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Probing chemical space with alkaloid-inspired libraries

Abstract

Screening of small-molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries because of their structural complexity and sp3-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp3 content, comparable to a basis set of representative natural products and were highly rule-of-five compliant.

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Figure 1: Strategic overview of natural-product families selected for library expansion and corresponding scaffold selection.
Figure 2: Construction of primary and secondary scaffolds.
Figure 3: Library construction from Stemonaceae and cylindricine alkaloid-inspired scaffolds.
Figure 4: Library construction from sparteine and mesembrine-inspired scaffolds.
Figure 5: Representative selection of library compounds used in cheminformatic analyses.
Figure 6: Cheminformatic analysis of alkaloid-inspired scaffolds and library members.

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Acknowledgements

The authors thank P. Porubsky and B. Neuenswander for purification of library compounds. The authors also acknowledge financial support from the US Institute of General Medical Sciences (P41 GM089164, Pilot-scale Libraries Initiative; 5P50GM069663, KU Chemical Methodologies and Library Development Center) and an NSF-MRI grant (CHE-0923449) for the purchase of an X-ray diffractometer.

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Authors and Affiliations

Authors

Contributions

M.C.M., J.N.P., D.R., G.S. and J.A. designed the experiments and analysed the data. M.C.M., J.N.P., D.R. and G.S. performed the synthesis and characterization. J.L.W. and M.C.M. performed the cheminformatic analysis and V.W.D. performed and analysed the X-ray structures. M.C.M. and J.A. wrote the manuscript.

Corresponding author

Correspondence to Jeffrey Aubé.

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The authors declare no competing financial interests.

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Crystallographic data for compound 3b (CIF 15 kb)

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Crystallographic data for compound 3c (CIF 15 kb)

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Crystallographic data for compound 3d (CIF 28 kb)

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Crystallographic data for compound 29d(2) (CIF 19 kb)

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Crystallographic data for compound 29c(8) (CIF 20 kb)

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Crystallographic data for compound 42(13) (CIF 17 kb)

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Crystallographic data for compound 43b(23) (CIF 19 kb)

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Crystallographic data for compound S3b (CIF 15 kb)

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Crystallographic data for compound S3c (CIF 27 kb)

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Crystallographic data for compound S3d (CIF 38 kb)

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Crystallographic data for compound S6 (CIF 19 kb)

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Crystallographic data for compound S14 (CIF 16 kb)

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McLeod, M., Singh, G., Plampin, J. et al. Probing chemical space with alkaloid-inspired libraries. Nature Chem 6, 133–140 (2014). https://doi.org/10.1038/nchem.1844

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