Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Principle and design of pseudo-natural products

Abstract

Natural products (NPs) are a significant source of inspiration towards the discovery of new bioactive compounds based on novel molecular scaffolds. However, there are currently only a small number of guiding synthetic strategies available to generate novel NP-inspired scaffolds, limiting both the number and types of compounds accessible. In this Perspective, we discuss a design approach for the preparation of biologically relevant small-molecule libraries, harnessing the unprecedented combination of NP-derived fragments as an overarching strategy for the synthesis of new bioactive compounds. These novel ‘pseudo-natural product’ classes retain the biological relevance of NPs, yet exhibit structures and bioactivities not accessible to nature or through the use of existing design strategies. We also analyse selected pseudo-NP libraries using chemoinformatic tools, to assess their molecular shape diversity and properties. To facilitate the exploration of biologically relevant chemical space, we identify design principles and connectivity patterns that would provide access to unprecedented pseudo-NP classes, offering new opportunities for bioactive small-molecule discovery.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Approaches to the design of biologically relevant compound collections.
Fig. 2: Development of pseudo-NP collections.
Fig. 3: Chemoinformatic analyses of pseudo-NPs.
Fig. 4: Illustration of possible NP fragment connectivities to guide synthesis and design of pseudo-NPs.
Fig. 5: NP scores of regioisomeric pyrrotropane and pyrroquinoline scaffolds.

Similar content being viewed by others

Data availability

The material and data reported in this study are available from the corresponding author upon request.

References

  1. Li, J. W.-H. & Vederas, J. C. Drug discovery and natural products: end of an era or an endless frontier? Science 325, 161–165 (2009).

    Article  PubMed  CAS  Google Scholar 

  2. Wetzel, S., Bon, R. S., Kumar, K. & Waldmann, H. Biology-oriented synthesis. Angew. Chem. Int. Ed. 50, 10800–10826 (2011).

    Article  CAS  Google Scholar 

  3. Huigens, R. W. et al. A ring distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products. Nat. Chem. 5, 195–202 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rafferty, R. J., Hicklin, R. W., Maloof, K. A. & Hergenrother, P. J. Synthesis of complex and diverse compounds through ring distortion of abietic acid. Angew. Chem. Int. Ed. 53, 220–224 (2014).

    Article  CAS  Google Scholar 

  5. Laraia, L. et al. Discovery of novel cinchona-alkaloid-inspired oxazatwistane autophagy inhibitors. Angew. Chem. Int. Ed. 56, 2145–2150 (2017).

    Article  CAS  Google Scholar 

  6. Foley, D. J. et al. Synthesis and demonstration of the biological relevance of sp 3-rich scaffolds distantly related to natural product frameworks. Chem. Eur. J. 23, 15227–15232 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Nielsen, T. E. & Schreiber, S. L. Towards the optimal screening collection: a synthesis strategy. Angew. Chem. Int. Ed. 47, 48–56 (2008).

    Article  CAS  Google Scholar 

  8. Pye, C. R., Bertin, M. J., Lokey, R. S., Gerwick, W. H. & Linington, R. G. Retrospective analysis of natural products provides insights for future discovery trends. Proc. Natl Acad. Sci. USA 114, 5601–5606 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Crane, E. A. & Gademann, K. Capturing biological activity in natural product fragments by chemical synthesis. Angew. Chem. Int. Ed. 55, 3882–3902 (2016).

    Article  CAS  Google Scholar 

  10. Klein, J. et al. Yeast synthetic biology platform generates novel chemical structures as scaffolds for drug discovery. ACS Synth. Biol. 3, 314–323 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Scherlach, K. & Hertweck, C. Triggering cryptic natural product biosynthesis in microorganisms. Org. Biomol. Chem. 7, 1753–1760 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Khaldi, N. et al. SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genet. Biol. 47, 736–741 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Erlanson, D. A., Fesik, S. W., Hubbard, R. E., Jahnke, W. & Jhoti, H. Twenty years on: the impact of fragments on drug discovery. Nat. Rev. Drug Discov. 15, 605–619 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Over, B. et al. Natural-product-derived fragments for fragment-based ligand discovery. Nat. Chem. 5, 21–28 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Vu, H. et al. Fragment-based screening of a natural product library against 62 potential malaria drug targets employing native mass spectrometry. ACS Infect. Dis. 4, 431–444 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Prescher, H. et al. Construction of a 3D-shaped, natural product like fragment library by fragmentation and diversification of natural products. Bioorg. Med. Chem. 25, 921–925 (2017).

