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

Research output: Contribution to journalArticle

34 Citations (Scopus)

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

Fingerprint

Prodrugs
Blood Vessels
Salts
Phosphates
Phenol
Tumors
Bearings (structural)
Tubulin Modulators
Neoplasms
Colchicine
Tubulin
Biological Products
Scaffolds
Doppler Ultrasonography
Antineoplastic Agents
SCID Mice
Ultrasonics
Cells
Color
Prostate

ASJC Scopus subject areas

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

Cite this

Hadimani, M. B., MacDonough, M. T., Ghatak, A., Strecker, T. E., Lopez, R., Sriram, M., ... 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

Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent. / Hadimani, Mallinath B.; MacDonough, Matthew T.; Ghatak, Anjan; Strecker, Tracy E.; Lopez, Ramona; Sriram, Madhavi; Nguyen, Benson L.; Hall, John J.; Kessler, Raymond J.; Shirali, Anupama R.; Liu, Li; Garner, Charles M.; Pettit, George R.; Hamel, Ernest; Chaplin, David J.; Mason, Ralph P.; Trawick, Mary Lynn; Pinney, Kevin G.

In: Journal of Natural Products, Vol. 76, No. 9, 27.09.2013, p. 1668-1678.

Research output: Contribution to journalArticle

Hadimani, MB, MacDonough, MT, Ghatak, A, Strecker, TE, Lopez, R, Sriram, M, Nguyen, BL, Hall, JJ, Kessler, RJ, Shirali, AR, Liu, L, Garner, CM, Pettit, GR, Hamel, E, Chaplin, DJ, Mason, RP, Trawick, ML & Pinney, KG 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, vol. 76, no. 9, pp. 1668-1678. https://doi.org/10.1021/np400374w
Hadimani, Mallinath B. ; MacDonough, Matthew T. ; Ghatak, Anjan ; Strecker, Tracy E. ; Lopez, Ramona ; Sriram, Madhavi ; Nguyen, Benson L. ; Hall, John J. ; Kessler, Raymond J. ; Shirali, Anupama R. ; Liu, Li ; Garner, Charles M. ; Pettit, George R. ; Hamel, Ernest ; Chaplin, David J. ; Mason, Ralph P. ; Trawick, Mary Lynn ; Pinney, Kevin G. / Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent. In: Journal of Natural Products. 2013 ; Vol. 76, No. 9. pp. 1668-1678.
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