title: Synthesis and evaluation of azetidinone analogues of combretastatin A-4 as tubulin targeting agents.
abstract: The synthesis and antiproliferative activity of a new series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. These novel compounds are also substituted at position 3 of the β-lactam ring with an aryl ring. A number of analogues showed potent nanomolar activity in human MCF-7 and MDA-MB-231 breast cancer cell lines, displayed in vitro inhibition of tubulin polymerization, and did not cause significant cytotoxicity in normal murine breast epithelial cells. 4-(4-Methoxyaryl)-substituted compound 32, 4-(3-hydroxy-4-methoxyaryl)-substituted compounds 35 and 41, and the 3-(4-aminoaryl)-substituted compounds 46 and 47 displayed the most potent antiproliferative activity of the series. β-Lactam 41 in particular showed subnanomolar activity in MCF-7 breast cancer cells (IC₅₀= 0.8 nM) together with significant in vitro inhibition of tubulin polymerization and has been selected for further biochemical assessment. These novel β-lactam compounds are identified as potentially useful scaffolds for the further development of antitumor agents that target tubulin.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Niamh M
authors.initials: NM
authors.lastname: O'Boyle
authors.forename: Miriam
authors.initials: M
authors.lastname: Carr
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Greene
authors.forename: Orla
authors.initials: O
authors.lastname: Bergin
authors.forename: Seema M
authors.initials: SM
authors.lastname: Nathwani
authors.forename: Thomas
authors.initials: T
authors.lastname: McCabe
authors.forename: David G
authors.initials: DG
authors.lastname: Lloyd
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Meegan
mesh_terms: D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001384:Azetidines; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C058728:fosbretabulin