Pseudo-Natural Products Inspired by Aspidospermidine-, Strychnos-, and Koumine Monoterpene Indole Alkaloids Reveal Pyrimidine Biosynthesis Inhibitors

In pseudo-natural product (PNP) design, natural product fragments are combined in arrangements not found in nature to afford novel biologically relevant NP-related compound classes. A pseudo-natural product compound collection inspired by aspidospermidine-, strychnos-, and koumine monoterpene alkaloids was designed and rapidly synthesized to afford a collection of 78 compounds representing eight structurally different PNP classes. Evaluation of the collection for biological relevance by means of the cell painting assay, including a recently reported subprofile analysis, revealed that one of the structural classes is enriched in and defines a new chemotype of de novo pyrimidine biosynthesis inhibitors. Our results exemplify the combination of pseudo-natural product design and unbiased morphological screening technologies as an efficient means to rapidly access and identify novel biologically relevant chemotypes.