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United States Department of Agriculture

Agricultural Research Service

Title: Antineoplastic agents 552. Oxidation of combretastatin A-1: Trapping the o-Quinone intermediate considered metabolic product of the corresponding phosphate prodrug

Authors
item Pettit, George - ARIZONA STATE UNIVERSITY
item Thornhill, Andrew - ARIZONA STATE UNIVERSITY
item Moser, Bryan
item Hogan, Fiona - ARIZONA STATE UNIVERSITY

Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 20, 2008
Publication Date: August 27, 2008
Citation: Pettit, G.R., Thornhill, A.J., Moser, B.R., Hogan, F. 2008. Antineoplastic agents 552. Oxidation of combretastatin A-1: Trapping the o-Quinone intermediate considered metabolic product of the corresponding phosphate prodrug. Journal of Natural Products. 71:1561-1563.

Interpretive Summary: Cancer affects millions of people throughout the world, often with disastrous consequences. A promising approach to uncovering cures for this dreaded disease is that of natural products chemistry whereby leads are developed through examination of the chemical constituents of plants and other organisms. One such chemical constituent, combretastatin A-1, was isolated from the South African willow tree Combretum caffrum and was found to possess promising anti-cancer properties. However, combretastatin A-1 undergoes chemical degradation relatively quickly and consequently looses its anti-cancer properties. Therefore, we set out to modify the chemical structure of combretastatin A-1 to impart improved stability without negatively affecting the anti-cancer properties of the original structure. We found that modification improved stability, as hoped, but the anti-cancer properties were slightly diminished in comparison to the original structure.

Technical Abstract: The very unstable (< 10 min at rt) o-quinone derived from the vicinol diphenol anticancer drug combretastatin A-1 has been obtained by careful oxidation with NaIO4 employing tetrabutylammonium bromide in water/dichloromethane. Immediate reaction with phenylenediamine allowed o-quinone 5 to be trapped as the stable phenazine derivative. For further confirmation, 5 was also captured as a dimethoxyphenylenediamine-derived phenazine. Both phenazines 7 and 11 significantly inhibited (ED50 ~ 0.2 :g/mL) growth of the murine P388 lymphocytic leukemia cell line and provided a new SAR insight in the combretastatin series of naturally occurring anticancer drugs. The current status of potassium combretastatin A-1 phosphate prodrug with respect to preclinical development and Phase I cancer clinical trials has been summarized.

Last Modified: 10/31/2014
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