Total synthesis of fostriecin (CI-920)
Total synthesis of fostriecin (CI-920)
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DOI：
10.1021/ja010195q
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发表时间：
2001-05-09
影响因子：
15
通讯作者：
Zhong, W
中科院分区：
文献类型：
--
作者：
Boger, DL;Ichikawa, S;Zhong, W
描述了强效抗肿瘤剂福斯特菌素 (CI-920) 的首次全合成，证实了相对和绝对立体化学分配。 Fostriecin 是一种独特的磷酸单酯，具有弱的拓扑异构酶 II 抑制作用 (IC50 40 muM) 和更有效的选择性蛋白磷酸酶 2A 和 4（PP2A 和 PP4）抑制作用（IC50 = 40-3 nM 和 1.5 nM），从而抑制有丝分裂进入检查点。福斯特曲星的 I 期临床试验是第一个探索这种新作用机制潜力的试验，但由于在天然衍生材料储存过程中观察到的药物稳定性问题，甚至在达到治疗浓度或建立剂量限制毒性之前就已停止。本文详述的磷三菌素的合成是努力的第一阶段，其可用于解决该或相关有前途的新抗肿瘤剂的临床检查的这些限制。
The first total synthesis of the potent antitumor agent fostriecin (CI-920) is described, confirming the relative and absolute stereochemistry assignments. Fostriecin is a unique phosphate monoester which exhibits weak topoisomerase II inhibition (IC50 40 muM) and more potent and selective protein phosphatase 2A and 4 (PP2A and PP4) inhibition (IC50 = 40-3 nM and 1.5 nM), resulting in mitotic entry checkpoint inhibition. Phase I clinical trials with fostriecin, which were the first to explore the potential of this novel mechanism of action, were halted even before therapeutic concentrations were reached or dose-limiting toxicity established due to problems of drug stability observed during storage of naturally derived material. The synthesis of fostriecin detailed herein is the first stage of efforts that may serve to address these limitations to the clinical examination of this or related promising new antitumor agents.