Pseudo Natural Products - Chemical Evolution of Natural Product Structure.

Small bioactive molecules are powerful tools for chemical biology and medicinal chemistry research. For their discovery, design principles and strategies that draw from previous insights into the structures of compound classes a priori endowed with biological relevance are particularly efficient, such as natural products (NPs). Pseudo-natural products (PNPs) combine natural product 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 NPs, 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, i.e. a chemical evolution of natural product structure.