Yatein 和7-Deoxypodophyllotoxin 衍生物的合成研究

Abstract

依托泊苷（Etoposide）是目前臨床使用的抗癌藥物，主要作用機制為抑制DNA拓樸異構酶II。雖然依托泊苷是世界衛生組織所列的基本藥物，但其製造需要從植物鬼臼中分離出（−）-鬼臼毒素（(−)-podophyllotoxin），再利用人工合成得到。在2015年Sattely團隊研究顯示，此合成中的起始物（−）-鬼臼毒素，是以松柏醇經由多個酵素（DIR、PLR、SDH、 P450、OMT1及2-ODD）催化反應步驟得到。其中，我們有興趣的是Yatein在酵素2-ODD催化下，進行分子內合環反應，得到7-脫氧鬼臼毒素（7-deoxypodophyllotoxin）。為了探討酵素的反應機制，以β-piperonyl-γ-butyrolactone作為共同前驅物，合成酵素的受質Yatein和推測產物7-脫氧鬼臼毒素及其衍生物。我們的結果表明，最初提出的羥基化中間體不太可能參與該反應。相反，苯甲基自由基及碳陽離子中間體的形成可用於觸發碳–碳鍵形成以構建（-）-鬼臼毒素的碳環。Etoposide is a clinically used anticancer drug. Its mechanism of action is inhibition of DNA topoisomerase II. Although etoposide is a basic drug listed by the World Health Organization, its manufacture requires the isolation of (−)-podophyllotoxin from plant scorpion as the precursor, followed by multi-step chemical synthesis. In 2015, Sattely’s team showed that the biosynthesis of (−)-podophyllotoxin was accomplished from coniferyl alcohol via multiple enzyme catalysis (DIR, PLR, SDH, P450, OMT1 and 2-ODD). In the biosynthetic pathway of (–)-podophyllotoxin, we have been interested to establish a reasonable reaction mechanism for 7-deoxypodophyllotoxin from yatein under 2-ODD-catalyzed oxidative cyclization. To study the 2-ODD catalyzed reaction, the synthesis of mechanistic probes, including yatein and deoxypodophyllotoxin analogs, started with β-piperonyl-γ- butyrolactone as a common precursorwas investigated.