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.

有效探索与生物相关的化学空间对于发现生物活性化合物至关重要。兼具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。这里报道了多样化的伪天然产物（PNP）策略，它将 PNP 概念的生物学相关性与来自多样性导向合成的合成多样化策略相结合。通过开发的吲哚脱芳构化方法，从常见的不同中间体合成了多种 PNP 集合，以提供可通过分子内偶联和/或一氧化碳插入进一步多样化的三维分子框架。总共合成了 154 个 PNP，代表八个不同的类别。化学信息学分析表明，不同类别的 PNP 在结构上存在差异。生物学研究揭示了该集合的不同生物活性富集程度，其中从四种不同的 PNP 类别中鉴定出 Hedgehog 信号传导、DNA 合成、从头嘧啶生物合成和微管蛋白聚合的四种抑制剂。