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.

Chemical Evolution of Natural Product Structure

“…A recent example of the pseudo-NP concept combined the indole-containing fragment 4 H -pyranoindole and the fragment-sized NP griseofulin to arrive at indofulvins ( Figure 4 a). 66 A collection of 19 indofulvins was obtained by employing an iso-oxa-Pictet Spengler (IOPS) reaction as the key step to combine the two fragments with a fusion spiro connection pattern. While the Pictet Spengler reaction is present in biosynthetic pathways, its iso-version is not currently in the biosynthetic repertoire, resulting in a novel arrangement of the 4 H -pyranoindole fragment.…”

Ketones as strategic building blocks for the synthesis of natural product-inspired compounds

“…We note the recent work by Laraia in which a truncated steroidal ketone was used as a key precursor for the generation of focused compound collections, from which novel selective inhibitors of the cholesterol transport protein Aster-C were developed. 116 We believe that this and earlier work on the synthesis of natural product inspired compound collections 96,193,200 clearly highlight the potential value to molecular discovery that may arise from using ketones as universal precursors to install natural product ring-systems.…”

“…[195][196][197][198][199] However, Waldmann recently described a ketone-tolerant oxa-Pictet-Spengler reaction using TfOH on SiO 2 as the catalyst (Scheme 34). 200 Hydroxyethyl-derived hetaryl compounds 143 were combined with ketones to rapidly produce the oxacycles 144 at room temperature. The procedure was operationally simple to perform, with the catalyst being readily removable by filtration.…”

“…indicates the location of the starting ketone. 21,42,59,67,87,96,104,116,119,193,200 Author contributions DJF and HW conceived the idea for the review. DJF performed the literature review.…”

“…Scheme 34 Oxa-Pictet-Spengler reactions of ketones using TfOH on SiO 2 as the catalyst 200. wrt = with respect to.…”