Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent

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 Pettit, Ernest Hamel, David J. Chaplin, Ralph P. Mason, Mary Lynn Trawick, Kevin G. Pinney

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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 (IC 50 = 1.1 μM) 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.

Original languageEnglish (US)
Pages (from-to)1668-1678
Number of pages11
JournalJournal of Natural Products
Volume76
Issue number9
DOIs
StatePublished - Sep 27 2013

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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    Hadimani, M. B., MacDonough, M. T., Ghatak, A., Strecker, T. E., Lopez, R., Sriram, M., Nguyen, B. L., Hall, J. J., Kessler, R. J., Shirali, A. R., Liu, L., Garner, C. M., Pettit, G., Hamel, E., Chaplin, D. J., Mason, R. P., Trawick, M. L., & Pinney, K. G. (2013). Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent. Journal of Natural Products, 76(9), 1668-1678. https://doi.org/10.1021/np400374w