Pseudo Natural Products—Chemical Evolution of Natural Product Structure

Abstract

Pseudo‐natural products (PNPs) combine natural product (NP) fragments in novel arrangements not accessible by current biosynthesis pathways. As such they can be regarded as non‐biogenic fusions of NP‐derived fragments. They inherit key biological characteristics of the guiding natural product, such as chemical and physiological properties, yet define small molecule chemotypes with unprecedented or unexpected bioactivity. We iterate the design principles underpinning PNP scaffolds and highlight their syntheses and biological investigations. We provide a cheminformatic analysis of PNP collections assessing their molecular properties and shape diversity. We propose and discuss how the iterative analysis of NP structure, design, synthesis, and biological evaluation of PNPs can be regarded as a human‐driven branch of the evolution of natural products, that is, a chemical evolution of natural product structure.

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

“…[ 37 ] In contrast to these two strategies, pseudo‐NPs are designed to generate new bioactivities, mode of actions, and/or targets through fragment combination while simultaneously losing the inherent bioactivity of the individual fragments or fragment‐sized NPs. [ 5 , 6 ]…”

“…[37] In contrast to these two strategies, pseudo-NPs are designed to generate new bioactivities, mode of actions, and/or targets through fragment combination while simultaneously losing the inherent bioactivity of the individual fragments or fragment-sized NPs. [5,6] www.advancedsciencenews.com www.advancedscience.com Table 1. The synthesis of an indofulvin collection via an iso-oxa-PS reaction, and the activity of the resulting pseudo-NPs in an autophagy inhibition assay.…”

“…We have recently introduced the pseudo‐natural product (pseudo‐NP) concept in which biosynthetically unrelated NP fragments are combined through de novo syntheses to afford novel scaffolds with arrangements of NP fragments not found in nature. [ 4 , 5 , 6 ] Pseudo‐NPs therefore resemble NPs but explore chemical space not covered by nature. Furthermore, pseudo‐NPs retain biological relevance yet may result in unexpected and/or novel bioactivities.…”

Combination of Pseudo‐Natural Product Design and Formal Natural Product Ring Distortion Yields Stereochemically and Biologically Diverse Pseudo‐Sesquiterpenoid Alkaloids

“…[1] Natural product (NP) structures harness biological relevance established in evolution and have served as inspiration for the discovery of novel bioactive compound classes [2] fori nstance by late-stage functionalization of NPs, [3] function-oriented synthesis (FOS) [4] and biology-oriented synthesis (BIOS). [5] However,t hese strategies yield compound collections which explore chemical and biological space closely related to the parent NPs.F or wider exploration of NP-inspired chemical and biological space,ring distortion by means of the complexity-to-diversity approach [6,7] and the development of pseudonatural products (pseudo-NPs) [8,9] have recently been introduced (Figure 1a).…”

Macrodiolide Diversification Reveals Broad Immunosuppressive Activity That Impairs the cGAS‐STING Pathway

“…By design of typically highly modular [28, 29] synthetic routes, a whole family of natural products and analogues bearing multiple modifications can be achieved within a minimized number of steps to facilitate biological studies [30, 31] . In addition, alternative synthesis paradigms that for example, seek to fuse natural product building blocks through unnatural connections [32, 33] or construct new complex scaffolds from abundant natural products [34, 35] has also been developed to access natural‐product‐like chemical space. Being a modest‐sized member of the C 2 ‐symmetric macrodiolide family [36, 37] vermiculine has attracted the attention of synthetic chemists, with the first (racemic) synthesis reported by Corey [38] .…”