Electronic complementarity permits hindered butenolide heterodimerization and discovery of novel cGAS/STING pathway antagonists

Abstract

sp3-hybridized attached-rings are common motifs in secondary metabolites and represent tetrahedral equivalents to the biaryl substructures that overpopulate synthetic libraries. Few methods are available that can link fully substituted carbon atoms of two rings with stereocontrol. Here we have developed a stereoselective, heteroselective butenolide coupling that exhibits an unusually fast rate of C–C bond formation driven by exquisite complementarity of the reacting π systems. Heterodimerization generates a compound collection with topological complexity and diverse principal moments of inertia. The special status of the sp3sp3 attached-ring motif is demonstrated in a high-throughput screen for inhibitors of the cyclic GMP-AMP synthase/stimulator of interferon genes pathway, which recruited these butenolide heterodimers from a field of 250,000 compounds. The driving forces underlying this general attached-ring coupling identify a novel paradigm for the accession of wider natural product chemical space, accelerating the discovery of selective lead compounds.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Attached rings bearing fully substituted bridgehead carbons are challenging motifs to form by direct intermolecular coupling.
Fig. 2: Vicinal fully substituted stereocentres from butenolide heterodimerization.
Fig. 3: Kinetics data excludes C–C bond formation as rate determining.
Fig. 4: Calculation of aggregate reaction barriers and deaggregation energies.
Fig. 5: Identification of butenolide heterodimer-based cGAS-STING pathway inhibitors from a cell-based chemical screen.

Data availability

All data generated or analysed during this study are included in this Article and its Supplementary Information. Other data that support the findings in this study include crystallographic data deposited with the Cambridge Crystallographic Data Centre under accession nos. CCDC 1849246 (compound SI-86), 1849245 (compound SI-46 minor), 1849244 (compound SI-46 major), 1849243 (compound SI-67), 1849242 (compound SI-93) and 1849241 (compound SI-66).

References

  1. 1.

    Leeson, P. D. & Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug. Discov. 6, 881–890 (2007).

    CAS  Article  Google Scholar 

  2. 2.

    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).

    CAS  Article  Google Scholar 

  3. 3.

    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).

    CAS  Article  Google Scholar 

  4. 4.

    Clemons, P. A. et al. Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles. Proc. Natl Acad. Sci. USA 107, 18787–18792 (2010).

    CAS  Article  Google Scholar 

  5. 5.

    Lovering, F. Escape from Flatland 2: complexity and promiscuity. ChemMedChem 4, 515–519 (2013).

    CAS  Google Scholar 

  6. 6.

    Feher, M. & Schmidt, J. M. Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J. Chem. Inf. Comput. Sci. 43, 218–227 (2003).

    CAS  Article  Google Scholar 

  7. 7.

    Lachance, H., Wetzel, S., Kumar, K. & Waldmann, H. Charting, navigating, and populating natural product chemical space for drug discovery. J. Med. Chem. 55, 5989–6001 (2012).

    CAS  Article  Google Scholar 

  8. 8.

    Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).

    CAS  Article  Google Scholar 

  9. 9.

    Brown, D. G., Gagnon, M. M. & Boström, J. Understanding our love affair with p-chlorophenyl: present day implications from historical biases of reagent selection. J. Med. Chem. 58, 2390–2405 (2015).

    CAS  Article  Google Scholar 

  10. 10.

    Ritchie, T. J. & Macdonald, S. J. F. The impact of aromatic ring count on compound developability—are too many aromatic rings a liability in drug design? Drug Discov. Today 14, 1011–1020 (2009).

    CAS  Article  Google Scholar 

  11. 11.

    Choi, J. & Fu, G. C. Transition metal–catalyzed alkyl–alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, 152–160 (2017).

    CAS  Article  Google Scholar 

  12. 12.

    Overman, L. E. & Velthuisen, E. J. Scope and facial selectivity of the prins-pinacol synthesis of attached rings. J. Org. Chem. 71, 1581–1587 (2006).

    CAS  Article  Google Scholar 

  13. 13.

    Daub, M. E., Prudhomme, J., Le Roch, K. & Vanderwal, C. D. Synthesis and potent antimalarial activity of kalihinol B. J. Am. Chem. Soc. 137, 4912–4915 (2015).

    CAS  Article  Google Scholar 

  14. 14.

    Tang, Z. et al. Highly enantioselective synthesis of bisoxindoles with two vicinal quaternary stereocenters via Lewis base mediated addition of oxindoles to isatin-derived ketimines. Org. Biomol. Chem. 12, 6085–6088 (2014).

    CAS  Article  Google Scholar 

  15. 15.

    Fuchs, J. R. & Funk, R. L. Total synthesis of (±)-perophoramidine. J. Am. Chem. Soc. 126, 5068–5069 (2004).

    CAS  Article  Google Scholar 

  16. 16.

    Movassaghi, M., Ahmad, O. K. & Lathrop, S. P. Directed heterodimerization: stereocontrolled assembly via solvent-caged unsymmetrical diazene fragmentation. J. Am. Chem. Soc. 133, 13002–13005 (2011).

    CAS  Article  Google Scholar 

  17. 17.

    Lu, H.-H., Martinez, M. D. & Shenvi, R. A. An eight-step gram-scale synthesis of (–)-jiadifenolide. Nat. Chem. 7, 604–607 (2015).

    CAS  Article  Google Scholar 

  18. 18.

    Ohtawa, M. et al. Synthesis of (–)-11-O-debenzoyltashironin: neurotrophic sesquiterpenes cause hyperexcitation. J. Am. Chem. Soc. 139, 9637–9644 (2017).

