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Synthesis of nimbolide and its analogues and their application as poly(ADP-ribose) polymerase-1 trapping inducers

Nature Synthesis volume 3, pages 378–385 (2024)Cite this article

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Abstract

Nimbolide, a ring seco-C limonoid natural product, was recently found to inhibit the poly(ADP)-ribosylation (PARylation)-dependent ubiquitin E3 ligase RNF114. In doing so, it induces the ‘supertrapping’ of both PARylated PARP1 and PAR-dependent DNA-repair factors. PARP1 inhibitors have reshaped the treatment of cancer patients with germline BRCA1/2 mutations partly through the PARP1 trapping mechanism. To this end, modular access to nimbolide analogues represents an opportunity to develop cancer therapeutics with enhanced PARP1 trapping capability. Here we report a convergent synthesis of nimbolide through a late-stage coupling strategy. Through a sulfonyl hydrazone-mediated etherification and a radical cyclization, this strategy uses a pharmacophore-containing building block and diversifiable hydrazone units to enable the modular synthesis of nimbolide and its analogues. The broad generality of our synthetic strategy allowed access to a variety of analogues with their preliminary cellular cytotoxicity and PARP1 trapping activity reported.

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Fig. 1: Anticancer reagent nimbolide as PARP1 trapping inducer and pharmacophore-derived retrosynthetic analysis.
Fig. 2: Fragment preparation and synthetic route towards nimbolide.
Fig. 3: Model studies and cyclization to nimbolide analogues.
Fig. 4: Late-stage diversification of nimbolide for synthesis of related limonoid natural products.
Fig. 5: Chemical structure of synthetic nimbolide analogues and their potency activity.
Fig. 6: PARP1 trapping as induced by nimbolide and the selected analogues.

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Data availability

Experimental data as well as characterization data for all new compounds prepared in the course of these studies and Supplementary figures and schemes are provided in Supplementary Information of this paper. Crystallographic data for the structures reported in the present article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition nos. CCDC 2289527 (10), 2289528 (22), 2289529 (41) and 2289530 (48) (see ‘X-ray crystallographic data’ in Supplementary Information). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures.

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Acknowledgements

Financial support for this work was provided by the National Institutes of Health (grant nos. R01GM141088 to T.Q. and 5R35GM134883, 1R01NS122533 and 1R21CA261018 to Y.Y.), the Welch Foundation (grant nos. I-2155-20230405 and I-2010-20190330 to T.Q. and I-1800 to Y.Y.) and UT Southwestern Eugene McDermott Scholarship (to T.Q.). We thank F. Lin (University of Texas Southwestern (UTSW)) for assistance with nuclear magnetic resonance (NMR) spectroscopy, H. Baniasadi (UTSW) for the high resolution mass spectrometry (HRMS) and V. Lynch (University of Texas, Austin) for X-ray crystallographic analysis. We thank U. Tambar (UTSW) for generous access to chiral high-performance liquid chromatography equipment, P. Baran (Scripps Research) and J. Porco (Boston University) for helpful discussions.

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Author notes

  1. Chiho Kim, Xudong Wang & Yonghao Yu

    Present address: Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA

  2. These authors contributed equally: Heping Deng, Hejun Deng.

Authors and Affiliations

  1. Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Heping Deng, Hejun Deng, Chiho Kim, Peng Li, Xudong Wang, Yonghao Yu & Tian Qin

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Contributions

Heping D. and Hejun D. performed synthetic experiments. C.K., P.L. and X.W. performed the cellular cytotoxicity, chromatin PAPR1 trapping and microirradiation experiments. Y.Y. and T.Q. designed and supervised the project. All the authors wrote the paper.

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Correspondence to Yonghao Yu or Tian Qin.

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Competing interests

Patent WO 2022/150667 ‘Nimbolide analogs and methods of use thereof’ has been filed on some aspects of the work in this paper, and H.D., H.D., C.K., P.L., Y.Y. and T.Q. are listed as inventors. Y.Y. and T.Q. are co-founders and shareholders of ProteoValent Therapeutics. The other authors declare no competing interests.

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Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

General experimental. Summary of first-generation synthesis and optimization. Model studies to construct the central THF ring. Summary of second-generation synthesis and optimization. The overview of final route. Experimental procedures and characterization data. Stereochemistry assignment for the CBS reduction of linear ketone. C–H oxidation of lactone substrate; radical ipso substitution. General synthetic route and procedure to access analogues. Natural products NMR comparisons. X-ray crystallography data. Reference. NMR spectra.

Reporting Summary

Supplementary Data 1

Crystallographic data for 10, CCDC 2289527.

Supplementary Data 2

Crystallographic data for 22, CCDC 2289528.

Supplementary Data 3

Crystallographic data for 41, CCDC 2289529.

Supplementary Data 4

Crystallographic data for 48, CCDC 2289530.

Supplementary Data 5

Source spreadsheet data for Supplementary Fig. 1.

Supplementary Data 6

Source spreadsheet data for Supplementary Fig. 2.

Source data

Source Data Fig. 6

Source spreadsheet data for Fig. 6b.

Source Data Fig. 6

Original blots scan for Fig. 6a (also included in Supplementary Information).

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Deng, H., Deng, H., Kim, C. et al. Synthesis of nimbolide and its analogues and their application as poly(ADP-ribose) polymerase-1 trapping inducers. Nat. Synth 3, 378–385 (2024). https://doi.org/10.1038/s44160-023-00437-w

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