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/ja067870m
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发表时间：
2007-03-07
影响因子：
15
通讯作者：
Koide, Kazunori
中科院分区：
文献类型：
--
作者：
Albert, Brian J.;Sivaramakrishnan, Ananthapadmanabhan;Koide, Kazunori
FR 901464是一种有效的抗癌天然产物，可降低癌基因和肿瘤抑制基因的mRNA水平。在这篇文章中，我们报告了一个收敛的不对称选择性合成FR 901464，这是在13个线性步骤完成。合成方法的核心是二烯-烯交联烯烃复分解反应以产生C6-C7烯烃，而不使用保护基作为最终步骤。另外的关键反应包括Zr/Ag促进的炔基化以设置C4立构中心，温和的和化学选择性的Red-Al还原，试剂控制的立体选择性Mislow-Evans型[2，3]-σ迁移重排以设置C5立构中心，Carreira不对称炔基化以产生C4'立构中心，以及高效的闭环易位-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FR 901464右侧片段的分解途径。通过β-消除容易的环氧化物开环得到两个烯酮，其中一个可以通过其半缩酮脱水形成呋喃。为了阻止这种分解途径，我们合理设计并合成了一个合适的片段。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片段类似物，在13个线性步骤中制备FR 901464类似物，美亚霉素。研究了合成的FR 901464和meayamycin对人乳腺癌MCF-7细胞增殖的抑制作用，测定了这些化合物的GI（50）值分别为1.1 nM和10 pM。因此，Meayamycin是不与DNA或微管结合的最有效的抗癌小分子之一。
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 GI(50) 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.