title: Synthesis and structure-activity relationship of griseofulvin analogues as inhibitors of centrosomal clustering in cancer cells.
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.
authors.affiliation: Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 201, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Mads H
authors.initials: MH
authors.lastname: Rønnest
authors.forename: Blanka
authors.initials: B
authors.lastname: Rebacz
authors.forename: Lene
authors.initials: L
authors.lastname: Markworth
authors.forename: Anette H
authors.initials: AH
authors.lastname: Terp
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Larsen
authors.forename: Alwin
authors.initials: A
authors.lastname: Krämer
authors.forename: Mads H
authors.initials: MH
authors.lastname: Clausen
mesh_terms: D000935:Antifungal Agents; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D006118:Griseofulvin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008938:Mitosis; D009369:Neoplasms / Q000473:pathology*; D010091:Oximes; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D010091:Oximes; D006118:Griseofulvin