    Article  CAS  PubMed  Google Scholar 

  17. Goto, Y., Ito, Y., Kato, Y., Tsunoda, S. & Suga, H. One-pot synthesis of azoline-containing peptides in a cell-free translation system integrated with a posttranslational cyclodehydratase. Chem. Biol. 21, 766–774 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Ozaki, T. et al. Dissection of goadsporin biosynthesis by in vitro reconstitution leading to designer analogues expressed in vivo. Nat. Commun. 8, 14207 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Asai, T. et al. Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides. Nat. Chem. 7, 737–743 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Kikuchi, H. et al. Monoterpene indole alkaloid-like compounds based on diversity-enhanced extracts of iridoid-containing plants and their immune checkpoint inhibitory activity. Org. Lett. 18, 5948–5951 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Karageorgis, G. et al. Chromopynones are pseudo natural product glucose uptake inhibitors targeting glucose transporters GLUT-1 and -3. Nat. Chem. 10, 1103–1111 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Schneidewind, T. et al. The pseudo natural product myokinasib is a myosin light chain kinase 1 inhibitor with unprecedented chemotype. Cell Chem. Biol. 26, 512–523 (2019).

    Article  CAS  PubMed  Google Scholar 

  23. Xu, H., Golz, C., Strohmann, C., Antonchick, A. P. & Waldmann, H. Enantiodivergent combination of natural product scaffolds enabled by catalytic enantioselective cycloaddition. Angew. Chem. Int. Ed. 55, 7761–7765 (2016).

    Article  CAS  Google Scholar 

  24. Vidadala, S. R., Golz, C., Strohmann, C., Daniliuc, C.-G. & Waldmann, H. Highly enantioselective intramolecular 1,3-dipolar cycloaddition: a route to piperidino-pyrrolizidines. Angew. Chem. Int. Ed. 54, 651–655 (2015).

    CAS  Google Scholar 

  25. Lee, Y.-C. et al. A ligand-directed divergent catalytic approach to establish structural and functional scaffold diversity. Nat. Commun. 8, 14043 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Nören-Müller, A. et al. Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis. Proc. Natl Acad. Sci. USA 103, 10606–10611 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Oliver Kappe, C. 100 years of the biginelli dihydropyrimidine synthesis. Tetrahedron 49, 6937–6963 (1993).

    Article  Google Scholar 

  28. Ertl, P., Roggo, S. & Schuffenhauer, A. Natural product-likeness score and its application for prioritization of compound libraries. J. Chem. Inf. Model. 48, 68–74 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Vanii Jayaseelan, K., Moreno, P., Truszkowski, A., Ertl, P. & Steinbeck, C. Natural product-likeness score revisited: an open-source, open-data implementation. BMC Bioinformatics 13, 106–112 (2012).

    Article  Google Scholar 

  30. Law, V. et al. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res. 42, D1091–D1097 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3–25 (1997).

    Article  CAS  Google Scholar 

  32. Sauer, W. H. B. & Schwarz, M. K. Molecular shape diversity of combinatorial libraries: a prerequisite for broad bioactivity. J. Chem. Inf. Comput. Sci. 43, 987–1003 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Lack, N. A. et al. Targeting the binding function 3 (BF3) site of the human androgen receptor through virtual screening. J. Med. Chem. 54, 8563–8573 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kureel, S. P., Kapil, R. S. & Popli, S. P. Terpenoid alkaloids from Murraya koenigii spreng. — II.: The constitution of cyclomahanimbine, bicyclomahanimbine, and mahanimbidine. Tetrahedron Lett. 10, 3857–3862 (1969).

    Article  Google Scholar 

  35. Reilly, S. W. et al. Highly selective dopamine D3 receptor antagonists with arylated diazaspiro alkane cores. J. Med. Chem. 60, 9905–9910 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Palmisano, G., Annunziata, R., Papeo, G. & Sisti, M. Oxindole alkaloids. A novel non-biomimetic entry to (−)-horsfiline. Tetrahedron Asymmetry 7, 1–4 (1996).

