Title
Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents
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
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.
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
DOI
https://doi.org/10.1021/jm101115u
Publication Details
Journal of Medicinal Chemistry, December 2010, Vol. 53, No. 24, Pages 8569 – 8584