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Signal transduction in a covalent post-assembly modification cascade

Abstract

Natural reaction cascades control the movement of biomolecules between cellular compartments. Inspired by these systems, we report a synthetic reaction cascade employing post-assembly modification reactions to direct the partitioning of supramolecular complexes between phases. The system is composed of a self-assembled tetrazine-edged FeII8L12 cube and a maleimide-functionalized FeII4L6 tetrahedron. Norbornadiene (NBD) functions as the stimulus that triggers the cascade, beginning with the inverse-electron-demand Diels–Alder reaction of NBD with the tetrazine moieties of the cube. This reaction generates cyclopentadiene as a transient by-product, acting as a relay signal that subsequently undergoes a Diels–Alder reaction with the maleimide-functionalized tetrahedron. Cyclooctyne can selectively inhibit the cascade by outcompeting NBD as the initial trigger. Initiating the cascade with 2-octadecyl NBD leads to selective alkylation of the tetrahedron upon cascade completion. The increased lipophilicity of the C18-tagged tetrahedron drives this complex into a non-polar phase, allowing its isolation from the initially inseparable mixture of complexes.

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Figure 1: Overview of syntheses and PAM cascade.
Figure 2: Depictions (same scale) of the X-ray crystal structures.
Figure 3: Monitoring the model PAM cascade.
Figure 4: Monitoring the inhibited PAM cascade.
Figure 5: Signal transduction leading to phase segregation of the two product complexes.

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Acknowledgements

B.S.P. acknowledges support from the Herchel Smith Research Fellowship, the Royal Commission for the Exhibition of 1851 Research Fellowship and the Fellowship from Corpus Christi College, Cambridge. D.A.R. acknowledges support from the Gates Cambridge Trust. This work was also supported by the UK Engineering and Physical Sciences Research Council (EPSRC, EP/M008258/1). The authors acknowledge Diamond Light Source (UK) for synchrotron beamtime on I19 (MT11397), the NMR facility at the University of Cambridge Chemistry Department and the EPSRC UK National Mass Spectrometry Facility at Swansea University.

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Contributions

B.S.P., D.A.R. and J.R.N. conceived the initial ideas for the project. B.S.P. and D.A.R. designed the complexes. B.S.P., D.A.R. and T.G.L. performed the synthetic work. B.S.P. and D.A.R. characterized the compounds, performed the cascades and grew the single crystals. T.K.R. collected diffraction data and solved and refined the X-ray crystal structures. B.S.P. prepared the initial draft of the paper and all authors contributed to the final draft of the paper.

Corresponding author

Correspondence to Jonathan R. Nitschke.

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Crystallographic data for compound 1b (CIF 7583 kb)

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Crystallographic data for compound 3 (CIF 3670 kb)

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Crystallographic data for compound 4a (CIF 13868 kb)

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Pilgrim, B., Roberts, D., Lohr, T. et al. Signal transduction in a covalent post-assembly modification cascade. Nature Chem 9, 1276–1281 (2017). https://doi.org/10.1038/nchem.2839

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