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Issue 9, 2017
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Discovery of (S)-3′-hydroxyblebbistatin and (S)-3′-aminoblebbistatin: polar myosin II inhibitors with superior research tool properties

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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.

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

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Article information


Submitted
02 Jan 2017
Accepted
07 Feb 2017
First published
07 Feb 2017

Org. Biomol. Chem., 2017,15, 2104-2118
Article type
Paper

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

S. Verhasselt, B. I. Roman, O. De Wever, K. Van Hecke, R. Van Deun, M. E. Bracke and C. V. Stevens, Org. Biomol. Chem., 2017, 15, 2104
DOI: 10.1039/C7OB00006E

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