Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides
Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides
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DOI：
10.1038/nchem.2308
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发表时间：
2015-09-01
期刊：
影响因子：
21.8
通讯作者：
Oshima, Yoshiteru
中科院分区：
文献类型：
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作者：
Asai, Teigo;Tsukada, Kento;Oshima, Yoshiteru
天然产物的结构复杂性和多样性使其成为潜在药物发现的有吸引力的来源，其特征来自每个生物合成途径中中间体的酶促和非酶促转化的多步组合。表现出多能性行为的中间体具有很大的潜力，可用作多样性导向合成的起点。受从简单中间体形成复杂代谢物的生物合成途径的启发，我们开发了一种结合异源生物合成和人工多样化的半合成方法。真菌聚酮中间体的异源生物合成导致新的低聚物的分离，并提供证据邻醌甲基等价物在其异色烯形式。异色烯聚酮的固有反应性使我们能够通过修饰和重塑聚酮核心以及通过与吲哚分子偶联来获得各种新的化学实体。因此，我们成功地通过该过程产生了非常多样化的伪天然聚酮化合物，并展示了使用生物合成中间体的先进方法。
The structural complexity and diversity of natural products make them attractive sources for potential drug discovery, with their characteristics being derived from the multi-step combination of enzymatic and non-enzymatic conversions of intermediates in each biosynthetic pathway. Intermediates that exhibit multipotent behaviour have great potential for use as starting points in diversity-oriented synthesis. Inspired by the biosynthetic pathways that form complex metabolites from simple intermediates, we developed a semi-synthetic process that combines heterologous biosynthesis and artificial diversification. The heterologous biosynthesis of fungal polyketide intermediates led to the isolation of novel oligomers and provided evidence for ortho-quinonemethide equivalency in their isochromene form. The intrinsic reactivity of the isochromene polyketide enabled us to access various new chemical entities by modifying and remodelling the polyketide core and through coupling with indole molecules. We thus succeeded in generating exceptionally diverse pseudo-natural polyketides through this process and demonstrated an advanced method of using biosynthetic intermediates.