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Synthesis and structure-activity relationship of griseofulvin analogues as inhibitors of centrosomal clustering in cancer cells.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2009 May 28; Vol. 52 (10), pp. 3342-7. - Publication Year :
- 2009
-
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.
- Subjects :
- Antifungal Agents
Antineoplastic Agents pharmacology
Carcinoma, Squamous Cell drug therapy
Carcinoma, Squamous Cell pathology
Cell Line, Tumor
Centrosome metabolism
Centrosome ultrastructure
Griseofulvin chemical synthesis
Griseofulvin pharmacology
Humans
Mitosis
Oximes
Structure-Activity Relationship
Antineoplastic Agents chemistry
Centrosome drug effects
Griseofulvin analogs & derivatives
Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 52
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19402668
- Full Text :
- https://doi.org/10.1021/jm801517j