Fusarisetin A: Scalable Total Synthesis and Related Studies.
Fusarisetin A: Scalable Total Synthesis and Related Studies.
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DOI：
10.1039/c2sc21308g
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发表时间：
2012-01-01
期刊：
影响因子：
8.4
通讯作者：
Theodorakis EA
中科院分区：
文献类型：
--
作者：
Xu J;Caro-Diaz EJ;Lacoske MH;Hung CI;Jamora C;Theodorakis EA
Fusarisetin A(1)是一种新近分离的天然产物，具有前所未有的化学结构和显著的生物活性，是一种有效的癌症转移抑制因子。我们在这里描述了我们的研究导致了高效和可扩展的1的全合成。该策略的关键是开发了一条形成该化合物的反式十氢萘部分的新路线，并应用了氧化自由基环化(ORC)反应，通过生物启发的过程从苦参素(2)中生成Fusarisetin A(1)。对TEMPO诱导和金属/O2促进的ORC反应进行了评价。体外生物筛选证实了已报道的(+)-1的效力。重要的是，体外研究表明，这种化合物能够抑制不同类型的细胞迁移。此外，(+)-1的C5同分异构体也被认为是一种有效的肿瘤转移抑制因子，而(−)-1和2的效力则显著降低。优化后的合成方法适用于克级规模，为类似物合成和生物方法学研究提供了坚实的平台。
Fusarisetin A (1) is a recently isolated natural product that displays an unprecedented chemical motif and remarkable bioactivities as a potent cancer migration inhibitor. We describe here our studies leading to an efficient and scalable total synthesis of 1. Essential to the strategy was the development of a new route for the formation of a trans-decalin moiety of this compound and the application of an oxidative radical cyclization (ORC) reaction that produces fusarisetin A (1) from equisetin (2) via a bio-inspired process. TEMPO-induced and metal/O2-promoted ORC reactions were evaluated. Biological screening in vitro confirms the reported potency of (+)-1. Importantly, ex vivo studies show that this compound is able to inhibit different types of cell migration. Moreover, the C5 epimer of (+)-1 was also identified as a potent cancer migration inhibitor, while (−)-1 and 2 were found to be significantly less potent. The optimized synthesis is applicable on gram scale and provides a solid platform for analogue synthesis and methodical biological study.