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

Nature Chemistry volume 12, pages 310–317 (2020)Cite this article

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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 sp3–sp3 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.

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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.

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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).

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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).

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Authors and Affiliations

  1. Department of Chemistry, Scripps Research, La Jolla, CA, USA

    Benjamin J. Huffman, J. Luca Schwarz, R. Erik Plata, Emily N. Chin, Luke L. Lairson & Ryan A. Shenvi

  2. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Shuming Chen & K. N. Houk

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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.

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

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

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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.

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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

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