Chemoenzymatic and ring E-modular approach to the (-)-podophyllotoxin skeleton. Synthesis of 3',4',5'-tridemethoxy-(-)-podophyllotoxin
Chemoenzymatic and ring E-modular approach to the (-)-podophyllotoxin skeleton. Synthesis of 3',4',5'-tridemethoxy-(-)-podophyllotoxin
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DOI：
10.1021/ja961489s
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发表时间：
1996-10-02
影响因子：
15
通讯作者：
Norman, BH
中科院分区：
文献类型：
--
作者：
Berkowitz, DB;Maeng, JH;Norman, BH
(-)-鬼臼毒素 (1) 充当抗有丝分裂剂，抑制微管蛋白组装。其半合成衍生物依托泊苷 (3) 和替尼泊苷 (4) 虽然不是抗有丝分裂剂，但却是重要的临床化疗药物。 1 多项体外研究确定了依托泊苷中 E 环的功能作用。例如，依托泊苷促进拓扑异构酶 II 介导的 DNA 断裂，2 和 E 环氧化可能是该活性所必需的。 3 另一方面，依托泊苷可通过环 E 的脱烷基氧化在体外被“激活”，产生能够裂解 DNA4a 或与蛋白质 4b、c 和 DNA 共价结合的衍生物（例如半醌或邻醌）。 4d然而，目前仍不确定 ViVo 中 E 环的氧化程度或氧化态是否与鬼臼毒素或依托泊苷的溶瘤特性有关。在此，我们描述了在 E 环中模块化的 (-)-鬼臼毒素骨架的合成方法，作为研究其功能作用的工具。作为原则证明，我们报告
(-)-Podophyllotoxin (1) acts as an antimitotic, inhibiting tubulin assembly. Its semisynthetic derivatives, etoposide (3) and teniposide (4), though not antimitotics, are important clinical chemotherapeutic agents. 1 Several in Vitro studies assign functional roles to ring E in etoposide. For example, etoposide promotes topoisomerase II-mediated DNA scission, 2 and ring E oxygenation may be required for this activity. 3 On the other hand, etoposide can be “activated” in Vitro by dealkylative oxidation of ring E to produce derivatives (eg the semiquinone or the o-quinone) capable of cleaving DNA4a or of covalently binding to proteins4b, c and DNA. 4dHowever, it remains uncertain whether the degree of oxygenation or the oxidation state of ring E is related to the oncolytic properties of podophyllotoxin or etoposide, in ViVo. Herein we describe the a synthetic approach to the (-)-podophyllotoxin skeleton that is modular in ring E, as a tool for the study of its functional role. As proof of principle, we report