德国马克斯·普朗克分子生理学研究所Waldmann, Herbert研究团队，报道了多样化中间体策略产生生物多样性的伪天然产品。相关研究成果发表在2024年2月16日出版的国际知名学术期刊《自然—化学》。

对生物相关化学空间的有效探索对于发现生物活性化合物至关重要。同时具有生物学相关性和结构多样性的分子设计原理可以更有效地产生富含多种生物活性的化合物集合。

该文报道了多样性伪天然产物（PNP）策略，该策略将PNP概念的生物学相关性与以多样性为导向合成的合成多样化策略相结合。通过开发的吲哚脱芳化方法，从一种常见的不同中间体合成了多样的PNP集合，以获得三维分子框架，该框架可以通过分子内偶联和/或一氧化碳插入进一步多样化。总共合成了代表八个不同类别的154个PNPs。

化学信息分析表明，PNPs在不同类别之间的结构是不同的。生物学研究揭示了该集合的不同生物活性富集程度，其中从四个不同PNPs类别中鉴定了四种Hedgehog信号传导、DNA合成、从头嘧啶生物合成和微管蛋白聚合的抑制剂。

附：英文原文

Title: A divergent intermediate strategy yields biologically diverse pseudo-natural products

Author: Bag, Sukdev, Liu, Jie, Patil, Sohan, Bonowski, Jana, Koska, Sandra, Schlermann, Beate, Zhang, Ruirui, Wang, Lin, Pahl, Axel, Sievers, Sonja, Brieger, Lukas, Strohmann, Carsten, Ziegler, Slava, Grigalunas, Michael, Waldmann, Herbert

Issue&Volume: 2024-02-16

Abstract: The efficient exploration of biologically relevant chemical space is essential for the discovery of bioactive compounds. A molecular design principle that possesses both biological relevance and structural diversity may more efficiently lead to compound collections that are enriched in diverse bioactivities. Here the diverse pseudo-natural product (PNP) strategy, which combines the biological relevance of the PNP concept with synthetic diversification strategies from diversity-oriented synthesis, is reported. A diverse PNP collection was synthesized from a common divergent intermediate through developed indole dearomatization methodologies to afford three-dimensional molecular frameworks that could be further diversified via intramolecular coupling and/or carbon monoxide insertion. In total, 154 PNPs were synthesized representing eight different classes. Cheminformatic analyses showed that the PNPs are structurally diverse between classes. Biological investigations revealed the extent of diverse bioactivity enrichment of the collection in which four inhibitors of Hedgehog signalling, DNA synthesis, de novo pyrimidine biosynthesis and tubulin polymerization were identified from four different PNP classes.

DOI: 10.1038/s41557-024-01458-4

Source: https://www.nature.com/articles/s41557-024-01458-4