| Title | Synthesis and Structure-Activity Relationship of Griseofulvin Analogues as Inhibitors of Centrosomal Clustering in Cancer Cells. | | Author(s) | Rønnest MH, Rebacz B, Markworth L, Terp AH, Larsen TO, Krämer A, Clausen MH | | Institution | Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 201, DK-2800 Kgs. Lyngby, Denmark, Center for Microbial Biotechnology, Department of Systems Biology, Søltofts Plads, Building 221, DK-2800 Kgs. Lyngby, Denmark, Clinical Cooperation Unit for Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Im Neuenheimer Feld 280 (TP4) 69120 Heidelberg, Germany. | | Source | J Med Chem 2009 Apr 29. | | Abstract | 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19402668 |
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