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Practical synthesis of the therapeutic leads tigilanol tiglate and its analogues

Nature Chemistry volume 14, pages 1421–1426 (2022)Cite this article

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Abstract

Tigilanol tiglate is a natural product diterpenoid in clinical trials for the treatment of a broad range of cancers. Its unprecedented protein kinase C isoform selectivity make it and its analogues exceptional leads for PKC-related clinical indications, which include human immunodeficiency virus and AIDS eradication, antigen-enhanced cancer immunotherapy, Alzheimer’s disease and multiple sclerosis. Currently, the only source of tigilanol tiglate is a rain forest tree, Fontainea picrosperma, whose limited number and restricted distribution (northeastern Australia) has prompted consideration of designed tree plantations to address supply needs. Here we report a practical laboratory synthesis of tigilanol tiglate that proceeds in 12 steps (12% overall yield, >80% average yield per step) and can be used to sustainably supply tigilanol tiglate and its analogues, the latter otherwise inaccessible from the natural source. The success of this synthesis is based on a unique strategy for the installation of an oxidation pattern common to many biologically active tiglianes, daphnanes and their analogues.

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Fig. 1: Structural analysis of tigilanol tiglate (1) and a retrosynthetic analysis of its synthesis from phorbol (2).
Fig. 2: Overview of the importance of the B-ring oxidation pattern in tigliane and daphnane natural products and the pharmacophore model.
Fig. 3: Reaction sequence from phorbol (2) to tigilanol tiglate (1).
Fig. 4: Representative biological data for synthetic EBC-46 and its analogues.

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Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information. The X-ray structure of phorbol-13-acetate bound to the PKC-C1 domain was obtained from the structure reported by Hurley (Protein Data Bank: 1PTR).

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NIH) (CA31845 and AI124743; Z.O.G., D.J.F., O.D.M., Q.H.L.-N and E.N.). O.D.M. thanks the Molecular Pharmacology Training Program for support. We also thank H. Rahn for thoughtful discussions and assistance in the purification. Confocal images were acquired at the Stanford Neuroscience Microscopy Services. High-resolution mass spectrometric data were acquired at the Vincent Coates Foundation Mass Spectrometry Laboratory, supported in part by NIH P30 CA124435 utilizing the Stanford Cancer Institute Proteomics/Mass Spectrometry Shared Resource. Computational efforts were performed on the Sherlock cluster (Stanford University).

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Authors and Affiliations

  1. Department of Chemistry, Stanford University, Stanford, CA, USA

    Paul A. Wender, Zachary O. Gentry, David J. Fanelli, Quang H. Luu-Nguyen, Owen D. McAteer & Edward Njoo

  2. Department of Systems and Chemical Biology, Stanford University, Stanford, CA, USA

    Paul A. Wender

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Contributions

Z.O.G., D.J.F., O.D.M., Q.H.L.-N. and E.N. prepared the compounds; D.J.F. performed the binding and translocation assays; E.N. performed the computational studies; P.A.W. and all the authors provided guidance on the design and analysis of experiments and wrote the manuscript.

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Correspondence to Paul A. Wender.

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Competing interests

A provisional patent application (docket number S21-064) has been filed by Stanford University, on behalf of Paul A. Wender (principal investigator), Zachary O. Gentry, David J. Fanelli, Quang H. Luu-Nguyen, Owen D. McAteer and Edward Njoo, that covers a method to synthesize tigilanol tiglate (EBC-46) and related compounds from readily available starting materials.

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Nature Chemistry thanks Mireille Bilonda and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Materials and Methods, Supplementary discussion, Figs. 1–11, Tables 1–4 and additional references 49–56.

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Wender, P.A., Gentry, Z.O., Fanelli, D.J. et al. Practical synthesis of the therapeutic leads tigilanol tiglate and its analogues. Nat. Chem. 14, 1421–1426 (2022). https://doi.org/10.1038/s41557-022-01048-2

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