Insights into the myosin II inhibitory potency of A-ring-modified (S)-blebbistatin analogs

Sigrid Verhasselt; Christian V Stevens; Tom Van den Broecke; Marc E Bracke; Bart I Roman

doi:10.1016/j.bmcl.2017.05.008

Insights into the myosin II inhibitory potency of A-ring-modified (S)-blebbistatin analogs

Bioorg Med Chem Lett. 2017 Jul 1;27(13):2986-2989. doi: 10.1016/j.bmcl.2017.05.008. Epub 2017 May 4.

Authors

Sigrid Verhasselt¹, Christian V Stevens², Tom Van den Broecke¹, Marc E Bracke³, Bart I Roman⁴

Affiliations

¹ SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Campus Coupure, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.
² SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Campus Coupure, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. Electronic address: [email protected].
³ Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
⁴ SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Campus Coupure, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. Electronic address: [email protected].

PMID: 28512027
DOI: 10.1016/j.bmcl.2017.05.008

Abstract

Myosin II is an interesting target for therapeutic intervention, as it is involved in a large number of motility-based diseases. (S)-Blebbistatin is a known micromolar inhibitor of this protein. A new series of (S)-blebbistatin derivatives with a modified A-ring was synthesized and the myosin II inhibitory properties were evaluated in vitro. In this way, we gained insight into the influence of structural modifications in this part of the scaffold on myosin II inhibitory potency. Our results indicate there are few possibilities for potency enhancement via ring A modification of the blebbistatin scaffold.

Keywords: A-ring modification; Blebbistatin; Myosin II.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dictyostelium / enzymology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Heterocyclic Compounds, 4 or More Rings / chemical synthesis
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Molecular Structure
Myosin Type II / antagonists & inhibitors*
Myosin Type II / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Heterocyclic Compounds, 4 or More Rings
blebbistatin
Myosin Type II