Synthesis and structure-activity relationship of griseofulvin analogues as inhibitors of centrosomal clustering in cancer cells

J Med Chem. 2009 May 28;52(10):3342-7. doi: 10.1021/jm801517j.


Griseofulvin was identified as an inhibitor of centrosomal clustering in a recently developed assay. Centrosomal clustering is an important cellular event that enables bipolar mitosis for cancer cell lines harboring supernumerary centrosomes. We report herein the synthesis and SAR of 34 griseofulvin analogues as inhibitors of centrosomal clustering. The variations in the griseofulvin structure cover five positions, namely the 4, 5, 2', 3', and 4' positions. Modification of the 4 and 5 positions affords inactive molecules. The enol ether must be at the 2' position, and the 4' position needs to be sp(2) hybridized. The most active analogues were the 2'-benzyloxy and 2'-(4-methylbenzyloxy) analogues as well as the oxime of the former with a 25-fold increase of activity compared to griseofulvin. Comparison of the results obtained in this work with prior reported growth inhibition data for dermatophytic fungi showed both similarities and differences.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Centrosome / drug effects*
  • Centrosome / metabolism
  • Centrosome / ultrastructure
  • Griseofulvin / analogs & derivatives*
  • Griseofulvin / chemical synthesis
  • Griseofulvin / pharmacology
  • Humans
  • Mitosis
  • Neoplasms / pathology*
  • Oximes
  • Structure-Activity Relationship


  • Antifungal Agents
  • Antineoplastic Agents
  • Oximes
  • Griseofulvin