Synthesis of C-ring-modified blebbistatin derivatives and evaluation of their myosin II ATPase inhibitory potency

Bioorg Med Chem Lett. 2018 Jul 15;28(13):2261-2264. doi: 10.1016/j.bmcl.2018.05.041. Epub 2018 May 22.

Abstract

(S)-Blebbistatin is a micromolar myosin II ATPase inhibitor that is extensively used in research. In search of analogs with improved potency, we have synthesized for the first time C-ring modified analogs. We introduced hydroxymethyl or allyloxymethyl functionalities in search of additional favorable interactions and a more optimal filling of the binding pocket. Unfortunately, the resulting compounds did not significantly inhibit the ATPase activity of rabbit skeletal-muscle myosin II. This and earlier reports suggest that rational design of potent myosin II inhibitors based on the architecture of the blebbistatin binding pocket is an ineffective strategy.

Keywords: ATPase; Blebbistatin; C-ring; Inhibitor; Myosin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Drug Design
  • Enzyme Assays
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Rabbits
  • Skeletal Muscle Myosins / antagonists & inhibitors*
  • Skeletal Muscle Myosins / chemistry
  • Stereoisomerism

Substances

  • Enzyme Inhibitors
  • Heterocyclic Compounds, 4 or More Rings
  • blebbistatin
  • Skeletal Muscle Myosins