title: Discovery of (S)-3'-hydroxyblebbistatin and (S)-3'-aminoblebbistatin: polar myosin II inhibitors with superior research tool properties.
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.
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. bart1.roman@ugent.be chris.stevens@ugent.be.
authors.forename: Sigrid
authors.identifier: http://orcid.org/0000-0002-2744-8951
authors.initials: S
authors.lastname: Verhasselt
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. bart1.roman@ugent.be chris.stevens@ugent.be.
authors.forename: Bart I
authors.identifier: http://orcid.org/0000-0002-9407-6721
authors.initials: BI
authors.lastname: Roman
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
authors.affiliation: Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281 S3, 9000 Ghent, Belgium.
authors.forename: Kristof
authors.identifier: http://orcid.org/0000-0002-2455-8856
authors.initials: K
authors.lastname: Van Hecke
authors.affiliation: Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281 S3, 9000 Ghent, Belgium.
authors.forename: Rik
authors.identifier: http://orcid.org/0000-0001-7091-6864
authors.initials: R
authors.lastname: Van Deun
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Bracke
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. bart1.roman@ugent.be chris.stevens@ugent.be.
authors.forename: Christian V
authors.identifier: http://orcid.org/0000-0003-4393-5327
authors.initials: CV
authors.lastname: Stevens
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D024462:Myosin Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; C472645:blebbistatin; D024462:Myosin Type II