Synthesis and evaluation of azetidinone analogues of combretastatin A-4 as tubulin targeting agents
Date
2010
Authors
O'Boyle, N.M.
Carr, M.
Greene, L.M.
Bergin, O.
Nathwani, S.M.
McCabe, T.
Lloyd, D.G.
Zisterer, D.M.
Meegan, M.J.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Journal of Medicinal Chemistry, 2010; 53(24):8569-8584
Statement of Responsibility
Conference Name
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.
School/Discipline
Dissertation Note
Provenance
Description
Link to a related website: http://www.tara.tcd.ie/bitstream/2262/81779/1/1.%20MJM%20Manuscript%20final%20draft.pdf, Open Access via Unpaywall
Access Status
Rights
Copyright 2010 American Chemical Society