Discovery of tetrahydro-beta-carbolines as inhibitors of the mitotic kinesin KSP

Bioorg Med Chem. 2010 Jun 15;18(12):4167-77. doi: 10.1016/j.bmc.2010.05.024. Epub 2010 May 11.

Abstract

Inhibitors of kinesin spindle protein (KSP) are a promising class of anticancer agents that cause mitotic arrest in cells from a failure to form functional bipolar mitotic spindles. Here, we report the synthesis and biological evaluation of a novel series of tetrahydro-beta-carboline analogs based on the structure of the known KSP inhibitor HR22C16. Preferred compounds 11b, 12a and 19b were identified as potent inhibitors in a KSP ATPase assay with good anti-proliferative activity in A549 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Carbolines / chemical synthesis
  • Carbolines / chemistry*
  • Carbolines / pharmacology
  • Cell Line, Tumor
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology
  • Kinesins / antagonists & inhibitors*
  • Kinesins / metabolism
  • Phenols / chemistry
  • Phenols / pharmacology
  • Spindle Apparatus / enzymology*

Substances

  • 1-(3-hydroxyphenyl)-2-(4-aminobenzoyl)-6-chloro-1,2,3,4-tetrahydro-beta-carboline
  • 1-(3-hydroxyphenyl)-2-(beta-aminopropionyl)-8-chloro-1,2,3,4-tetrahydro-beta-carboline
  • 6-methyl-1-(indol-3-yl)-2-butyryl-1,2,3,4-tetrahydro-beta-carboline
  • Antineoplastic Agents
  • Carbolines
  • Enzyme Inhibitors
  • HR22C16
  • Indoles
  • Phenols
  • Kinesins