Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

Authors

Niamh O'Boyle, Technological University DublinFollow
Miriam Carr, University of Dublin, Trinity CollegeFollow
Lisa M. Greene, University of Dublin, Trinity CollegeFollow
Orla Bergin, University College Dublin, Ireland
Seema M. Nathwani, University of Dublin, Trinity CollegeFollow
Thomas McCabe, University of Dublin, Trinity College
David G. Lloyd, University of Dublin, Trinity College
Daniela M. Zisterer, University of Dublin, Trinity College
Mary J. Meegan, University of Dublin, Trinity CollegeFollow

Document Type

Article

Rights

This item is available under a Creative Commons License for non-commercial use only

Disciplines

Organic Chemistry, Biochemistry and molecular biology

Publication Details

Journal of Medicinal Chemistry, December 2010, Vol. 53, No. 24, Pages 8569 – 8584

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 anti-proliferative activity of the series. β-Lactam 41 in particular showed sub-nanomolar 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 antitumour agents which target tubulin.

DOI

https://doi.org/10.1021/jm101115u

Recommended Citation

O'Boyle, N. et al (2010). Synthesis and evaluation of azetidinone analogues of combretastatin A-4 as tubulin targeting agents. Journal of Medicinal Chemistry, 53,(24), pp. 8569 – 8584. doi:10.1021/jm101115u