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

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 (IC₅₀ = 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.

• Authors: 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
• Journal: Journal of natural products (J Nat Prod) Vol. 76 Issue 9 Pg. 1668-78 (Sep 27 2013) ISSN: 1520-6025 [Electronic] United States
• PMID: 24016002 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Bibenzyls
• Indoles
• OXi8007 compound
• Organophosphates
• Prodrugs
• Stilbenes
• Tubulin
• combretastatin
• fosbretabulin
• Colchicine

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Bibenzyls (chemistry, pharmacology)
• Colchicine (pharmacology)
• Drug Screening Assays, Antitumor
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Inhibitory Concentration 50
• Male
• Mice
• Molecular Structure
• Organophosphates (chemical synthesis, chemistry, pharmacology)
• Prodrugs (pharmacology)
• Prostatic Neoplasms (drug therapy)
• Stilbenes
• Structure-Activity Relationship
• Tubulin (drug effects, metabolism)