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Simplified immunosuppressive and neuroprotective agents based on gracilin A

Abstract

The architecture and bioactivity of natural products frequently serve as embarkation points for the exploration of biologically relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure–activity relationships. However, synthetic strategies towards a natural product are not always guided by hypotheses regarding the structural features required for bioactivity. Here, we report an approach to natural product total synthesis that we term ‘pharmacophore-directed retrosynthesis’. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in the structural complexity of this minimal structure enable development of a structure–activity relationship profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort, as demonstrated here for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activity.

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Data availability

Crystallographic data for the structure reported in this Article have been deposited at the Cambridge Crystallographic Data Centre under deposition number CCDC 1557733 ((–)-21b). A copy of the data can be obtained free of charge at https://www.ccdc.cam.ac.uk/structures/. All other data supporting the findings of this study are available within the Article and its Supplementary Information, or from the corresponding author upon reasonable request.

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Acknowledgements

The authors acknowledge support from the NIH (R37 GM052964 to D.R.), NSF (CHE-1800411, to D.R.) the Robert A. Welch Foundation (AA-1280 to D.R.), FEDER co-funded grants from CONSELLERIA DE Cultura, EDUCACION e ordenación Universitaria Xunta de Galicia (2017 GRC GI-1682, ED431C 2017/01), CDTI and Technological Funds, supported by Ministerio de Economía, Industria y Competitividad (AGL2014-58210-R, AGL2016-78728-R, AEI/FEDER, UE) (to L.M.B.), ISCIII/PI1/01830 (to A.A.) and RTC-2016-5507-2 and ITC-20161072, from EU POCTEP 0161-Nanoeaters-1-E-1, Interreg AlertoxNet EAPA-317-2016 and H2020 778069-EMERTOX (to L.M.B.) and from the European Union’s Seventh Framework Programme managed by the Research Executive Agency (FP7/2007-2013 under grant agreement 312184 PHARMASEA to L.M.B. and M.J.). N. Bhuvanesh and J. Reibenspies (Center for X-ray Analysis, TAMU) secured X-ray data and W. Russell (Laboratory for Biological Mass Spectrometry, TAMU) provided mass data. Correspondence and requests for materials should be directed to D. Romo (chemistry) and L. Botana (biology).

Author information

M.E.A., C.M.C. and M.C. synthesized and characterized all gracilin A derivatives described herein. R.A. and J.A.S. performed the neuroprotection and immunosuppression assays and compiled and wrote the assay data, respectively. L.M.B., E.A. and A.A. designed, analysed and wrote the neuroprotection and immunosuppression assay results and data. D.R. and M.E.A. analysed SARs and wrote the manuscript with input from all authors. M.J. provided samples of the initial lead compound, gracilin A.

Competing interests

The authors declare no competing interests.

Correspondence to Luis M. Botana or Daniel Romo.

Supplementary Information

  1. Supplementary Information

    Synthetic procedures and characterization data for all new compounds, assay descriptions.

  2. Reporting Summary

  3. Crystallographic data

    CIF for compound (–)-21b; CCDC reference: 1557733.

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Fig. 1: Pharmacophore-directed retrosynthesis (PDR) applied to gracilin A and comparison to other synthetic strategies harvesting the rich information content of natural products.
Fig. 2: Select members of the gracilin A family and application of PDR to gracilin A.
Fig. 3: Pharmacophore-directed retrosynthesis applied to gracilin A.
Fig. 4: Synthesis of gracilin A derivatives toward SAR profile gap filling.
Fig. 5: Immunosuppressive activity of gracilin A derivatives.
Fig. 6: Activity of gracilin A derivatives as neuroprotective agents.
Fig. 7: SAR profile of gracilin A for both immunosuppressive and neuroprotective activity enabled through application of PDR.