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

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VIEWED BY OTHERS POLY(ADP-RIBOSE) POLYMERASE INHIBITION: PAST, PRESENT AND FUTURE Article 03 September 2020 MINIMIZING DNA TRAPPING WHILE MAINTAINING ACTIVITY INHIBITION VIA SELECTIVE PARP1

DEGRADER Article Open access 18 December 2024 MECHANISM OF SUBSTRATE HYDROLYSIS BY THE HUMAN NUCLEOTIDE POOL SANITISER DNPH1 Article Open access 26 October 2023 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

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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. AUTHOR INFORMATION Author notes * 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 * These authors contributed equally: Heping Deng, Hejun Deng. AUTHORS AND AFFILIATIONS * 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 Authors * Heping Deng

View author publications You can also search for this author inPubMed Google Scholar * Hejun Deng View author publications You can also search for this author inPubMed Google Scholar * Chiho

Kim View author publications You can also search for this author inPubMed Google Scholar * Peng Li View author publications You can also search for this author inPubMed Google Scholar *

Xudong Wang View author publications You can also search for this author inPubMed Google Scholar * Yonghao Yu View author publications You can also search for this author inPubMed Google

Scholar * Tian Qin View author publications You can also search for this author inPubMed Google Scholar 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.

CORRESPONDING AUTHORS Correspondence to Yonghao Yu or Tian Qin. ETHICS DECLARATIONS 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. PEER REVIEW PEER REVIEW INFORMATION _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. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional

claims in published maps and institutional affiliations. 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). RIGHTS AND PERMISSIONS Springer Nature or its licensor (e.g. a society or other

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article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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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