Total syntheses, fragmentation studies, and antitumor/antiproliferative activities of FR901464 and its low picomolar analogue.
Total syntheses, fragmentation studies, and antitumor/antiproliferative activities of FR901464 and its low picomolar analogue.
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DOI：
10.1021/ja076891t
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发表时间：
2007-03
影响因子：
15
通讯作者：
B. J. Albert;A. Sivaramakrishnan;T. Naka;N. Czaicki;K. Koide
中科院分区：
文献类型：
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作者：
B. J. Albert;A. Sivaramakrishnan;T. Naka;N. Czaicki;K. Koide
FR901464 是一种有效的抗癌天然产物，可降低癌基因和抑癌基因的 mRNA 水平。在本文中，我们报告了 FR901464 的收敛对映选择性合成，该合成通过 13 个线性步骤完成。该合成方法的核心是二烯-烯交叉烯烃复分解反应，以生成 C6-C7 烯烃，而最终步骤不使用保护基团。其他关键反应包括 Zr/Ag 促进的炔基化以设置 C4 立体中心、温和的化学选择性 Red-Al 还原、试剂控制的立体选择性 Mislow-Evans 型 [2,3]-σ 重排以安装 C5 立体中心、Carreira 不对称炔基化以生成 C4' 立体中心，以及高效的闭环复分解-烯丙基氧化序列以形成不饱和内酯。在生理相关条件下研究了 FR901464 右侧片段的分解途径。通过β-消除反应轻松打开环氧化物，得到两个烯酮，其中一个可以通过其半缩酮脱水形成呋喃。为了防止这种分解途径，合理设计和合成了正确的片段。该类似物比天然产物的正确片段稳定 12 倍。使用这种更稳定的右侧片段类似物，通过 13 个线性步骤制备了 FR901464 类似物美亚霉素。研究了合成的 FR901464 和美雅霉素对人乳腺癌 MCF-7 细胞增殖的抑制作用，确定这些化合物的 GI50 值分别为 1.1 nM 和 10 pM。因此，美亚霉素是最有效的抗癌小分子之一，不与 DNA 或微管结合。
FR901464 is a potent anticancer natural product that lowers the mRNA levels of oncogenes and tumor suppressor genes. In this article, we report a convergent enantioselective synthesis of FR901464, which was accomplished in 13 linear steps. Central to the synthetic approach was the diene-ene cross olefin metathesis reaction to generate the C6-C7 olefin without the use of protecting groups as the final step. Additional key reactions include a Zr/Ag-promoted alkynylation to set the C4 stereocenter, a mild and chemoselective Red-Al reduction, a reagent-controlled stereoselective Mislow-Evans-type [2,3]-sigmatropic rearrangement to install the C5 stereocenter, a Carreira asymmetric alkynylation to generate the C4' stereocenter, and a highly efficient ring-closing metathesis-allylic oxidation sequence to form an unsaturated lactone. The decomposition pathways of FR901464's right fragment were studied under physiologically relevant conditions. Facile epoxide opening by beta-elimination gave two enones, one of which could undergo dehydration via its hemiketal to form a furan. To prevent this decomposition pathway, a right fragment was rationally designed and synthesized. This analogue was 12 times more stable than the right fragment of the natural product. Using this more stable right fragment analogue, an FR901464 analogue, meayamycin, was prepared in 13 linear steps. The inhibitions of human breast cancer MCF-7 cell proliferation by synthetic FR901464 and meayamycin were studied, and the GI50 values for these compounds were determined to be 1.1 nM and 10 pM, respectively. Thus, meayamycin is among the most potent anticancer small molecules that do not bind to either DNA or microtubule.