006e},
  volume       = {15},
  year         = {2017},
}

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