Antineoplastic agents 320: synthesis of a practical pancratistatin prodrug.
Owing to its sparingly soluble properties, the potential anticancer drug pancratistatin (1) resisted conventional drug formulation procedures and the synthesis of a water-soluble prodrug became necessary. That important objective for further pre-clinical development was met by devising a route to a disodium phosphate derivative (5). The key step in the synthesis of the phenolic phosphate was phosphorylation of 1,2,3,4-tetraacetoxy-pancratistatin (2) with dibenzyloxy(N,N-diisopropylamido)-phosphine. Subsequent oxidation with m-chloroperbenzoic acid afforded phosphate 4a. Hydrogenolysis of the benzyl esters followed by base-catalysed hydrolysis of the acetate groups led to the water-soluble prodrug 5 in high yield.
Pettit
G R
GR
Cancer Research Institute, Arizona State University, Tempe 85287-1604, USA.
Freeman
S
S
Simpson
M J
MJ
Thompson
M A
MA
Boyd
M R
MR
Williams
M D
MD
Pettit
G R
GR
Doubek
D L
DL
D047151:Amaryllidaceae Alkaloids; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis*; D007546:Isoquinolines / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000138:chemical synthesis*; D013057:Spectrum Analysis
D047151:Amaryllidaceae Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D007546:Isoquinolines; D011355:Prodrugs; C044997:pancratistatin