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

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• 作者：Niamh M. O’ ; Boyle ; Miriam Carr ; Lisa M. Greene ; Orla Bergin ; Seema M. Nathwani ; Thomas McCabe ; David G. Lloyd ; Daniela M Zisterer ; Mary J. Meegan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：December 23, 2010
• 年：2010
• 卷：53
• 期：24
• 页码：8569-8584
• 全文大小：1410K
• 年卷期：v.53,no.24(December 23, 2010)
• ISSN：1520-4804

文摘

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.