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.
Pettit
George R
GR
Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 872404, Tempe, Arizona 85287, USA. bpettit@asu.edu
Thornhill
Andrew J
AJ
Moser
Bryan R
BR
Hogan
Fiona
F
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D007941:Leukemia P388; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D011809:Quinones / Q000737:chemistry*; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; D011355:Prodrugs; D011809:Quinones; D013267:Stilbenes; C063690:combretastatin A-1; C058728:fosbretabulin