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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.

References

  1. Huang, A., Garraway, L. A., Ashworth, A. & Weber, B. Synthetic lethality as an engine for cancer drug target discovery. Nat. Rev. Drug Discov. 19, 23–38 (2020).

    Article  CAS  PubMed  Google Scholar 

  2. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    Article  CAS  PubMed  ADS  Google Scholar 

  3. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    Article  CAS  PubMed  ADS  Google Scholar 

  4. Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  5. Ashworth, A. & Lord, C. J. Synthetic lethal therapies for cancer: what’s next after PARP inhibitors? Nat. Rev. Clin. Oncol. 15, 564–576 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Chan, C. Y., Tan, K. V. & Cornelissen, B. PARP inhibitors in cancer diagnosis and therapy. Clin. Cancer Res. 27, 1585–1594 (2021).

    Article  CAS  PubMed  Google Scholar 

  7. Chambon, P., Weill, J. D. & Mandel, P. Nicotinamide mononucleotide activation of a new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem. Biophys. Res. Commun. 11, 39–43 (1963).

    Article  CAS  PubMed  Google Scholar 

  8. Kraus, W. L. PARPs and ADP-ribosylation: 50 years … and counting. Mol. Cell 58, 902–910 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pommier, Y., O’Connor, M. J. & De Bono, J. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci. Transl. Med. 8, 362ps17 (2016).

    Article  PubMed  Google Scholar 

  10. Murai, J. et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 72, 5588–5599 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang, S. et al. Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation. Nat. Chem. Biol. 15, 1223–1231 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kim, C., Wang, X.-D. & Yu, Y. PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response. eLife. 9, e60637 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hopkins, T. A. et al. PARP1 trapping by PARP inhibitors drives cytotoxicity in both cancer cells and healthy bone marrow. Mol. Cancer Res. 17, 409–419 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Rodrigues, T., Reker, D., Schneider, P. & Schneider, G. Counting on natural products for drug design. Nat. Chem. 8, 531–541 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Li, P. et al. Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer. Sci. Adv. 9, eadg7752 (2023).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  16. Yu, Y. et al. Nimbolide analogs and methods of use thereof. Patent WO 2022/150667 (2022).

  17. Spradlin, J. N. et al. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat. Chem. Biol. 15, 747–755 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ekong, D. E. U. Chemistry of the meliacins (limonoids). The structure of nimbolide, a new meliacin from Azadirachta indica. Chem. Commun. https://doi.org/10.1039/C1967000808A (1967).

  19. Breslin, C. et al. The XRCC1 phosphate-binding pocket binds poly(ADP-ribose) and is required for XRCC1 function. Nucleic Acids Res. 43, 6934–6944 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dias, D. A., Urban, S. & Roessner, U. A historical overview of natural products in drug discovery. Metabolites 2, 303–336 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nicolaou, K. C. & Montagnon, T. Molecules That Changed the World (Wiley-VCH, 2008).

  22. Li, Q. et al. Synthetic group A streptogramin antibiotics that overcome Vat resistance. Nature 586, 145–150 (2020).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  23. Murphy, S. K., Zeng, M. & Herzon, S. B. A modular and enantioselective synthesis of the pleuromutilin antibiotics. Science 356, 956–959 (2017).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  24. Li, J., Chen, F. & Renata, H. Concise chemoenzymatic synthesis of gedunin. J. Am. Chem. Soc. 144, 19238–19242 (2022).

    Article  CAS  PubMed  Google Scholar 

  25. Renata, H., Zhou, Q. & Baran, P. S. Strategic redox relay enables a scalable synthesis of ouabagenin, a bioactive cardenolide. Science 339, 59–63 (2013).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  26. Logan, M. M., Toma, T., Thomas-Tran, R. & Du Bois, J. Asymmetric synthesis of batrachotoxin: enantiomeric toxins show functional divergence against Nav. Science 354, 865–869 (2016).