    CAS  Article  Google Scholar 

  19. 19.

    Kraus, G. A. & Roth, B. Michael addition reactions of angelica lactone. Tetrahedron Lett. 18, 3129–3132 (1977).

    Article  Google Scholar 

  20. 20.

    Chabaud, L., Jousseaume, T., Retailleau, P. & Guillou, C. Vinylogous Mukaiyama–Michael reactions between 2-silyloxyfurans and cyclic enones or unsaturated oxo esters. Eur. J. Org. Chem. 2010, 5471–5481 (2010).

    Article  Google Scholar 

  21. 21.

    Jackson, P. A., Widen, J. C., Harki, D. A. & Brummond, K. M. Covalent modifiers: a chemical perspective on the reactivity of α,β-unsaturated carbonyls with thiols via hetero-Michael addition reactions. J. Med. Chem. 60, 839–885 (2017).

    CAS  Article  Google Scholar 

  22. 22.

    Kolonko, K. J., Wherritt, D. J. & Reich, H. J. Mechanistic studies of the lithium enolate of 4-fluoroacetophenone: rapid-injection NMR study of enolate formation, dynamics, and aldol reactivity. J. Am. Chem. Soc. 137, 16774–16777 (2011).

    Article  Google Scholar 

  23. 23.

    Singleton, D. & Thomas, A. High-precision simultaneous determination of multiple small kinetic isotope effects at natural abundance. J. Am. Chem. Soc. 117, 9357–9358 (1995).

    CAS  Article  Google Scholar 

  24. 24.

    Kaumanns, O., Lucius, R. & Mayr, H. Determination of the electrophilicity parameters of diethyl benzylidenemalonates in dimethyl sulfoxide: reference electrophiles for characterizing strong nucleophiles. Chem. Eur. J. 14, 9675–9682 (2008).

    CAS  Article  Google Scholar 

  25. 25.

    Wheeler, S. E. & Houk, K. N. Substituent effects in the benzene dimer are due to direct interactions of the substituents with the unsubstituted benzene. J. Am. Chem. Soc. 130, 10854–10855 (2008).

    CAS  Article  Google Scholar 

  26. 26.

    Gaulton, A. et al. The ChEMBL database in 2017. Nucleic Acids Res. 45, D945–D954 (2017).

    CAS  Article  Google Scholar 

  27. 27.

    Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type i interferon pathway. Science 339, 786–791 (2013).

    CAS  Article  Google Scholar 

  28. 28.

    Cai, X., Chiu, Y.-H. & Chen, Z. J. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol. Cell 54, 289–296 (2014).

    CAS  Article  Google Scholar 

  29. 29.

    Crow, Y. J. & Manel, N. Aicardi–Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15, 429–440 (2015).

    CAS  Article  Google Scholar 

  30. 30.

    Wetzel, S., Schuffenhauer, A., Roggo, S., Ertl, P. & Waldmann, H. Cheminformatic analysis of natural products and their chemical space. Chimia 61, 355–360 (2007).

    CAS  Article  Google Scholar 

  31. 31.

    Huffman, B. J. & Shenvi, R. A. Natural products in the marketplace: interfacing synthesis and biology. J. Am. Chem. Soc. 141, 7709–7714 (2019).

    Article  Google Scholar 

Download references

Acknowledgements

We thank D.-H. Huang and L. Pasternack for NMR analysis, C. Moore and A. L. Rheingold for X-ray crystallographic analysis, H. M. Petrassi for PMI analysis and the ACS for use of data from ref. 1. We thank D. L. Boger for helpful discussions. Financial support for this work was provided by the NSF (NSF Graduate Research Fellowships Program to B.J.H., CHE-1352587 and CHE-1856747 to R.A.S., and CHE-1764328 to K.N.H.). All calculations were performed on the Hoffman2 cluster at the University of California, Los Angeles and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the NSF (OCI-1053575).

Author information

Affiliations

Authors

Contributions

B.J.H. and R.A.S. conceived the work, all authors designed the experiments, B.J.H., R.E.P., J.L.S. and E.N.C. performed the experiments. S.C. performed the calculations. All authors contributed to analysis of the data and composition of the manuscript.

Corresponding authors

Correspondence to Luke L. Lairson or K. N. Houk or Ryan A. Shenvi.

Ethics declarations

Competing interests

A provisional patent has been submitted: US serial no. 62/776,306.

Additional information

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

Supplementary information

Supplementary Information

Materials and methods, experimental procedures, experimental data, spectral data, copies of spectra, description of computational methods and results, description of cell culture and biological assay.

Reporting Summary

Crystallographic data

Crystallographic data for compound SI-46 major. CCDC reference 1849244.

Crystallographic data

Crystallographic data for compound SI-46 minor. CCDC reference 1849245.

Crystallographic data

Crystallographic data for compound SI-66. CCDC reference 1849241.

Crystallographic data

Crystallographic data for compound SI-67. CCDC reference 1849243.

Crystallographic data

Crystallographic data for compound SI-86. CCDC reference 1849246.

Crystallographic data

Crystallographic data for compound SI-93. CCDC reference 1849242.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Huffman, B.J., Chen, S., Schwarz, J.L. et al. Electronic complementarity permits hindered butenolide heterodimerization and discovery of novel cGAS/STING pathway antagonists. Nat. Chem. 12, 310–317 (2020). https://doi.org/10.1038/s41557-019-0413-8

Download citation

Further reading

Search

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