Pettit G R, Freeman S, Simpson M J, Thompson M A, Boyd M R, Williams M D, Pettit G R, Doubek D L
Cancer Research Institute, Arizona State University, Tempe 85287-1604, USA.
Anticancer Drug Des. 1995 Apr;10(3):243-50.
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.
由于潜在的抗癌药物 pancratistatin（1）具有微溶特性，它无法通过传统的药物制剂程序，因此有必要合成一种水溶性前药。通过设计一条合成磷酸二钠衍生物（5）的路线，实现了这一对于进一步临床前开发至关重要的目标。酚磷酸盐合成中的关键步骤是用二苄氧基（N，N - 二异丙基氨基）膦对 1,2,3,4 - 四乙酰氧基 - pancratistatin（2）进行磷酸化。随后用间氯过苯甲酸氧化得到磷酸盐 4a。苄酯的氢解反应，接着通过碱催化水解乙酸酯基团，以高收率得到水溶性前药 5。
