Abstract
Natural product (NP) structures are a rich source of inspiration for the discovery of new biologically relevant chemical matter. In natural product inspired pseudo‐NPs, NP‐derived fragments are combined de novo in unprecedented arrangements. Described here is the design and synthesis of a 155‐member pyrroquinoline pseudo‐NP collection in which fragments characteristic of the tetrahydroquinoline and pyrrolidine NP classes are combined with eight different connectivities and regioisomeric arrangements. Cheminformatic analysis and biological evaluation of the compound collection by means of phenotyping in the morphological “cell painting” assay followed by principal component analysis revealed that the pseudo‐NP classes are chemically diverse and that bioactivity patterns differ markedly, and are dependent on connectivity and regioisomeric arrangement of the fragments.
Highlights
Relevant natural products (NPs) generated through evolution have served as inspiration in the design of new bioactive small molecule classes,[1] for example, in the establishment of Biology Oriented Synthesis (BIOS)[2] and the complexity to diversity (CtD) approach.[3,4]
Pyrrolidine and tetrahydroquinoline are two fragments found in a variety of biologically active NPs (Figure 2)
The tetrahydroquinoline containing NP yaequinolone J1 displayed insecticidal properties[23] and virantmycin has been identified as a potent antiviral antibiotic.[24]
Summary
Relevant natural products (NPs) generated through evolution have served as inspiration in the design of new bioactive small molecule classes,[1] for example, in the establishment of Biology Oriented Synthesis (BIOS)[2] and the complexity to diversity (CtD) approach.[3,4] We have recently introduced the design and synthesis of pseudo natural products (pseudo-NPs) as new strategy for the discovery of novel bioactive chemical matter.[5,6]. Pseudo-NPs are synthesized through de novo combinations of NP fragments[7] in unprecedented arrangements Thereby, they go beyond the chemical space explored in NP biosynthesis and may have new biological targets and modes of action. Angewandte Chemie International Edition published by Wiley-VCH GmbH. We provide proof-of-principle for this notion by means of design, synthesis, cheminformatic characterization and biological evaluation of a 155-membered pyrroquinoline (PQ) pseudo-NP collection which combines fragments characteristic for the biosynthetically unrelated tetrahydroquinoline- and pyrrolidine NP classes in eight different connectivities and regioisomeric arrangements. The NP-likeness[20] and bioactivity patterns differ markedly between the eight scaffolds, and depend on connectivity and regioisomeric arrangement of the fragments in the isomeric pseudo-NP classes
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