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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.
Highlights
Small molecules are powerful tools for the dissection of complex biological processes due to their ability to acutely modulate their biological targets in a tuneable manner, and are the dominant chemical entities[1] in our arsenal to treat disease.[2]
Diversity-Oriented Synthesis (DOS)[5] is an approach aimed towards the preparation of compound libraries whereby creation of molecular diversity is an embedded part of the synthetic strategy (Figure 1A)
In this review we describe the development of the pseudo-natural products (NPs) concept, the principles of pseudo-NP-library design, and their relationship to the biological evolution of NP structure
Summary
Small molecules are powerful tools for the dissection of complex biological processes due to their ability to acutely modulate their biological targets in a tuneable manner, and are the dominant chemical entities[1] in our arsenal to treat disease.[2]. BIOS scaffolds may inherit the same kind of bioactivity as the guiding NPs, limiting the exploration of biological space.[14] To overcome these limitations and take advantage of the biological relevance of NPs, the design of novel scaffolds can benefit from the efficient sampling of chemical space offered by fragment-based compound design.[15] This argument is supported by the fact that NPs may already be fragment-sized,[16] or can be converted into fragment-sized ring-systems,[17] and the properties of NPs are retained in these NP-derived fragments.[18] combining NP-derived fragments in unprecedented ways can provide access to molecular scaffolds which inherit the biological characteristics of NPs, yet lie in biologically relevant regions of chemical space not attainable by nature. We describe syntheses of pseudoNP compound collections and their investigation in different biological settings, showing that pseudo-NPs can harbour novel bioactivity not shared by the guiding NPs
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