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. 2008 Sep;71(9):1561-3.
doi: 10.1021/np800179g. Epub 2008 Aug 27.

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

George R Pettit  1 , Andrew J Thornhill, Bryan R Moser, Fiona Hogan
Affiliations

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

George R Pettit et al. J Nat Prod. 2008 Sep.

Abstract

The very unstable (<10 min at rt) o-quinone 5 derived from the vicinal diphenol anticancer drug combretastatin A-1 (1) has been obtained by careful oxidation with NaIO4 and tetrabutylammonium bromide in water/dichloromethane. Immediate reaction with phenylenediamine (6) allowed o-quinone 5 to be trapped as the stable phenazine derivative 7. For further confirmation, 5 was also captured as a dimethoxyphenylenediamine-derived phenazine (11). Both phenazines 7 and 11 significantly inhibited (ED50 approximately 0.2 microg/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.

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Figures

Figure 1
Figure 1
Structures of combretastatin A-1 (1) and A-4 (2) and the phosphate prodrugs of A-4 (3) and A-1 (4).
Figure 2
Figure 2
Synthesis of phenazine 7 from CA1 (1).
Figure 3
Figure 3
Synthesis of phenazine 11.
None
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