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

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.