Collective Synthesis of Sarpagine and Macroline Alkaloid‐Inspired Compounds

Abstract

AbstractDesign strategies that can access natural‐product‐like chemical space in an efficient manner may facilitate the discovery of biologically relevant compounds. We have employed a divergent intermediate strategy to construct an indole alkaloid‐inspired compound collection derived from two different molecular design principles, i.e. biology‐oriented synthesis and pseudo‐natural products. The divergent intermediate was subjected to acid‐catalyzed or newly discovered Sn‐mediated conditions to selectively promote intramolecular C‐ or N‐acylation, respectively. After further derivatization, a collection totalling 84 compounds representing four classes was obtained. Morphological profiling via the cell painting assay coupled with a subprofile analysis showed that compounds derived from different design principles have different bioactivity profiles. The subprofile analysis suggested that a pseudo‐natural product class is enriched in modulators of tubulin, and subsequent assays led to the identification of compounds that suppress in vitro tubulin polymerization and mitotic progression.