Synthesis of Indofulvin Pseudo‐Natural Products Yields a New Autophagy Inhibitor Chemotype

Abstract Chemical and biological limitations in bioactive compound design based on natural product (NP) structure can be overcome by the combination of NP‐derived fragments in unprecedented arrangements to afford “pseudo‐natural products” (pseudo‐NPs). A new pseudo‐NP design principle is described, i.e., the combination of NP‐fragments by transformations that are not part of current biosynthesis pathways. A collection of indofulvin pseudo‐NPs is obtained from 2‐hydroxyethyl‐indoles and ketones derived from the fragment‐sized NP griseofulvin by means of an iso‐oxa‐Pictet‐Spengler reaction. Cheminformatic analysis indicates that the indofulvins reside in an area of chemical space sparsely covered by NPs, drugs, and drug‐like compounds and they may combine favorable properties of these compound classes. Biological evaluation of the compound collection in different cell‐based assays and the unbiased high content cell painting assay reveal that the indofulvins define a new autophagy inhibitor chemotype that targets mitochondrial respiration.