    Article  CAS  Google Scholar 

  37. Ding, L., Maier, A., Fiebig, H.-H., Lin, W.-H. & Hertweck, C. A family of multicyclic indolosesquiterpenes from a bacterial endophyte. Org. Biomol. Chem. 9, 4029–4031 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. MacLellan, P. & Nelson, A. A conceptual framework for analysing and planning synthetic approaches to diverse lead-like scaffolds. Chem. Commun. 49, 2383–2393 (2013).

    Article  CAS  Google Scholar 

  39. Canham, S. M., Overman, L. E. & Tanis, P. S. Identification of an unexpected 2-oxonia[3,3]sigmatropic rearrangement/aldol pathway in the formation of oxacyclic rings. Total synthesis of (+)-aspergillin PZ. Tetrahedron 67, 9837–9843 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lee, M.-L. & Schneider, G. Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries. J. Comb. Chem. 3, 284–289 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Grabowski, K., Baringhaus, K.-H. & Schneider, G. Scaffold diversity of natural products: inspiration for combinatorial library design. Nat. Prod. Rep. 25, 892–904 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Muhuhi, J. & Spaller, M. R. Expanding the synthetic method and structural diversity potential for the intramolecular aza Diels−Alder cyclization. J. Org. Chem. 71, 5515–5526 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Duan, J. et al. Tricyclic sulfones as RORγ modulators and their preparations. US patent WO 2016179460 A1 (2016).

  45. Sun, H., Tawa, G. & Wallqvist, A. Classification of scaffold-hopping approaches. Drug Discov. Today 17, 310–324 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Lipkus, A. H. et al. Structural diversity of organic chemistry. A scaffold analysis of the CAS registry. J. Org. Chem. 73, 4443–4451 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Guo, J., Bai, X., Wang, Q. & Bu, Z. Diastereoselective construction of indole-bridged chroman spirooxindoles through a TfOH-catalyzed michael addition-inspired cascade reaction. J. Org. Chem. 83, 3679–3687 (2018).

    Article  CAS  PubMed  Google Scholar 

  48. Sandoval, C., Lim, N.-K. & Zhang, H. Two-step synthesis of 3,4-dihydropyrrolopyrazinones from ketones and piperazin-2-ones. Org. Lett. 20, 1252–1255 (2018).

    Article  CAS  PubMed  Google Scholar 

  49. Mullard, A. The phenotypic screening pendulum swings. Nat. Rev. Drug Discov. 14, 807–809 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article  CAS  Google Scholar 

  51. Rigor, R. R., Shen, Q., Pivetti, C. D., Wu, M. H. & Yuan, S. Y. Myosin light chain kinase signaling in endothelial barrier dysfunction. Med. Res. Rev. 33, 911–933 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Butler, D. New fronts in an old war. Nature 406, 670–672 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Caicedo, J. C. et al. Data-analysis strategies for image-based cell profiling. Nat. Methods 14, 849–863 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jafari, R. et al. The cellular thermal shift assay for evaluating drug target interactions in cells. Nat. Protoc. 9, 2100–2122 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Chessum, N. E. A. et al. Demonstrating in-cell target engagement using a pirin protein degradation probe (CCT367766). J. Med. Chem. 61, 918–933 (2018).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the Max-Planck-Gesellschaft. G.K. is grateful to the Alexander von Humboldt Foundation for a fellowship. D.J.F. is grateful to the European Commission for a Marie Skłodowska-Curie Fellowship (grant 794259). L.L. is grateful to the Novo Nordisk Foundation and DTU for funding.

Author information

Authors and Affiliations

Authors

Contributions

G.K. performed the cheminformatic analyses. All authors contributed to discussions about the connectivity types and design principles for pseudo-natural product classes. G.K., D.J.F, L.L. and H.W. wrote the paper.

Corresponding author

Correspondence to Herbert Waldmann.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary information

Supplementary Information contains Supplementary Figures 1–7 and Supplementary Tables 1–17.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karageorgis, G., Foley, D.J., Laraia, L. et al. Principle and design of pseudo-natural products. Nat. Chem. 12, 227–235 (2020). https://doi.org/10.1038/s41557-019-0411-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-019-0411-x

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing