Design, Synthesis, and Biological Evaluation of Chemically and Biologically Diverse Pyrroquinoline Pseudo Natural Products

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.

Keywords: cell painting; cheminformatics; cycloaddition; heterocycles; natural products.

Figure 1

Concept and design of pseudo‐NPs. Biosynthetically unrelated NP fragments are recombined in diverse connectivities to yield a stereogenic compound collection.

Figure 2

Design of pyrroquinoline (PQ) pseudo‐NPs. Diverse connectivities (edge, spiro and bridged fusion) and saturation states lead to eight pseudo‐NP classes A–H.

Scheme 1

Synthesis of PQs. a,b) Scaffolds A, B were synthesized through intramolecular cycloadditions and were oxidized to their unsaturated structures F, G using DDQ. c, d) Scaffolds C, D were synthesized through intermolecular cycloaddition reactions. e) Scaffold H was synthesized via a Cu^I‐catalyzed 1,3‐dipolar cycloaddition of quinolinium salts. f) A Mannich/Friedel–Crafts reaction cascade followed by intramolecular amidation afforded scaffold D.

Figure 3

a) Average NP likeness scores for PQ scaffolds. b) NP likeness scores of PQs compared to compounds from Drugbank and the ChEMBL database. c) Chemical similarities of the different PQ scaffold libraries calculated from the Tanimoto index.

Figure 4

a) Biological similarity table for measurements at 10 μM calculated by Distance correlation. b) Biological similarities determined for measurements at different concentrations for scaffold B indicating a homogeneous cellular response at 10 μM but decreasingly so at higher concentrations.

Figure 5

a) PCA of saturated PQ scaffolds A (marine) and B (brown) with induction 5–15 %. Explained variance: 76 %; b) PCA of unsaturated PQ scaffolds F (red), G (green), H (purple) with induction 5–15 %. Explained variance: 52 %; c) PCA of the saturated scaffolds A (marine) and B (brown) with their unsaturated derivatives F (red) and G (green). Explained variance: 64 %; d) PCA between three‐dimensional scaffolds with different connectivity. Explained variance: 51 %; e) PCA for the three‐dimensional scaffolds D, E (orange and blue) and the planar F, G and H (red, green and purple). Explained variance: 50 %.