Synthetic studies on mitotic kinesin Eg5 inhibitors: synthesis and structure-activity relationships of novel 2,4,5-substituted-1,3,4-thiadiazoline derivatives

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3961-3. doi: 10.1016/j.bmcl.2014.06.034. Epub 2014 Jun 20.

Abstract

The 2,4,5-substituted-1,3,4-thiadiazoline derivative 1a has been identified as a new class of mitotic kinesin Eg5 inhibitor. With the aim of enhancement of the mitotic phase accumulation activity, structure optimization of side chains at the 2-, 4-, and 5-positions of the 1,3,4-thiadiazoline ring of 1a was performed. The introduction of sulfonylamino group at the side chain at the 5-position and bulky acyl group at the 2- and 4-position contributed to a significant increase in the mitotic phase accumulation activity and Eg5 inhibitory activity. As a result, a series of optically active compounds exhibited an increased antitumor activity in a human ovarian cancer xenograft mouse model that was induced by oral administration.

Keywords: Mitotic kinesin Eg5 inhibitor; Thiadiazoline derivatives.

MeSH terms

  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kinesins / antagonists & inhibitors*
  • Kinesins / metabolism
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiazolidines / chemical synthesis
  • Thiazolidines / chemistry
  • Thiazolidines / pharmacology*

Substances

  • Enzyme Inhibitors
  • KIF11 protein, human
  • Thiazolidines
  • Kinesins