Design, synthesis and biological evaluation of chemically and biologically diverse pyrroquinoline pseudo natural products

Liu J, Cremosnik GS, Otte F, Pahl A, Sievers S, Strohmann C, Waldmann H  (2020) Angew Chem Int Ed Engl


Natural product (NP) structure is 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 to unprecedented arrangements. This design principle will be particularly efficient, if the combination of a set of common fragments in different connectivity patterns or regioisomeric arrangements yield chemically diverse compound collections with diverse biological performance. We describe the design and synthesis of a 155-membered pyrroquinoline pseudo-NP collection in which fragments characteristic of the tetrahydroquinoline- and pyrrolidine NP classes are combined in 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 markedly differ dependent of connectivity and regioisomeric arrangement of the fragments.

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