Abstract
Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.
Highlights
Natural product structure and fragment-based compound development inspire pseudonatural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse
In light of this proven ability to characterize small molecule bioactivity in a broader cellular context, we hypothesized that the cell painting assay” (CPA) would enable biological characterization and differentiation of structurally related pseudo-natural products (PNPs) classes that will be obtained through different combinations of a given set of natural product (NP)-fragments
We describe the design, synthesis, and cheminformatic analysis of a PNP collection obtained by combination of four readily accessible, fragment-sized NPs15–18 and several smaller fragments representing two different NP classes, namely indoles and chromanones (Fig. 1)
Summary
Natural product structure and fragment-based compound development inspire pseudonatural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. Cell painting has been employed to differentiate bioactivity profiles based on structural variances and chemical properties[12,13], to identify small molecule targets[6], to identify mode of action even when the target is not a protein[14], and to delineate qualitative structure-activity relationships[4] In light of this proven ability to characterize small molecule bioactivity in a broader cellular context, we hypothesized that the CPA would enable biological characterization and differentiation of structurally related PNP classes that will be obtained through different combinations of a given set of NP-fragments. Compounds with correctly predicted phenotypic behaviors were synthesized
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