    Article  CAS  PubMed  ADS  Google Scholar 

  27. Jorgensen, L. et al. 14-step synthesis of (+)-ingenol from (+)-3-carene. Science 341, 878–882 (2013).

    Article  CAS  PubMed  ADS  Google Scholar 

  28. Wan, K. K. & Shenvi, R. A. Conjuring a supernatural product—delmarine. Synlett. 27, 1145–1164 (2016).

    Article  CAS  Google Scholar 

  29. Abbasov, M. E. et al. Simplified immunosuppressive and neuroprotective agents based on gracilin A. Nat. Chem. 11, 342–350 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Veitch, G. E., Boyer, A. & Ley, S. V. The azadirachtin story. Angew. Chem. Int. Ed. 47, 9402–9429 (2008).

    Article  CAS  Google Scholar 

  31. Veitch, G. E. et al. Synthesis of azadirachtin: a long but successful journey. Angew. Chem. Int. Ed. 46, 7629–7632 (2007).

    Article  CAS  Google Scholar 

  32. Li, F.-Z. et al. A chiral pool approach for asymmetric syntheses of (−)-antrocin, (+)-asperolide C, and (−)-trans-ozic acid. Chem. Commun. 52, 12426–12429 (2016).

    Article  CAS  ADS  Google Scholar 

  33. Hamulić, D. et al. Synthesis and biological studies of (+)-liquiditerpenoic acid A (abietopinoic acid) and representative analogues: SAR studies. J. Nat. Prod. 82, 823–831 (2019).

    Article  PubMed  Google Scholar 

  34. Michl, G., Rettenbacher, C. & Haslinger, E. Synthesis of 12-methoxyabietic acid methylester, a feeding deterrent of the larch sawfly Pristiphora erichsonii (Hartig). Monatshefte Chem. Chem. Mon. 119, 833–838 (1988).

    Article  CAS  Google Scholar 

  35. Pelletier, S. W., Iyer, K. N. & Chang, C. W. J. Oxidative degradation of resin acids. J. Org. Chem. 35, 3535–3538 (1970).

    Article  CAS  Google Scholar 

  36. Larock, R. C., Hightower, T. R., Kraus, G. A., Hahn, P. & Zheng, D. A simple, effective, new, palladium-catalyzed conversion of enol silanes to enones and enals. Tetrahedron Lett. 36, 2423–2426 (1995).

    Article  CAS  Google Scholar 

  37. Kawamura, S., Chu, H., Felding, J. & Baran, P. S. Nineteen-step total synthesis of (+)-phorbol. Nature 532, 90–93 (2016).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  38. Curci, R., D’Accolti, L. & Fusco, C. A novel approach to the efficient oxygenation of hydrocarbons under mild conditions. Superior oxo transfer selectivity using dioxiranes. Acc. Chem. Res. 39, 1–9 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Kawamata, Y. et al. Scalable, electrochemical oxidation of unactivated C–H bonds. J. Am. Chem. Soc. 139, 7448–7451 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Aranda, G. et al. Practical and efficient 1α-hydroxylation of 4,4-dimethyl-2-ene derivatives in terpenic series. Synth. Commun. 27, 45–60 (1997).

    Article  CAS  Google Scholar 

  41. Barluenga, J., Barrio, P., Riesgo, L., López, L. A. & Tomás, M. A general and regioselective synthesis of cyclopentenone derivatives through nickel (0)-mediated [3+ 2] cyclization of alkenyl Fischer carbene complexes and internal alkynes. J. Am. Chem. Soc. 129, 14422–14426 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Ohashi, M., Taniguchi, T. & Ogoshi, S. Nickel-catalyzed formation of cyclopentenone derivatives via the unique cycloaddition of α,β-unsaturated phenyl esters with alkynes. J. Am. Chem. Soc. 133, 14900–14903 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Jenkins, A. D., Herath, A., Song, M. & Montgomery, J. Synthesis of cyclopentenols and cyclopentenones via nickel-catalyzed reductive cycloaddition. J. Am. Chem. Soc. 133, 14460–14466 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Ahlin, J. S. E., Donets, P. A. & Cramer, N. Nickel (0)‐catalyzed enantioselective annulations of alkynes and arylenoates enabled by a chiral NHC ligand: efficient access to cyclopentenones. Angew. Chem. Int. Ed. 53, 13229–13233 (2014).

