Development of Synthetic Methodology Suitable for the Radiosynthesis of Combretastatin A-1 (CA1) and Its Corresponding Prodrug CA1P

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• 作者：Anupama Shirali ; Madhavi Sriram ; John J. Hall ; Benson L. Nguyen ; Rajsekhar Guddneppanavar ; Mallinath B. Hadimani ; J. Freeland Ackley ; Rogelio Siles ; Christopher J. Jelinek ; Phyllis Arthasery ; Rodney C
• 刊名：Journal of Natural Products
• 出版年：2009
• 出版时间：March 27, 2009
• 年：2009
• 卷：72
• 期：3
• 页码：414-421
• 全文大小：218K
• 年卷期：v.72,no.3(March 27, 2009)
• ISSN：1520-6025

文摘

Synthetic methodology has been established suitable for the preparation of combretastatin A-1 (CA1) and its corresponding phosphate prodrug salt (CA1P) in high specific activity radiolabeled form. Judicious selection of appropriate phenolic protecting groups to distinguish positions on the A-ring from the B-ring of the stilbenoid was paramount for the success of this project. Methylation of the C-4′ phenolic moiety by removal of the tert-butyldimethylsilyl protecting group in the presence of methyl iodide was accomplished in excellent yield without significant Z to E isomerization. This step (carried out with ¹²C-methyl iodide as proof of concept in this study) represents the process in which a ¹⁴C radioisotope could be incorporated in an actual radiosynthesis. CA1 is a natural product isolated from the African bush willow tree (Combretum caffrum) that has important medicinal value due, in part, to its ability to inhibit tubulin assembly. As a prodrug, CA1P (OXi4503) is in human clinical trials as a vascular disrupting agent.