Antineoplastic agents 389. New syntheses of the combretastatin A-4 prodrug.
Combretastatin A-4 (1) as the phosphate ester prodrug (3d) is a potent antineoplastic and antiangiogenesis substance and is in advanced preclinical development. For the purpose of improving the phosphorylation synthetic sequence from combretastatin A-4, new routes were investigated. The phosphorylation step was found to be considerably improved using in situ-generated dibenzyl chlorophosphite. Cleavage of the benzyl esters employing a trimethylchlorosilane/sodium iodide procedure, followed by treatment with sodium methoxide, led to the water-soluble prodrug (3d) in high yield.
Pettit
G R
GR
Cancer Research Institute, Arizona State University, Tempe 85287-2404, USA.
Rhodes
M R
MR
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D010766:Phosphorylation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D013267:Stilbenes; C058728:fosbretabulin