    Article  CAS  Google Scholar 

  45. Shi, X., Gorin, D. J. & Toste, F. D. Synthesis of 2-cyclopentenones by gold(I)-catalyzed Rautenstrauch rearrangement. J. Am. Chem. Soc. 127, 5802–5803 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Sha, C.-K. & Huang, S.-J. Synthesis of β-substituted α-iodocycloalkenones. Tetrahedron Lett. 36, 6927–6928 (1995).

    Article  CAS  Google Scholar 

  47. Barluenga, J., Tomás‐Gamasa, M., Aznar, F. & Valdés, C. Straightforward synthesis of ethers: metal‐free reductive coupling of tosylhydrazones with alcohols or phenols. Angew. Chem. Int. Ed. 49, 4993–4996 (2010).

    Article  CAS  Google Scholar 

  48. Chandrasekhar, S., Rajaiah, G., Chandraiah, L. & Swamy, D. N. Direct conversion of tosylhydrazones to tert-butyl ethers under Bamford–Stevens reaction conditions. Synlett. 2001, 1779–1780 (2001).

    Article  Google Scholar 

  49. Crossley, S. W. M., Obradors, C., Martinez, R. M. & Shenvi, R. A. Mn-, Fe-, and Co-catalyzed radical hydrofunctionalizations of olefins. Chem. Rev. 116, 8912–9000 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nicolaou, K. C. et al. Studies toward the synthesis of azadirachtin. Part 2: construction of fully functionalized ABCD ring frameworks and unusual intramolecular reactions induced by close-proximity effects. Angew. Chem. Int. Ed. 44, 3447–3452 (2005).

    Article  CAS  Google Scholar 

  51. Hasegawa, E. et al. Tris(trimethylsilyl)silane promoted radical reaction and electron-transfer reaction in benzotrifluoride. Tetrahedron 64, 7724–7728 (2008).

    Article  CAS  Google Scholar 

  52. Chatgilialoglu, C., Ferrei, C., Landais, Y. & Timokhin, V. I. Thirty years of (TMS)3SiH: a milestone in radical-based synthetic chemistry. Chem. Rev. 118, 6516–6572 (2008).

    Article  Google Scholar 

  53. Overman, L. E., Abelman, M. M., Kucera, D. J., Tran, V. D. & Ricca, D. J. Palladium-catalyzed, polyene cyclizations. Pure Appl. Chem. 64, 1813–1819 (1992).

    Article  CAS  Google Scholar 

  54. Green, S. A., Huffman, T. R., McCourt, R. O., van der Puyl, V. & Shenvi, R. A. Hydroalkylation of olefins to form quaternary carbons. J. Am. Chem. Soc. 141, 7709–7714 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cui, B. et al. Limonoids from Azadirachta excelsa. Phytochemistry. 47, 1283–1287 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Bokel, M., Cramer, R., Gutzeit, H., Reeb, S. & Kraus, W. Tetranortriterpenoids related to nimbin and nimbolide from Azadirachta indica A. Juss (Meliaceae). Tetrahedron. 46, 775–782 (1990).

    Article  CAS  Google Scholar 

  57. Kraus, W. & Cramer, R. Pentanortriterpenoide aus Azadirachta indica A. Juss (Meliaceae). Chem. Ber. 114, 2375–2381 (1981).

    Article  CAS  Google Scholar 

  58. Peterson, L. A. Reactive metabolites in the biotransformation of molecules containing a furan ring. Chem. Res. Toxicol. 26, 6–25 (2013).

    Article  CAS  PubMed  ADS  Google Scholar 

Download references

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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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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