Synthesis of a 2-Aryl-3-aroyl Indole Salt (OXi8007) Resembling Combretastatin A-4 with Application as a Vascular Disrupting Agent

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• 作者：Mallinath B. Hadimani ; Matthew T. MacDonough ; Anjan Ghatak ; Tracy E. Strecker ; Ramona Lopez ; Madhavi Sriram ; Benson L. Nguyen ; John J. Hall ; Raymond J. Kessler ; Anupama R. Shirali ; Li Liu ; Charles M. Garner ; George R. Pettit ; Ernest Hamel ; David J. Chaplin ; Ralph P. Mason ; Mary Lynn Trawick ; Kevin G. Pinney
• 刊名：Journal of Natural Products
• 出版年：2013
• 出版时间：September 27, 2013
• 年：2013
• 卷：76
• 期：9
• 页码：1668-1678
• 全文大小：573K
• 年卷期：v.76,no.9(September 27, 2013)
• ISSN：1520-6025

文摘

The natural products colchicine and combretastatin A-4 are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI₅₀ = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC₅₀ = 1.1 渭M) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent that may prove useful for the treatment of cancer.